A phase 1/2a, open label study to evaluate the safety and efficacy of a plasmid DNA encoding human hepatocyte growth factor in patients with Charcot-Marie-Tooth disease 1A

A phase 1/2a, open label study to evaluate the safety and efficacy of a plasmid DNA encoding human hepatocyte growth factor in patients with Charcot-Marie-Tooth disease 1A | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A phase 1/2a, open label study to evaluate the safety and efficacy of a plasmid DNA encoding human hepatocyte growth factor in patients with Charcot-Marie-Tooth disease 1A Hyemi Kwon, Hyun Su Kim, Sang Ah Chi, Soo Hyun Nam, Hye Jin Kim, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4220356/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Mar, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 5 You are reading this latest preprint version Abstract Background This is the first gene therapy trial in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Intramuscular injectionsof VM202, a plasmid DNA encoding human hepatocyte growth factor, was safe, tolerable and potentially effective in patients with CMT1A. Methods This study was a phase 1/2a, nonrandomized controlled trial. Thirteen patients with CMT1A were screened, and 12 consented and enrolled between September 2020 and November 2020. Patients received intramuscular injections of 14 mg of VM202 at baseline, and on days 14, 90, and 104 in both legs. Safety evaluations and clinical assessments using the CMT neuropathy score version 2 (CMTNSv2), CMT examination score (CMTES), Rasch-modified CMTNSv2 (CMTNSv2-R), Rasch-modified CMTES (CMTES-R), functional disability scale (FDS), overall neuropathy limitation score, and 10-meter walk test were performed throughout a 270-day follow-up period. A Wilcoxon signed-rank test was used for statistical comparisons of continuous variables. Results The primary objective of this study was to assess the safety and tolerability of intramuscular injections of VM202 in patients with CMT1A. All participants tolerated VM202 well, without any serious adverse events related to the study drug. The secondary objective was to evaluate potential therapeutic efficacy. CMTNSv2, CMTES, CMTNSv2-R, and CMTES-R significantly decreased between baseline and day 270 with mean decreases of 2.17, 2.50, 2.08, and 2.33 points, respectively ( p < 0.01). Also FDS significantly decreased with a mean percent decrease of 0.58 ( p < 0.05). Conclusions Intramuscular injections of VM202 appear to be safe and well tolerated in CMT1A patients with potentially encouraging clinical results. Charcot-Marie-Tooth disease gene therapy PMP22 hepatocyte growth factor Figures Figure 1 Trial Registration Information Name of the trial registry (VM202 for CMT1A), Registration number (NCT05361031), URL of the registry (www.clinicaltrials.gov) and date of registration (2022-03-31, retrospectively registered) Introduction Charcot-Marie-Tooth disease (CMT) is one of the most common hereditary neuromuscular disorders, comprised of a group of clinically and genetically heterogeneous motor and sensory peripheral neuropathies [ 1 ]. Typical clinical manifestations include progressive distal muscle weakness, sensory loss, and areflexia, and more than 140 causative genes have been reported to date [ 1 ]. The most common form of the disease is CMT type 1A (CMT1A), which accounts for about half of all occurrences [ 2 ]. CMT1A is an autosomal dominant demyelinating polyneuropathy that results from overexpression of the peripheral myelin protein 22 (PMP22) gene on chromosome 17 [ 2 ]. PMP22 is one of the major constituents of myelin, which is present in the plasma membrane of Schwann cells [ 2 ]. Demyelination accompanied by hyperplasia of myelinating Schwann cells is the hallmark of CMT1A [ 3 ]. Although a substantial variability in the clinical course of the disease exists among patients, progressive neuromuscular deficit leading to significant clinical morbidity and impaired quality of life is common among the population [ 1 , 4 , 5 ]. Despite the advances in research made in understanding the genetic background of the disease, and promising results obtained from several approaches aiming at various pharmacological targets, there are no FDA-approved drugs for the treatment of CMT1A, and supportive measures remain the mainstay of the treatment [ 6 , 7 ]. Hepatocyte growth factor (HGF) is a mesenchymal cell-derived regulator that was first discovered as a potent mitogen for hepatocytes and later found to contain various properties including neurotrophic, angiogenic, and antifibrotic activities [ 8 ]. These actions are mediated by the activation of its receptor, c-Met, which is expressed by various types of cells including Schwann cells, peripheral neurons, and muscle stem cells [ 9 – 11 ]. HGF has been reported to demonstrate trophic effects on peripheral sensory and motor neurons by enhancing axonal outgrowth and neuronal survival [ 11 – 13 ]. It acts through various mechanisms, including suppression of astrocytosis and microgliosis, reduction of cytotoxic cytokine release, facilitation of motor unit reinnervation, and limitation of cell death by inhibiting caspase signaling [ 14 – 16 ]. HGF has also been shown to improve neurogenic muscle atrophy by upregulating the expression of miR-206, a microRNA that is known to facilitate muscle differentiation by regulating the expression of myogenic regulatory factors [ 17 ]. VM202 (Engensis) is a novel nonviral plasmid DNA product that is designed to express two wild type isoforms of HGF: HGF 728 and HGF 723 [ 18 ]. Clinical trials of VM202 have demonstrated clinical efficacy for neurologic symptoms in patients with painful diabetic peripheral neuropathy and those with amyotrophic lateral sclerosis [ 11 , 19 ]. Furthermore, the agent has proven to be safe and well tolerated in patients with a number of clinical conditions including ischemic heart disease and critical limb ischemia [ 11 , 19 – 21 ]. The properties of HGF in regards to its interaction with peripheral nerve and muscle tissue, and previous clinical trial results make VM202 an ideal potential candidate for the treatment of CMT1A patients. The primary objective of this study was to assess the safety and tolerability of intramuscular VM202 injections in patients with CMT1A. The secondary objective was to evaluate the potential clinical efficacy of the agent. Materials and methods Study design This was a phase 1/2a, open-label, non-placebo controlled, single-center study designed to evaluate the safety, tolerability, and potential clinical efficacy of intramuscular injections of VM202 in CMT1A patients. Between September 2020 and November 2020, 13 patients with CMT1A were screened and 12 were consented and enrolled in the study. Patients received intramuscular injections of 14 mg of VM202 at baseline and on days 14, 90, and 104 in bilateral lower legs (Fig. 1 a). Study drug VM202 (pCK-HGF-X7) is a plasmid DNA designed to produce each of two isoforms of the HGF protein, consisting of either 723 or 728 amino acids; detailed information about VM202 has been described in previous studies [ 18 , 21 ]. VM202 was supplied in a sterile vial and stored between 2 and 8°C. It was reconstituted with 5.0 ml of sterile water for injections with a final VM202 concentration of 0.5 mg/ml. 14 mg of VM202 was administered via intramuscular injection using one-mL syringes with 29-gauge needles. Injections were given at the peroneus longus, gastrocnemius, and tibialis anterior muscles of bilateral lower legs at 6, 12, and 10 sites, with administered VM202 doses of 3, 6, and 5 mg, respectively. Patient eligibility Eligible patients were non-pregnant individuals of ≥ 19 years to ≤ 65 years of age diagnosed with CMT1A through genetic analysis, had mild-to-moderate clinical severity with a CMT neuropathy score version 2 (CMTNSv2) between 3 and 20, and presented ankle dorsiflexion weakness. Female patients were advised to avoid becoming pregnant during the follow-up period (Fig. 1 b). Patients were excluded if they had comorbidities such as renal failure, chronic liver disease, inflammatory bowel disease, diabetes, other neuromuscular disorders, major psychiatric disorders, any conditions that could confound the study assessment; morbid obesity with a body mass index of ≥ 37; or uncontrolled hypertension with systolic blood pressure of ≥ 160 or diastolic blood pressure of ≥ 100. Also excluded were patients who had experienced a major cerebrovascular or cardiovascular event within the 12 months prior, ankle contracture, lower extremity surgery that could influence the evaluation of lower extremity muscle function; or an orthopedic procedure of the lower extremity within the 6 months prior. Patients were also considered exclusionary if they were receiving immunosuppressive medications, chemotherapy or radiation therapy; had evidence of malignancies other than fully resolved basal or squamous cell carcinoma of the skin; or had positive human immunodeficiency virus, hepatitis B, or hepatitis C serological test results. This study was approved by the institutional review board at our institution (IRB No.SMC 2020-05-038-003). All patients gave written informed consent to participate in the study. Safety parameters Safety was the primary end point and was assessed by evaluating all adverse events, conducting complete blood cell counts, serum chemistries, and urinalysis with microscopy at baseline, and on days 14, 90, 104, 180, and 270. Vital signs including systolic and diastolic blood pressure, body temperature, pulse rate, and respiration rate were