Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy

Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy | 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 Article Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy oranee sanmaneechai, Peerada Pongsakornkullachart, Pimchanok Kulsirichawaroj, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4555695/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Apr, 2025 Read the published version in Gene Therapy → Version 1 posted 9 You are reading this latest preprint version Abstract Objective Supported by encouraging trial outcomes, onasemnogene abeparvovec (OA) was authorized for treating spinal muscular atrophy (SMA) in children under 2 years of age. Nevertheless, the efficacy of OA in advanced SMA patients remains underexplored. This investigation assessed the clinical effectiveness and adverse effects of OA in a patient cohort including those with advanced SMA, and compared these outcomes to historical survival data for SMA type 1 patients in Thailand. Methods We conducted an observational cohort study at Siriraj Hospital, Thailand, from May 2019 to April 2022. The study enrolled eight SMA patients receiving OA therapy. We monitored safety through laboratory tests and clinical evaluations. Patient outcomes, such as motor scores, motor milestones, and survival status, were analyzed. Results The cohort comprised five SMA type 1 patients treated at median age of 16.7 months (6.5–24.9 months) and three SMA type 2 patients treated at median age of 20.3 months (19–31.5 months). Before receiving OA, all type 1 patients needed invasive ventilation and nutritional support by feeding tubes. Posttreatment, these patients did not achieve new motor milestones, their survival rates remained static, and each patient experienced severe adverse events, including fatalities. Conversely, type 2 patients exhibited improved motor scores without experiencing serious adverse events. Interpretation: This real-world evaluation revealed that OA did not significantly improve outcomes or survival rates among advanced SMA type 1 patients, with all such cases resulting in mortality. These findings suggest the need for additional caution and revised guidelines when administering OA to this subgroup. Gene therapy Onasemnogene abeparvovec Spinal muscular atrophy Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder marked by hypotonia, progressive muscle weakening, and areflexia. This condition stems from a homozygous deletion of the survival motor neuron 1 ( SMN1 ) gene, leading to diminished levels of functional survival motor neuron (SMN) protein. 1 SMA is categorized based on the age of onset and achieved motor milestones. Type I SMA, which constitutes 60–70% of cases, typically appears within the first 6 months of life, and the severity of muscle weakness increases over time. 1 In the absence of intervention, patients with type 1 SMA generally need invasive ventilation by 11 months of age and often succumb to the disease before their second birthday. 2 Type 2 SMA, which is moderately severe, emerges between 6 and 18 months of age and is characterized by hypotonia and proximal muscle weakness, rendering patients unable to walk independently. Additionally, individuals with type 2 SMA frequently develop complications such as kyphoscoliosis and respiratory insufficiency, requiring positive pressure support. 1 Since 2016, the advent of targeted disease-modifying therapies has notably altered the trajectory of SMA. These treatments include nusinersen (Spinraza), risdiplam (Everydi), branaplam (LMI070), and a gene replacement therapy (onasemnogene abeparvovec, Zolgensma), each contributing to significant clinical improvements. 3–9 Onasemnogene abeparvovec (OA) is a single-dose intravenous gene therapy engineered to introduce a functional copy of the human SMN gene via the adeno-associated virus serotype 9 (AAV9) vector. 9 Approved by the United States Food and Drug Administration in 2019, OA is indicated for the treatment of SMA patients under 2 years of age with biallelic mutations in the SMN1 gene. 5 The efficacy of this therapy was underscored by results from phase 3 clinical trials, such as the STR1VE-US study. That study demonstrated a significant improvement in clinical outcomes: 91% of enrolled SMA type 1 patients survived without permanent ventilation at 14 months of age, compared to only 26% in the untreated cohort from the Pediatric Neuromuscular Clinical Research Network. 2, 10, 11 However, due to a scarcity of supporting data, the use of OA is currently limited in advanced SMA patients who are already permanently ventilated. 