also assessed likewise, and pre- and post-injection values were assessed on injection visits. Serum levels of anti-HGF antibodies were assessed at the baseline and at day 270 using an enzyme-linked immunosorbent assay (ELISA) developed by Helixmith Co., Ltd (Seoul, Korea). Clinical assessment Clinical outcome measures for CMT1A including the CMTNSv2, CMT Examination Score (CMTES), Rasch-modified CMTNSv2 (CMTNSv2-R), and Rasch-modified CMTES (CMTES-R) were evaluated at baseline and at day 270 [ 22 – 24 ]. CMTNSv2 is a composite score consisting of clinical symptoms, signs, and neurophysiologic components. The CMTES represents the CMTNSv2 without the electrophysiological items. All items of CMTNSv2 and CMTES contribute identically to the total score. Otherwise, the CMTNSv2-R and CMTES-R consist of weighted category responses for representing more accurate estimates of the actual values measuring disease severity. The CMTNSv2 ranges from 0 (no deficit) to 36 (maximal deficit) [ 24 ]. This scale assigns mild impairment as scores 0–10, moderate as 11–20, and severe as 21–36. The maximum CMTES is 28 [ 23 ]. The CMTES assigns mild impairment as scores 0–7, moderate as 8–14, and severe as 15–28. In addition, disease severity based on the CMTNSv2-R was classified into three groups (mild 0–10, moderate 11–20, and severe 21–40), as it was for the CMTES-R (mild 0–9, moderate 10–18, and severe 19–32) [ 23 ]. Functional assessment Lower extremity function of the patients was assessed using a functional disability scale (FDS), the ONLS (Overall Neuropathy Limitation Score) leg scale, and a 10-meter walk test (10MWT) at baseline and at day 270. A nine-point FDS was assessed to determine disease severity in terms of the ability to walk and run as follows: 0 = normal; 1 = normal, but with cramps and fatigability; 2 = inability to run; 3 = walking difficult but still possible unaided; 4 = able to walk with a cane; 5 = able to walk with crutches; 6 = able to walk with a walker; 7 = wheelchair bound; 8 = bedridden [ 22 ]. A seven-point ONLS leg scale was assessed to measure the limitations of the lower limbs as follows: 0 = walking/climbing stairs/running not affected; 1 = walking/climbing stairs/running affected, but gait does not look abnormal; 2 = walks independently but gait looks abnormal; 3 = requires unilateral support to walk 10 meters (stick, single crutch, one arm); 4 = requires bilateral support to walk 10 meters (sticks, crutches, crutch and arm, frame); 5 = requires wheelchair to travel 10 meters but able to stand and walk 1 meter with the help of one person; 6 = restricted to wheelchair, unable to stand and walk 1 meter with the help of one person, but able to make some purposeful leg movements; 7 = restricted to wheelchair or bed most of the day, unable to make any purposeful movements of the legs [ 25 ]. For the 10MWT, patients were asked to walk a 10-meter distance, and the time taken was measured in seconds. Three sets of measurements were taken to obtain an average value, which was measured at baseline and at day 270. Electrophysiologic studies Electrophysiologic studies were performed to assess the nerve regeneration potential of the patients. Motor nerve conduction velocities (MNCVs), compound muscle action potentials (CMAPs), sensory nerve conduction velocities (SNCVs), and sensory nerve action potentials (SNAPs) were measured at baseline and at day 270. MNCVs and CMAPs were measured for bilateral median, ulnar, radial, tibial, and peroneal nerves. SNCVs and SNAPs were measured for bilateral median, ulnar, and sural nerves. Statistical analysis Safety and tolerability were assessed for the safety set, and efficacy analyses were based on the intention-to-treat (ITT) population. A Wilcoxon signed-rank test for continuous variables was performed to assess the clinical outcomes between baseline and day 270 after intramuscular injection of VM202. Statistical significance was defined at a two-sided p -value of < 0.05. All statistical analyses were performed using R Statistical Software (version 3.6.3; Foundation for Statistical Computing, Vienna, Austria). Results Safety and tolerability Detailed demographics of the participants are shown in Table 1 , and detailed incidents of adverse events are summarized in Table 2 . A total of four adverse events were reported in three patients (25%). There were no serious adverse events attributable to VM202. Injection site pruritus and peripheral edema, which occurred in separate patients (2/12, 16.7%) and were mild in degree, were the only adverse events that were possibly related to the treatment. They resolved without additional treatment. Two serious adverse events were observed in one patient (1/12, 8.3%; they were pneumonia and uterine myoma. They were non-drug-related and no death was observed during the study. No clinically significant changes compared with those assessed at the baseline were demonstrated in serum, urine lab results, or vital signs. No patients developed antibodies to the HGF protein during the study period. Table 1 Baseline demographics of the 12 participants Total ( N = 12) Sex Male 7 (58.3%) Female 5 (41.7%) Age (years) Mean ± SD 40.2 ± 14.8 Median (range) 42 (19–60) Height (cm) Mean ± SD 168.8 ± 9.3 Median (range) 171.8 (153.8-180.1) Weight (kg) Mean ± SD 68.3 ± 15.5 Median (range) 68.7 (36.4–93.3) BMI (kg/m 2 ) Mean ± SD 23.7 ± 3.7 Median (range) 23.2 (15.4–28.8) Smoking Current smoker 1 (8.3%) Former smoker 2 (16.7%) Non-smoker 9 (75.0%) Alcohol Current drinker 5 (41.7%) Former drinker 1 (8.3%) Non-drinker 6 (50.0%) BMI body mass index, SD standard deviation Table 2 Adverse events reported from the study Screening No. Adverse event Severity Relationship with gene therapy Outcome S01013 Injection site pruritus NOS Mild Possibly related Resolved S01006 Ankle edema Mild Possibly related Resolved S01008 Pneumonia Severe Not related Resolved S01008 Uterine myoma Severe Not related Resolved Clinical severity evaluation Statistical comparison results of the CMTNSv2, CMTES, CMTNSv2-R and CMTES-R assessed at the baseline and at day 270 are summarized on Table 3 and Additional file 1: Fig. S1 a. The total CMTNSv2, CMTES, CMTNSv2-R, and CMTES-R significantly decreased between the two timepoints, with mean decreases of 2.17 ( p < 0.01), 2.50 ( p < 0.01), 2.08 ( p < 0.01), and 2.33 points ( p < 0.01), respectively. Sign and symptom components of CMTNSv2 also showed significant changes between the two timepoints ( p = 0.0035 and 0.0069, respectively). These improvements did arise from sensory symptoms and sensory signs rather than motor symptoms and strength (Additional file 1: Table S1 ). Table 4 summarizes the score groups of CMTNSv2, CMTNSv2-R, CMTES, and CMTES-R between two time points. The patients in the severe or moderate groups of CMTNSv2-R, CMTES, and CMTES-R improved to mild or moderate groups by day 270. Table 3 Changes in CMTNSv2, CMTES, CMTNSv2-R, CMTES-R, and CMTNSv2 components from baseline to 270 days. Comparison results of the functional disability scale, overall neuropathy limitation score leg scale, and 10-meter walk test time Baseline ( N = 12) Day 270 ( N = 12) Change between the two timepoints p Mean ± SD Median Mean ± SD Median Mean ± SD Median Functional assessments CMTNSv2 15.6 ± 3.4 16.5 13.4 ± 2.7 14.5 -2.17 ± 1.11 -2.0 0.0035 * CMTES 12.1 ± 2.8 12.5 9.6 ± 2.3 10.5 -2.50 ± 1.31 -3.0 0.0036 * CMTNSv2-R 18.2 ± 3.4 18.5 16.1 ± 3.1 16.5 -2.08 ± 1.31 -2.0 0.0036 * CMTES-R 14.4 ± 2.9 15.3 12.1 ± 2.4 12.1 -2.33 ± 1.50 -2.5 0.0035 * FDS 2.67 ± 0.65 2.67 2.08 ± 0.79 2.08 -0.58 ± 0.51 -1.00 0.0107 * ONLS leg scale 2.08 ± 0.29 2.08 1.75 ± 0.45 1.75 -0.33 ± 0.49 0 0.0719 10MWT time (sec) 8.96 ± 1.96 9.02 8.34 ± 1.27 8.3 -0.62 ± 1.75 -0.44 0.3013 CMTNSv2 components Signs 7.3 ± 1.7 7.5 5.8 ± 1.4 6.0 -1.50 ± 0.80 -2.0 0.0035 * Symptoms 4.8 ± 1.3 5.0 3.8 ± 1.1 4.0 -1.00 ± 0.74 -1.0 0.0069 * Neurophysiologic component 3.5 ± 0.9 4.0 3.8 ± 0.7 4.0 0.33 ± 0.49 0.33 0.0719 CMAP summatory (mV) † 41.9 ± 14.7 41.0 43.3 ± 17.4 40.26 1.42 ± 14.78 1.42 0.1424 MNCV (m/s) ‡ 19.6 ± 3.9 18.75 19.6 ± 3.4 19.13 0.06 ± 1.48 -0.13 0.9185 CMAP compound muscle action potential, CMTES CMT examination score, CMTES-R Rasch-modified CMTES, CMTNSv2 CMT neuropathy score version 2, CMTNSv2-R Rasch-modified CMT neuropathy score version 2, FDS functional disability scale, ONLS overall neuropathy limitation score, 10MWT 10-meter walk test * Indicates statistical significance † CMAP summatory: sum of compound action potential of the three motor nerves (ulnar, median, and peroneal nerves) ‡ Mean from median and ulnar nerves Table 4 Group changes between the CMT neuropathy score version 2 and CMT examination score Baseline (%) ( n = 12) Day 270 (%) ( n = 12) CMTNSv2 Mild (0–10) 2 (16.7%) 2 (16.7%) Moderate (11–20) 10 (83.3%) 10 (83.3%) Severe (21–36) 0 (0%) 0 (0%) CMTNSv2-R Mild (0–10) 0 (0%) 1 (8.3%) Moderate (11–20) 9 (75%) 11 (91.7%) Severe (21–40) 3 (25%) 0 (0%) CMTES Mild (0–7) 1 (8.3%) 2 (16.7%) Moderate (8–14) 9 (75%) 10 (83.3%) Severe (15–28) 2 (16.7%) 0 (0%) CMTES-R Mild (0–9) 2 (16.7%) 2 (16.7%) Moderate (10–18) 9 (75%) 10 (83.3%) Severe (19–32) 1 (8.3%) 0 (0%) CMTNSv2 CMT neuropathy score version 2, CMTNSv2-R Rasch-modified CMT neuropathy score version 2, CMTES CMT examination score, CMTES-R Rasch-modified CMT examination score Function of lower extremities Table 3 and Additional file 1: Fig. S1 b summarize the statistical comparison results of the FDS, ONLS, and 10MWT times assessed at the baseline and at 270 days. The FDS significantly decreased between the baseline and day 270, with a mean decrease of 0.58 ( p < 0.05). The ONLS leg scale and 10MWT times gradually decreased, but the changes were not statistically significant. Discussion This prospective trial was the first clinical study to assess the safety and tolerability of intramuscular VM202 injections in patients with CMT1A. We demonstrated that intramuscular administration of plasmid DNA expressing two isoforms of human HGF is safe and well tolerated by CMT1A patients. Moreover, we observed potential clinical benefits of VM202 administration in CMT1A patients as documented by a significant improvement in clinical scores. There were no serious adverse events attributable to VM202. The injection site pruritus and peripheral edema that occurred in a small number of patients were the only adverse events that were possibly related to the agent, and both resolved without treatment. VM202 was well tolerated without any reports of serious adverse events associated with the agent in studies performed on painful diabetic peripheral neuropathy, amyotrophic lateral sclerosis, and critical limb ischemia patients [ 11 , 19 , 20 ]. The excellent safety profile of VM202 can be explained by the fact that HGF expression from VM202 is short-lived and tends to be restricted to the area of injection [ 11 , 19 ]. Heparan sulfate, which is abundant in the extracellular matrix, limits the diffusion of secreted HGF by binding to the N-terminal of HGF [ 11 ]. Even though plasmid DNA and the HGF protein can reach circulation, the possible biologic effect would be insignificant, as their half-lives in the bloodstream are only a few minutes long [ 26 , 27 ]. Furthermore, no patients developed antibodies to the HGF protein in our study. Taken together with the safety results of previous studies and theoretical background that support the safety profile of VM202, our results suggest that intramuscular injection of this agent could be safe and well tolerated in CMT1A patients. The pathologic hallmark of CMT1A patients is demyelination associated with length-dependent axonal degeneration of both sensory and motor nerves [ 3 , 28 ]. Disability in CMT1A patients has been reported to correlate with the degree of axonal degeneration [ 29 ]. Thus, it has been suggested that therapeutic approaches to ameliorate disability in CMT1A patients should be directed toward preventing axonal degeneration and promoting axonal regeneration [ 28 ]. However, current treatment options are mostly palliative, rather than targeting the mechanisms underlying CMT1A. Animal studies have revealed that the intramuscular injection of VM202 leads to HGF production and that its interaction with the c-Met receptor present in Schwann cells and sensory neurons via ERK and AP-1 signaling pathways, respectively, promotes axon outgrowth [ 30 , 31 ]. Clinical severity assessed by the CMTNSv2 demonstrated significant improvement at the last follow-up with a mean decrease of 2.17 points ( p < 0.01). This was most attributable to significant improvements of signs ( p = 0.0050) and symptoms ( p = 0.0147). Clinical disability scores including CMTES, CMTNSv2-R, and CMTES-R also demonstrated significant improvements between timepoints with mean decreases of 2.50, 2.08, and 2.33 points, respectively ( p < 0.01). In addition, a score group comparison was conducted to find the clinical effects of the VM202 injections. The patients in the severe group of CMTNSv2-R, CMTES, and CMTES-R showed significant changes in comparison to the mild and moderate groups. This suggests that VM202 injections had clinical benefits in CMT1A patients. In addition, function as assessed by the FDS significantly decreased between the baseline and day 270 ( p < 0.05). Although the true effect of transient gene expression via VM202 injection in CMT1A patients is not completely understood, theoretical background regarding the trophic effects of HGF on peripheral sensory, motor nerves, and muscle cells may explain the positive results of our study [ 11 – 13 , 17 ]. One concern raised before initiating the study was that the relatively large number of intramuscular injections (56 sites of injection per visit) would not be tolerable to some patients. It was originally thought that VM202 injections would provide short-term therapeutic benefits, thus requiring repeated treatment, because plasmid DNA would be short-lived in vivo and give only transient gene expression. As such, it was initially expected that the discomfort caused by the multiple injections would be an issue. However, the fact that there were no withdrawals from this study suggests that the injection scheme could be well tolerated. Conclusions This is the first phase 1/2a gene therapy trial performed for patients with CMT1A. Our data suggest that the intramuscular administration of VM202 is safe and well tolerated in CMT1A patients. Preliminary efficacy of the agent has been demonstrated by improved clinical scores over the study period. Considering the high unmet medical need in CMT1A patients, performance of a phase 2b randomized, double-blind clinical trial in these patients is warranted. Abbreviations 10MWT 10-meter walk test CMAPs Compound muscle action potentials CMT Charcot-Marie-Tooth disease CMTES CMT examination score CMTES-R Rasch-modified CMT examination score CMTNSv2 CMT neuropathy score version 2 CMTNSv2-R Rasch-modified CMT neuropathy score version 2 FDS Functional disability scale HGF Hepatocyte growth factor MNCVs Motor nerve conduction velocities NCS Nerve Conduction Study ONLS Overall Neuropathy Limitation Score SNAPs Sensory nerve action potentials SNCVs Sensory nerve conduction velocities Declarations Acknowledgements Not applicable Author contributions Dr Choi had full access to allof the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: All authors. Acquisition, analysis, or interpretation of data: Kwon, SB Kim, Chi, Choi. Drafting of the manuscript: Kwon, HS Kim, Choi. Critical revision of the manuscript for important intellectualcontent: All authors. Statistical analysis: Kwon, HJ Kim, Chi. Obtained funding: Choi. Administrative, technical, or material support: Nam, SB Kim, HS Kim. Supervision: Kwon, Kim, Choi Funding This research was funded by Helixmith Co., Ltd., and supported by grants from the National Research Foundation (2020M3H4A1A03084600, 2021R1A4A2001389, and 2022M3E5E9016662), Korean Health Technology R&D Project, Ministry of Health and Welfare (HR22C1363), and Future Medicine 2030 Project of the Samsung Medical Center (SMX122005), Republic of Korea. Data availability Not applicable Ethics approval and consent to participate This study was approved by the institutional review board at our institution (IRB No.SMC 2020-05-038-003). All patients gave written informed consent to participate in the study. Consent for publication The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. 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Sadjadi R, Reilly MM, Shy ME, Pareyson D, Laura M, Murphy S, et al. Psychometrics evaluation of Charcot-Marie-Tooth Neuropathy Score (CMTNSv2) second version, using Rasch analysis. J Peripher Nerv Syst. 2014;19(3):192-6. Graham RC, Hughes RA. A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale. J Neurol Neurosurg Psychiatry. 2006;77(8):973-6. Appasamy R, Tanabe M, Murase N, Zarnegar R, Venkataramanan R, Van Thiel DH, et al. Hepatocyte growth factor, blood clearance, organ uptake, and biliary excretion in normal and partially hepatectomized rats. Lab Invest. 1993;68(3):270-6. Ido A, Moriuchi A, Kim I, Numata M, Nagata-Tsubouchi Y, Hasuike S, et al. Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein. Hepatol Res. 2004;30(3):175-81. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 2000;123 ( Pt 7):1516-27. Berciano J, Combarros O, Calleja J, Polo JM, Leno C. The application of nerve conduction and clinical studies to genetic counseling in hereditary motor and sensory neuropathy type I. Muscle Nerve. 1989;12(4):302-6. Ko KR, Lee J, Lee D, Nho B, Kim S. Hepatocyte Growth Factor (HGF) Promotes Peripheral Nerve Regeneration by Activating Repair Schwann Cells. Sci Rep. 2018;8(1):8316. Ko KR, Lee J, Nho B, Kim S. c-Fos is necessary for HGF-mediated gene regulation and cell migration in Schwann cells. Biochem Biophys Res Commun. 2018;503(4):2855-60. Supplementary Files Additionalfile1.docx Additional file 1: Table S1: The CMT neuropathy score version 2 and CMT examination score at baseline and day 270 for all PATIENTS. Figure S1: The statistical comparison results of the CMTNSv2, CMTES, CMTNSv2-R, CMTES-R, FDS, ONLS leg scale, and 10MWT time. FigureS1.pdf VMCMT001ProtocolV4.0ENclean.pdf trendchecklistCMTstudy.docx Cite Share Download PDF Status: Published Journal Publication published 05 Mar, 2026 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Editorial decision: Major revision 19 Dec, 2025 Reviewers agreed at journal 17 Nov, 2024 Reviewers invited by journal 31 May, 2024 Editor assigned by journal 14 May, 2024 First submitted to journal 10 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4220356","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":308951316,"identity":"cb0d2c2b-3f5e-4745-84bc-ea8778bf3120","order_by":0,"name":"Hyemi Kwon","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYBCDBAYG5gNEqmUD4gMMBkAtbAkka+ExIE6H/PzmY9IfKv7k8bP3fHvws80mn4H98NEN+LQYHGNLkzhwxqBYsufsdsPetjTLBp60tBt4tbDxGBscbDNI3HAjd5sEz5nDBgwSPGZ4tci38X8Ga9l//80zyT9n/hPWwnCMh/EB2BYJHjZpnooDhLUYHEszfHDmjHHijDNpZtIyFclAlxLwi3zz4QcHKirkEvvbDz+TfGNgZ8DPfvgYfodhADbSlI+CUTAKRsEowAYAY8NJ1HtG51sAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-3978-1855","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hyemi","middleName":"","lastName":"Kwon","suffix":""},{"id":308951317,"identity":"07154072-200e-434f-9d9a-310bb51a8858","order_by":1,"name":"Hyun Su Kim","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hyun","middleName":"Su","lastName":"Kim","suffix":""},{"id":308951318,"identity":"f0cd6f29-9e4a-4982-91fa-6079f79d3a51","order_by":2,"name":"Sang Ah Chi","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sang","middleName":"Ah","lastName":"Chi","suffix":""},{"id":308951319,"identity":"5e465ae3-11d9-49e6-8442-55c8efa890f2","order_by":3,"name":"Soo Hyun Nam","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Soo","middleName":"Hyun","lastName":"Nam","suffix":""},{"id":308951320,"identity":"9bc4256e-712d-4560-9b62-0201d6ffe02b","order_by":4,"name":"Hye Jin Kim","email":"","orcid":"","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Hye","middleName":"Jin","lastName":"Kim","suffix":""},{"id":308951321,"identity":"3945e30c-4d56-4683-a04d-4025f6350a81","order_by":5,"name":"Sang Beom Kim","email":"","orcid":"","institution":"Kyung Hee University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Sang","middleName":"Beom","lastName":"Kim","suffix":""},{"id":308951322,"identity":"bd24ca5f-f7e1-4171-9d04-5124132f7145","order_by":6,"name":"Byung-Ok Choi","email":"","orcid":"https://orcid.org/0000-0001-5459-1772","institution":"Samsung Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Byung-Ok","middleName":"","lastName":"Choi","suffix":""}],"badges":[],"createdAt":"2024-04-05 02:31:32","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4220356/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4220356/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13023-026-04252-2","type":"published","date":"2026-03-05T15:57:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58385088,"identity":"088345a7-b1b5-44c4-84c2-76dd09b75bff","added_by":"auto","created_at":"2024-06-14 18:38:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":207142,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea\u003c/strong\u003eTrial design. \u003cstrong\u003eb\u003c/strong\u003e CONSORT diagram: participant enrollment, intervention allocation, and follow-up.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4220356/v1/837ecdc1e515452b9979e4d3.png"},{"id":104251550,"identity":"c67a66a7-bc5a-4bff-be76-037ea40aaec2","added_by":"auto","created_at":"2026-03-09 16:13:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1232906,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4220356/v1/8e228d2e-f919-49f2-8097-ffcaada53c1a.pdf"},{"id":58385092,"identity":"d3b8ea22-2618-4b0c-9991-19f3ff7211f1","added_by":"auto","created_at":"2024-06-14 18:38:34","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":193539,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 1: \u003c/strong\u003eTable S1: The CMT neuropathy score version 2 and CMT examination score at baseline and day 270 for all PATIENTS. Figure S1: The statistical comparison results of the CMTNSv2, CMTES, CMTNSv2-R, CMTES-R, FDS, ONLS leg scale, and 10MWT time.\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4220356/v1/fb57f6e325363b1942812c13.docx"},{"id":58385090,"identity":"bf95f1f1-089c-4756-b8da-7a79e6f2354c","added_by":"auto","created_at":"2024-06-14 18:38:31","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1847489,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4220356/v1/f98b118100713e9ac52e3508.pdf"},{"id":58385087,"identity":"98802b45-e2b5-4708-bff8-2b3966139845","added_by":"auto","created_at":"2024-06-14 18:38:30","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":2917411,"visible":true,"origin":"","legend":"","description":"","filename":"VMCMT001ProtocolV4.0ENclean.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4220356/v1/ab622ce68e2b94c5b255e492.pdf"},{"id":58385094,"identity":"1c599ab2-f8e3-4779-8e4d-11bc9a70cf2d","added_by":"auto","created_at":"2024-06-14 18:38:36","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":46322,"visible":true,"origin":"","legend":"","description":"","filename":"trendchecklistCMTstudy.docx","url":"https://assets-eu.researchsquare.com/files/rs-4220356/v1/a9b17fc5701d47762f6d7cee.docx"}],"financialInterests":"","formattedTitle":"A phase 1/2a, open label study to evaluate the safety and efficacy of a plasmid DNA encoding human hepatocyte growth factor in patients with Charcot-Marie-Tooth disease 1A","fulltext":[{"header":"Trial Registration Information","content":"\u003cp\u003eName of the trial registry (VM202 for CMT1A), Registration number (NCT05361031), URL of the registry (www.clinicaltrials.gov) and date of registration (2022-03-31, retrospectively registered)\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eCharcot-Marie-Tooth disease (CMT) is one of the most common hereditary neuromuscular disorders, comprised of a group of clinically and genetically heterogeneous motor and sensory peripheral neuropathies [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Typical clinical manifestations include progressive distal muscle weakness, sensory loss, and areflexia, and more than 140 causative genes have been reported to date [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The most common form of the disease is CMT type 1A (CMT1A), which accounts for about half of all occurrences [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. CMT1A is an autosomal dominant demyelinating polyneuropathy that results from overexpression of the peripheral myelin protein 22 (PMP22) gene on chromosome 17 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. PMP22 is one of the major constituents of myelin, which is present in the plasma membrane of Schwann cells [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Demyelination accompanied by hyperplasia of myelinating Schwann cells is the hallmark of CMT1A [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although a substantial variability in the clinical course of the disease exists among patients, progressive neuromuscular deficit leading to significant clinical morbidity and impaired quality of life is common among the population [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Despite the advances in research made in understanding the genetic background of the disease, and promising results obtained from several approaches aiming at various pharmacological targets, there are no FDA-approved drugs for the treatment of CMT1A, and supportive measures remain the mainstay of the treatment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHepatocyte growth factor (HGF) is a mesenchymal cell-derived regulator that was first discovered as a potent mitogen for hepatocytes and later found to contain various properties including neurotrophic, angiogenic, and antifibrotic activities [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These actions are mediated by the activation of its receptor, c-Met, which is expressed by various types of cells including Schwann cells, peripheral neurons, and muscle stem cells [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. HGF has been reported to demonstrate trophic effects on peripheral sensory and motor neurons by enhancing axonal outgrowth and neuronal survival [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. It acts through various mechanisms, including suppression of astrocytosis and microgliosis, reduction of cytotoxic cytokine release, facilitation of motor unit reinnervation, and limitation of cell death by inhibiting caspase signaling [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. HGF has also been shown to improve neurogenic muscle atrophy by upregulating the expression of miR-206, a microRNA that is known to facilitate muscle differentiation by regulating the expression of myogenic regulatory factors [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVM202 (Engensis) is a novel nonviral plasmid DNA product that is designed to express two wild type isoforms of HGF: HGF\u003csub\u003e728\u003c/sub\u003e and HGF\u003csub\u003e723\u003c/sub\u003e [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Clinical trials of VM202 have demonstrated clinical efficacy for neurologic symptoms in patients with painful diabetic peripheral neuropathy and those with amyotrophic lateral sclerosis [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Furthermore, the agent has proven to be safe and well tolerated in patients with a number of clinical conditions including ischemic heart disease and critical limb ischemia [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The properties of HGF in regards to its interaction with peripheral nerve and muscle tissue, and previous clinical trial results make VM202 an ideal potential candidate for the treatment of CMT1A patients.\u003c/p\u003e \u003cp\u003eThe primary objective of this study was to assess the safety and tolerability of intramuscular VM202 injections in patients with CMT1A. The secondary objective was to evaluate the potential clinical efficacy of the agent.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis was a phase 1/2a, open-label, non-placebo controlled, single-center study designed to evaluate the safety, tolerability, and potential clinical efficacy of intramuscular injections of VM202 in CMT1A patients. Between September 2020 and November 2020, 13 patients with CMT1A were screened and 12 were consented and enrolled in the study. Patients received intramuscular injections of 14 mg of VM202 at baseline and on days 14, 90, and 104 in bilateral lower legs (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy drug\u003c/h2\u003e \u003cp\u003eVM202 (pCK-HGF-X7) is a plasmid DNA designed to produce each of two isoforms of the HGF protein, consisting of either 723 or 728 amino acids; detailed information about VM202 has been described in previous studies [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. VM202 was supplied in a sterile vial and stored between 2 and 8\u0026deg;C. It was reconstituted with 5.0 ml of sterile water for injections with a final VM202 concentration of 0.5 mg/ml. 14 mg of VM202 was administered via intramuscular injection using one-mL syringes with 29-gauge needles. Injections were given at the peroneus longus, gastrocnemius, and tibialis anterior muscles of bilateral lower legs at 6, 12, and 10 sites, with administered VM202 doses of 3, 6, and 5 mg, respectively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatient eligibility\u003c/h2\u003e \u003cp\u003eEligible patients were non-pregnant individuals of \u0026ge;\u0026thinsp;19 years to \u0026le;\u0026thinsp;65 years of age diagnosed with CMT1A through genetic analysis, had mild-to-moderate clinical severity with a CMT neuropathy score version 2 (CMTNSv2) between 3 and 20, and presented ankle dorsiflexion weakness. Female patients were advised to avoid becoming pregnant during the follow-up period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003ePatients were excluded if they had comorbidities such as renal failure, chronic liver disease, inflammatory bowel disease, diabetes, other neuromuscular disorders, major psychiatric disorders, any conditions that could confound the study assessment; morbid obesity with a body mass index of \u0026ge;\u0026thinsp;37; or uncontrolled hypertension with systolic blood pressure of \u0026ge;\u0026thinsp;160 or diastolic blood pressure of \u0026ge;\u0026thinsp;100. Also excluded were patients who had experienced a major cerebrovascular or cardiovascular event within the 12 months prior, ankle contracture, lower extremity surgery that could influence the evaluation of lower extremity muscle function; or an orthopedic procedure of the lower extremity within the 6 months prior. Patients were also considered exclusionary if they were receiving immunosuppressive medications, chemotherapy or radiation therapy; had evidence of malignancies other than fully resolved basal or squamous cell carcinoma of the skin; or had positive human immunodeficiency virus, hepatitis B, or hepatitis C serological test results.\u003c/p\u003e \u003cp\u003e This study was approved by the institutional review board at our institution (IRB No.SMC 2020-05-038-003). All patients gave written informed consent to participate in the study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSafety parameters\u003c/h2\u003e \u003cp\u003eSafety was the primary end point and was assessed by evaluating all adverse events, conducting complete blood cell counts, serum chemistries, and urinalysis with microscopy at baseline, and on days 14, 90, 104, 180, and 270. Vital signs including systolic and diastolic blood pressure, body temperature, pulse rate, and respiration rate were also assessed likewise, and pre- and post-injection values were assessed on injection visits. Serum levels of anti-HGF antibodies were assessed at the baseline and at day 270 using an enzyme-linked immunosorbent assay (ELISA) developed by Helixmith Co., Ltd (Seoul, Korea).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eClinical assessment\u003c/h2\u003e \u003cp\u003eClinical outcome measures for CMT1A including the CMTNSv2, CMT Examination Score (CMTES), Rasch-modified CMTNSv2 (CMTNSv2-R), and Rasch-modified CMTES (CMTES-R) were evaluated at baseline and at day 270 [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. CMTNSv2 is a composite score consisting of clinical symptoms, signs, and neurophysiologic components. The CMTES represents the CMTNSv2 without the electrophysiological items. All items of CMTNSv2 and CMTES contribute identically to the total score. Otherwise, the CMTNSv2-R and CMTES-R consist of weighted category responses for representing more accurate estimates of the actual values measuring disease severity. The CMTNSv2 ranges from 0 (no deficit) to 36 (maximal deficit) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. This scale assigns mild impairment as scores 0\u0026ndash;10, moderate as 11\u0026ndash;20, and severe as 21\u0026ndash;36. The maximum CMTES is 28 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The CMTES assigns mild impairment as scores 0\u0026ndash;7, moderate as 8\u0026ndash;14, and severe as 15\u0026ndash;28. In addition, disease severity based on the CMTNSv2-R was classified into three groups (mild 0\u0026ndash;10, moderate 11\u0026ndash;20, and severe 21\u0026ndash;40), as it was for the CMTES-R (mild 0\u0026ndash;9, moderate 10\u0026ndash;18, and severe 19\u0026ndash;32) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eFunctional assessment\u003c/h2\u003e \u003cp\u003eLower extremity function of the patients was assessed using a functional disability scale (FDS), the ONLS (Overall Neuropathy Limitation Score) leg scale, and a 10-meter walk test (10MWT) at baseline and at day 270. A nine-point FDS was assessed to determine disease severity in terms of the ability to walk and run as follows: 0\u0026thinsp;=\u0026thinsp;normal; 1\u0026thinsp;=\u0026thinsp;normal, but with cramps and fatigability; 2\u0026thinsp;=\u0026thinsp;inability to run; 3\u0026thinsp;=\u0026thinsp;walking difficult but still possible unaided; 4\u0026thinsp;=\u0026thinsp;able to walk with a cane; 5\u0026thinsp;=\u0026thinsp;able to walk with crutches; 6\u0026thinsp;=\u0026thinsp;able to walk with a walker; 7\u0026thinsp;=\u0026thinsp;wheelchair bound; 8\u0026thinsp;=\u0026thinsp;bedridden [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A seven-point ONLS leg scale was assessed to measure the limitations of the lower limbs as follows: 0\u0026thinsp;=\u0026thinsp;walking/climbing stairs/running not affected; 1\u0026thinsp;=\u0026thinsp;walking/climbing stairs/running affected, but gait does not look abnormal; 2\u0026thinsp;=\u0026thinsp;walks independently but gait looks abnormal; 3\u0026thinsp;=\u0026thinsp;requires unilateral support to walk 10 meters (stick, single crutch, one arm); 4\u0026thinsp;=\u0026thinsp;requires bilateral support to walk 10 meters (sticks, crutches, crutch and arm, frame); 5\u0026thinsp;=\u0026thinsp;requires wheelchair to travel 10 meters but able to stand and walk 1 meter with the help of one person; 6\u0026thinsp;=\u0026thinsp;restricted to wheelchair, unable to stand and walk 1 meter with the help of one person, but able to make some purposeful leg movements; 7\u0026thinsp;=\u0026thinsp;restricted to wheelchair or bed most of the day, unable to make any purposeful movements of the legs [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. For the 10MWT, patients were asked to walk a 10-meter distance, and the time taken was measured in seconds. Three sets of measurements were taken to obtain an average value, which was measured at baseline and at day 270.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eElectrophysiologic studies\u003c/h2\u003e \u003cp\u003eElectrophysiologic studies were performed to assess the nerve regeneration potential of the patients. Motor nerve conduction velocities (MNCVs), compound muscle action potentials (CMAPs), sensory nerve conduction velocities (SNCVs), and sensory nerve action potentials (SNAPs) were measured at baseline and at day 270. MNCVs and CMAPs were measured for bilateral median, ulnar, radial, tibial, and peroneal nerves. SNCVs and SNAPs were measured for bilateral median, ulnar, and sural nerves.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSafety and tolerability were assessed for the safety set, and efficacy analyses were based on the intention-to-treat (ITT) population. A Wilcoxon signed-rank test for continuous variables was performed to assess the clinical outcomes between baseline and day 270 after intramuscular injection of VM202. Statistical significance was defined at a two-sided \u003cem\u003ep\u003c/em\u003e-value of \u0026lt;\u0026thinsp;0.05. All statistical analyses were performed using R Statistical Software (version 3.6.3; Foundation for Statistical Computing, Vienna, Austria).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSafety and tolerability\u003c/h2\u003e \u003cp\u003eDetailed demographics of the participants are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and detailed incidents of adverse events are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A total of four adverse events were reported in three patients (25%). There were no serious adverse events attributable to VM202. Injection site pruritus and peripheral edema, which occurred in separate patients (2/12, 16.7%) and were mild in degree, were the only adverse events that were possibly related to the treatment. They resolved without additional treatment. Two serious adverse events were observed in one patient (1/12, 8.3%; they were pneumonia and uterine myoma. They were non-drug-related and no death was observed during the study. No clinically significant changes compared with those assessed at the baseline were demonstrated in serum, urine lab results, or vital signs. No patients developed antibodies to the HGF protein during the study period.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographics of the 12 participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (58.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42 (19\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHeight (cm)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e168.8\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e171.8 (153.8-180.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight (kg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.3\u0026thinsp;\u0026plusmn;\u0026thinsp;15.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68.7 (36.4\u0026ndash;93.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.2 (15.4\u0026ndash;28.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlcohol\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent drinker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (41.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer drinker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-drinker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (50.0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eBMI\u003c/em\u003e body mass index, \u003cem\u003eSD\u003c/em\u003e standard deviation\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events reported from the study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScreening No.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSeverity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRelationship with gene therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS01013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInjection site pruritus NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePossibly related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResolved\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS01006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnkle edema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePossibly related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResolved\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS01008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNot related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResolved\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eS01008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUterine myoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNot related\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResolved\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eClinical severity evaluation\u003c/h2\u003e \u003cp\u003eStatistical comparison results of the CMTNSv2, CMTES, CMTNSv2-R and CMTES-R assessed at the baseline and at day 270 are summarized on Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Additional file 1: Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003ea. The total CMTNSv2, CMTES, CMTNSv2-R, and CMTES-R significantly decreased between the two timepoints, with mean decreases of 2.17 (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.01), 2.50 (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.01), 2.08 (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.01), and 2.33 points (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.01), respectively. Sign and symptom components of CMTNSv2 also showed significant changes between the two timepoints (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0035 and 0.0069, respectively). These improvements did arise from sensory symptoms and sensory signs rather than motor symptoms and strength (Additional file 1: Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e summarizes the score groups of CMTNSv2, CMTNSv2-R, CMTES, and CMTES-R between two time points. The patients in the severe or moderate groups of CMTNSv2-R, CMTES, and CMTES-R improved to mild or moderate groups by day 270.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in CMTNSv2, CMTES, CMTNSv2-R, CMTES-R, and CMTNSv2 components from baseline to 270 days. Comparison results of the functional disability scale, overall neuropathy limitation score leg scale, and 10-meter walk test time\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBaseline (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eDay 270 (\u003cem\u003eN\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eChange between the two timepoints\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFunctional assessments\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMTNSv2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e15.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e13.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-2.17\u0026thinsp;\u0026plusmn;\u0026thinsp;1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0035\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMTES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e9.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-2.50\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0036\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMTNSv2-R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e18.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e16.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-2.08\u0026thinsp;\u0026plusmn;\u0026thinsp;1.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0036\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMTES-R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e12.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-2.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0035\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e2.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0107\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eONLS leg scale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e2.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e1.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-0.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0719\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10MWT time (sec)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e8.96\u0026thinsp;\u0026plusmn;\u0026thinsp;1.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e8.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-0.62\u0026thinsp;\u0026plusmn;\u0026thinsp;1.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.3013\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCMTNSv2 components\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSigns\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-1.50\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0035\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSymptoms\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e-1.00\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-1.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0069\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeurophysiologic component\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e3.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.0719\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCMAP summatory (mV)\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e41.9\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e41.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e43.3\u0026thinsp;\u0026plusmn;\u0026thinsp;17.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e40.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;14.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.1424\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMNCV (m/s)\u003c/b\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e19.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e \u003cp\u003e19.6\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e \u003cp\u003e0.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-0.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.9185\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cem\u003eCMAP\u003c/em\u003e compound muscle action potential, \u003cem\u003eCMTES\u003c/em\u003e CMT examination score, \u003cem\u003eCMTES-R\u003c/em\u003e Rasch-modified CMTES, \u003cem\u003eCMTNSv2\u003c/em\u003e CMT neuropathy score version 2, \u003cem\u003eCMTNSv2-R\u003c/em\u003e Rasch-modified CMT neuropathy score version 2, \u003cem\u003eFDS\u003c/em\u003e functional disability scale, \u003cem\u003eONLS\u003c/em\u003e overall neuropathy limitation score, \u003cem\u003e10MWT\u003c/em\u003e 10-meter walk test\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003csup\u003e*\u003c/sup\u003eIndicates statistical significance\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003eCMAP summatory: sum of compound action potential of the three motor nerves (ulnar, median, and peroneal nerves)\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003eMean from median and ulnar nerves\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGroup changes between the CMT neuropathy score version 2 and CMT examination score\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline (%) (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDay 270 (%) (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCMTNSv2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild (0\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate (11\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere (21\u0026ndash;36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCMTNSv2-R\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild (0\u0026ndash;10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate (11\u0026ndash;20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (91.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere (21\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCMTES\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild (0\u0026ndash;7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate (8\u0026ndash;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere (15\u0026ndash;28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCMTES-R\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild (0\u0026ndash;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate (10\u0026ndash;18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere (19\u0026ndash;32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eCMTNSv2\u003c/em\u003e CMT neuropathy score version 2, \u003cem\u003eCMTNSv2-R\u003c/em\u003e Rasch-modified CMT neuropathy score version 2, \u003cem\u003eCMTES\u003c/em\u003e CMT examination score, \u003cem\u003eCMTES-R\u003c/em\u003e Rasch-modified CMT examination score\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eFunction of lower extremities\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Additional file 1: Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003eb summarize the statistical comparison results of the FDS, ONLS, and 10MWT times assessed at the baseline and at 270 days. The FDS significantly decreased between the baseline and day 270, with a mean decrease of 0.58 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The ONLS leg scale and 10MWT times gradually decreased, but the changes were not statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis prospective trial was the first clinical study to assess the safety and tolerability of intramuscular VM202 injections in patients with CMT1A. We demonstrated that intramuscular administration of plasmid DNA expressing two isoforms of human HGF is safe and well tolerated by CMT1A patients. Moreover, we observed potential clinical benefits of VM202 administration in CMT1A patients as documented by a significant improvement in clinical scores.\u003c/p\u003e \u003cp\u003eThere were no serious adverse events attributable to VM202. The injection site pruritus and peripheral edema that occurred in a small number of patients were the only adverse events that were possibly related to the agent, and both resolved without treatment. VM202 was well tolerated without any reports of serious adverse events associated with the agent in studies performed on painful diabetic peripheral neuropathy, amyotrophic lateral sclerosis, and critical limb ischemia patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The excellent safety profile of VM202 can be explained by the fact that HGF expression from VM202 is short-lived and tends to be restricted to the area of injection [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Heparan sulfate, which is abundant in the extracellular matrix, limits the diffusion of secreted HGF by binding to the N-terminal of HGF [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Even though plasmid DNA and the HGF protein can reach circulation, the possible biologic effect would be insignificant, as their half-lives in the bloodstream are only a few minutes long [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Furthermore, no patients developed antibodies to the HGF protein in our study. Taken together with the safety results of previous studies and theoretical background that support the safety profile of VM202, our results suggest that intramuscular injection of this agent could be safe and well tolerated in CMT1A patients.\u003c/p\u003e \u003cp\u003eThe pathologic hallmark of CMT1A patients is demyelination associated with length-dependent axonal degeneration of both sensory and motor nerves [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Disability in CMT1A patients has been reported to correlate with the degree of axonal degeneration [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Thus, it has been suggested that therapeutic approaches to ameliorate disability in CMT1A patients should be directed toward preventing axonal degeneration and promoting axonal regeneration [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, current treatment options are mostly palliative, rather than targeting the mechanisms underlying CMT1A. Animal studies have revealed that the intramuscular injection of VM202 leads to HGF production and that its interaction with the c-Met receptor present in Schwann cells and sensory neurons via ERK and AP-1 signaling pathways, respectively, promotes axon outgrowth [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClinical severity assessed by the CMTNSv2 demonstrated significant improvement at the last follow-up with a mean decrease of 2.17 points (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). This was most attributable to significant improvements of signs (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0050) and symptoms (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0147). Clinical disability scores including CMTES, CMTNSv2-R, and CMTES-R also demonstrated significant improvements between timepoints with mean decreases of 2.50, 2.08, and 2.33 points, respectively (\u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.01). In addition, a score group comparison was conducted to find the clinical effects of the VM202 injections. The patients in the severe group of CMTNSv2-R, CMTES, and CMTES-R showed significant changes in comparison to the mild and moderate groups. This suggests that VM202 injections had clinical benefits in CMT1A patients. In addition, function as assessed by the FDS significantly decreased between the baseline and day 270 (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Although the true effect of transient gene expression via VM202 injection in CMT1A patients is not completely understood, theoretical background regarding the trophic effects of HGF on peripheral sensory, motor nerves, and muscle cells may explain the positive results of our study [\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOne concern raised before initiating the study was that the relatively large number of intramuscular injections (56 sites of injection per visit) would not be tolerable to some patients. It was originally thought that VM202 injections would provide short-term therapeutic benefits, thus requiring repeated treatment, because plasmid DNA would be short-lived \u003cem\u003ein vivo\u003c/em\u003e and give only transient gene expression. As such, it was initially expected that the discomfort caused by the multiple injections would be an issue. However, the fact that there were no withdrawals from this study suggests that the injection scheme could be well tolerated.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis is the first phase 1/2a gene therapy trial performed for patients with CMT1A. Our data suggest that the intramuscular administration of VM202 is safe and well tolerated in CMT1A patients. Preliminary efficacy of the agent has been demonstrated by improved clinical scores over the study period. Considering the high unmet medical need in CMT1A patients, performance of a phase 2b randomized, double-blind clinical trial in these patients is warranted.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003e10MWT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;10-meter walk test\u003c/p\u003e\n\u003cp\u003eCMAPs\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Compound muscle action potentials\u003c/p\u003e\n\u003cp\u003eCMT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Charcot-Marie-Tooth disease\u003c/p\u003e\n\u003cp\u003eCMTES\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;CMT examination score\u003c/p\u003e\n\u003cp\u003eCMTES-R\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Rasch-modified CMT examination score\u003c/p\u003e\n\u003cp\u003eCMTNSv2\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;CMT neuropathy score version 2\u003c/p\u003e\n\u003cp\u003eCMTNSv2-R\u0026nbsp; \u0026nbsp;\u0026nbsp;Rasch-modified CMT neuropathy score version 2\u003c/p\u003e\n\u003cp\u003eFDS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Functional disability scale\u003c/p\u003e\n\u003cp\u003eHGF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Hepatocyte growth factor\u003c/p\u003e\n\u003cp\u003eMNCVs\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Motor nerve conduction velocities\u003c/p\u003e\n\u003cp\u003eNCS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Nerve Conduction Study\u003c/p\u003e\n\u003cp\u003eONLS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Overall Neuropathy Limitation Score\u003c/p\u003e\n\u003cp\u003eSNAPs\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Sensory nerve action potentials\u003c/p\u003e\n\u003cp\u003eSNCVs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Sensory nerve conduction velocities\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr Choi had full access to allof the data in the study and takes responsibility\u0026nbsp;for the integrity of the data and the accuracy of the data analysis.\u003c/p\u003e\n\u003cp\u003eConcept and design: All authors.\u003c/p\u003e\n\u003cp\u003eAcquisition, analysis, or interpretation of data: Kwon, SB Kim, Chi, Choi.\u003c/p\u003e\n\u003cp\u003eDrafting of the manuscript: Kwon, HS Kim, Choi.\u003c/p\u003e\n\u003cp\u003eCritical revision of the manuscript for important intellectualcontent: All authors.\u003c/p\u003e\n\u003cp\u003eStatistical analysis: Kwon, HJ Kim, Chi.\u003c/p\u003e\n\u003cp\u003eObtained funding: Choi.\u003c/p\u003e\n\u003cp\u003eAdministrative, technical, or material support: Nam, SB Kim, HS Kim.\u003c/p\u003e\n\u003cp\u003eSupervision: Kwon, Kim, Choi\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by Helixmith Co., Ltd., and supported by grants from the National Research Foundation (2020M3H4A1A03084600, 2021R1A4A2001389, and\u0026nbsp;2022M3E5E9016662), Korean Health Technology R\u0026amp;D Project, Ministry of Health and Welfare (HR22C1363), and\u0026nbsp;Future Medicine 2030 Project of the Samsung Medical Center (SMX122005),\u0026nbsp;Republic of Korea.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional review board at our institution (IRB No.SMC 2020-05-038-003). All patients gave written informed consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe authors declare no competing interests\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8(7):654-67.\u003c/li\u003e\n\u003cli\u003eHaney C, Snipes GJ, Shooter EM, Suter U, Garcia C, Griffin JW, et al. Ultrastructural distribution of PMP22 in Charcot-Marie-Tooth disease type 1A. 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Orphanet J Rare Dis. 2021;16(1):433.\u003c/li\u003e\n\u003cli\u003eMiniou P, Fontes M. Therapeutic Development in Charcot Marie Tooth Type 1 Disease. Int J Mol Sci. 2021;22(13):6755.\u003c/li\u003e\n\u003cli\u003eNakamura T, Sakai K, Nakamura T, Matsumoto K. Hepatocyte growth factor twenty years on: Much more than a growth factor. J Gastroenterol Hepatol. 2011;26 Suppl 1:188-202.\u003c/li\u003e\n\u003cli\u003eHashimoto N, Yamanaka H, Fukuoka T, Dai Y, Obata K, Mashimo T, et al. Expression of HGF and cMet in the peripheral nervous system of adult rats following sciatic nerve injury. Neuroreport. 2001;12(7):1403-7.\u003c/li\u003e\n\u003cli\u003eHashimoto N, Yamanaka H, Fukuoka T, Obata K, Mashimo T, Noguchi K. Expression of hepatocyte growth factor in primary sensory neurons of adult rats. Brain Res Mol Brain Res. 2001;97(1):83-8.\u003c/li\u003e\n\u003cli\u003eKessler JA, Shaibani A, Sang CN, Christiansen M, Kudrow D, Vinik A, et al. Gene therapy for diabetic peripheral neuropathy: A randomized, placebo-controlled phase III study of VM202, a plasmid DNA encoding human hepatocyte growth factor. Clin Transl Sci. 2021;14(3):1176-84.\u003c/li\u003e\n\u003cli\u003eMaina F, Hilton MC, Ponzetto C, Davies AM, Klein R. Met receptor signaling is required for sensory nerve development and HGF promotes axonal growth and survival of sensory neurons. Genes Dev. 1997;11(24):3341-50.\u003c/li\u003e\n\u003cli\u003eWong V, Glass DJ, Arriaga R, Yancopoulos GD, Lindsay RM, Conn G. Hepatocyte growth factor promotes motor neuron survival and synergizes with ciliary neurotrophic factor. J Biol Chem. 1997;272(8):5187-91.\u003c/li\u003e\n\u003cli\u003eIshihara N, Takagi N, Niimura M, Takagi K, Nakano M, Tanonaka K, et al. Inhibition of apoptosis-inducing factor translocation is involved in protective effects of hepatocyte growth factor against excitotoxic cell death in cultured hippocampal neurons. J Neurochem. 2005;95(5):1277-86.\u003c/li\u003e\n\u003cli\u003ePasinelli P, Houseweart MK, Brown RH, Jr., Cleveland DW. Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2000;97(25):13901-6.\u003c/li\u003e\n\u003cli\u003eYuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000;407(6805):802-9.\u003c/li\u003e\n\u003cli\u003eChoi W, Lee J, Lee J, Ko KR, Kim S. Hepatocyte Growth Factor Regulates the miR-206-HDAC4 Cascade to Control Neurogenic Muscle Atrophy following Surgical Denervation in Mice. Mol Ther Nucleic Acids. 2018;12:568-77.\u003c/li\u003e\n\u003cli\u003ePyun WB, Hahn W, Kim DS, Yoo WS, Lee SD, Won JH, et al. Naked DNA expressing two isoforms of hepatocyte growth factor induces collateral artery augmentation in a rabbit model of limb ischemia. Gene Ther. 2010;17(12):1442-52.\u003c/li\u003e\n\u003cli\u003eSufit RL, Ajroud-Driss S, Casey P, Kessler JA. Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(3-4):269-78.\u003c/li\u003e\n\u003cli\u003eKibbe MR, Hirsch AT, Mendelsohn FO, Davies MG, Pham H, Saucedo J, et al. Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia. Gene Ther. 2016;23(3):306-12.\u003c/li\u003e\n\u003cli\u003eKim JS, Hwang HY, Cho KR, Park EA, Lee W, Paeng JC, et al. Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: phase I clinical study. Gene Ther. 2013;20(7):717-22.\u003c/li\u003e\n\u003cli\u003eBirouk N, Gouider R, Le Guern E, Gugenheim M, Tardieu S, Maisonobe T, et al. Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain. 1997;120 ( Pt 5):813-23.\u003c/li\u003e\n\u003cli\u003eMicallef J, Attarian S, Dubourg O, Gonnaud PM, Hogrel JY, Stojkovic T, et al. Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2009;8(12):1103-10.\u003c/li\u003e\n\u003cli\u003eSadjadi R, Reilly MM, Shy ME, Pareyson D, Laura M, Murphy S, et al. Psychometrics evaluation of Charcot-Marie-Tooth Neuropathy Score (CMTNSv2) second version, using Rasch analysis. J Peripher Nerv Syst. 2014;19(3):192-6.\u003c/li\u003e\n\u003cli\u003eGraham RC, Hughes RA. A modified peripheral neuropathy scale: the Overall Neuropathy Limitations Scale. J Neurol Neurosurg Psychiatry. 2006;77(8):973-6.\u003c/li\u003e\n\u003cli\u003eAppasamy R, Tanabe M, Murase N, Zarnegar R, Venkataramanan R, Van Thiel DH, et al. Hepatocyte growth factor, blood clearance, organ uptake, and biliary excretion in normal and partially hepatectomized rats. Lab Invest. 1993;68(3):270-6.\u003c/li\u003e\n\u003cli\u003eIdo A, Moriuchi A, Kim I, Numata M, Nagata-Tsubouchi Y, Hasuike S, et al. Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein. Hepatol Res. 2004;30(3):175-81.\u003c/li\u003e\n\u003cli\u003eKrajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 2000;123 ( Pt 7):1516-27.\u003c/li\u003e\n\u003cli\u003eBerciano J, Combarros O, Calleja J, Polo JM, Leno C. The application of nerve conduction and clinical studies to genetic counseling in hereditary motor and sensory neuropathy type I. Muscle Nerve. 1989;12(4):302-6.\u003c/li\u003e\n\u003cli\u003eKo KR, Lee J, Lee D, Nho B, Kim S. Hepatocyte Growth Factor (HGF) Promotes Peripheral Nerve Regeneration by Activating Repair Schwann Cells. Sci Rep. 2018;8(1):8316.\u003c/li\u003e\n\u003cli\u003eKo KR, Lee J, Nho B, Kim S. c-Fos is necessary for HGF-mediated gene regulation and cell migration in Schwann cells. Biochem Biophys Res Commun. 2018;503(4):2855-60.\u003cstrong\u003e\u003cbr\u003e \u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Charcot-Marie-Tooth disease, gene therapy, PMP22, hepatocyte growth factor","lastPublishedDoi":"10.21203/rs.3.rs-4220356/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4220356/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eThis is the first gene therapy trial in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Intramuscular injectionsof VM202, a plasmid DNA encoding human hepatocyte growth factor, was safe, tolerable and potentially effective in patients with CMT1A.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e This study was a phase 1/2a, nonrandomized controlled trial. Thirteen patients with CMT1A were screened, and 12 consented and enrolled between September 2020 and November 2020. Patients received intramuscular injections of 14 mg of VM202 at baseline, and on days 14, 90, and 104 in both legs. Safety evaluations and clinical assessments using the CMT neuropathy score version 2 (CMTNSv2), CMT examination score (CMTES), Rasch-modified CMTNSv2 (CMTNSv2-R), Rasch-modified CMTES (CMTES-R), functional disability scale (FDS), overall neuropathy limitation score, and 10-meter walk test were performed throughout a 270-day follow-up period. A Wilcoxon signed-rank test was used for statistical comparisons of continuous variables.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e The primary objective of this study was to assess the safety and tolerability of intramuscular injections of VM202 in patients with CMT1A. All participants tolerated VM202 well, without any serious adverse events related to the study drug. The secondary objective was to evaluate potential therapeutic efficacy. CMTNSv2, CMTES, CMTNSv2-R, and CMTES-R significantly decreased between baseline and day 270 with mean decreases of 2.17, 2.50, 2.08, and 2.33 points, respectively (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.01). Also FDS significantly decreased with a mean percent decrease of 0.58 (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003eIntramuscular injections of VM202 appear to be safe and well tolerated in CMT1A patients with potentially encouraging clinical results.\u003c/p\u003e","manuscriptTitle":"A phase 1/2a, open label study to evaluate the safety and efficacy of a plasmid DNA encoding human hepatocyte growth factor in patients with Charcot-Marie-Tooth disease 1A","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-14 18:38:22","doi":"10.21203/rs.3.rs-4220356/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-12-20T04:37:24+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-11-18T03:33:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-31T07:07:02+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-15T03:57:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2024-05-10T08:39:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7b4ae5b3-846a-4b60-ad4a-4dc23431eb15","owner":[],"postedDate":"June 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-09T16:09:24+00:00","versionOfRecord":{"articleIdentity":"rs-4220356","link":"https://doi.org/10.1186/s13023-026-04252-2","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2026-03-05 15:57:04","publishedOnDateReadable":"March 5th, 2026"},"versionCreatedAt":"2024-06-14 18:38:22","video":"","vorDoi":"10.1186/s13023-026-04252-2","vorDoiUrl":"https://doi.org/10.1186/s13023-026-04252-2","workflowStages":[]},"version":"v1","identity":"rs-4220356","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4220356","identity":"rs-4220356","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}