9 Most clinical and observational studies have concentrated on SMA patients under 2 years of age who maintain adequate respiratory and bulbar functions, whether they are treatment-naive or have previously received nusinersen. 10–16 In Thailand, SMA ranks as the second most common neuromuscular disorder among children. 17, 18 Despite its prevalence, diagnosing SMA in Thailand poses significant challenges. This is primarily due to the lack of a national newborn screening program and limited access to genetic testing. Genetic testing is available only in tertiary medical centers and is not covered by the Universal Coverage Scheme (a government health insurance program). These constraints impede the timely diagnosis of SMA across the country. Previously, specific treatments for SMA were neither approved nor available in Thailand. The care of SMA patients has traditionally depended on supportive interventions, including physical therapy, occupational therapy, and respiratory and nutritional support, which aligns with the most recent guidelines. 19, 20 However, the approval of specific SMA treatments in Thailand, including OA and risdiplam, marked a major advancement in the therapeutic options available for SMA patients. This real-world observational study aimed to evaluate the outcomes and safety of OA, including in advanced SMA patients in Thailand, and to compare the survival status of these patients with that of historical controls within the Thai context. In this study, OA was provided through the Zolgensma Accelerated Access Program and the Global Managed Access Program to five SMA type 1 patients and three SMA type 2 patients. 2. Methods 2.1 Study design and patient population This observational cohort study included all SMA patients who were treated with OA between May 2019 to April 2022 at Siriraj Hospital, Mahidol University, Thailand. All patients were confirmed to have genetic biallelic mutations in exons 7 and 8 of the SMN1 gene, were under the age of 2 years at the time of program registration, and had no contraindications for OA. 9 Risks and benefits were thoroughly discussed with the parents, and informed consent was obtained before treatment. No exclusion criteria were applied. Additionally, our study incorporated a historical control group comprising 21 patients who were diagnosed with SMA type 1, had not received any specific treatment, and were under follow-up at Siriraj Hospital from 2006 to 2021. This group was used for comparative analysis. The study protocol was approved by the Siriraj Institutional Review Board (Si 405/2022), also the historical control data was approved by the Siriraj Institutional Review Board (Si 860/2021), and the research was conducted in accordance with the principles of the Declaration of Helsinki. 2.2 Procedure Baseline laboratory evaluations were conducted within 2 weeks before drug administration. These tests were comprehensive: a complete blood count, liver function tests, cardiac enzymes (troponin-I or troponin-T), blood chemistry, and coagulogram. In scenarios where troponin-T was unavailable, troponin-I was utilized as an alternative for monitoring cardiac enzyme levels. Additionally, pretreatment echocardiography was performed to assess cardiac function. The patients were admitted to the hospital 1 day before the infusion and were transferred to the pediatric critical care unit on the day of infusion. OA was delivered as a single 60-minute intravenous infusion at a dosage of 1.1 × 10 14 vector genomes per kilogram (vg/kg) of body weight through a peripheral vein. 9 Following infusion, patients were observed in the critical care unit for 4 hours before being moved to a general department, where they remained for 48 hours of inpatient monitoring prior to discharge. All patients received prednisolone starting 24 hours before the infusion at a daily dose of 1 mg/kg. It was continued for at least 30 days postinfusion, with dosage adjustments and tapering based on liver function test results. Clinical and laboratory evaluations were also integral to the posttreatment follow-up. Patients underwent weekly laboratory tests for the first month postinfusion, followed by tests every 2 weeks for at least another 3 months. 2.3 Functional and laboratory outcomes Motor function was systematically assessed prior to treatment initiation and subsequently every 3 months until the final follow-up. For patients under 2 years of age, motor function was measured using the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND, total score range 0–64) and the Hammersmith Infant Neurological Examination–Module 2 (HINE-2, total score range 0–26). Patients aged 2 years or older or those who achieved the maximum score on the CHOP-INTEND were evaluated using the Hammersmith Functional Motor Scale–Expanded (HFMSE, total score range 0–66), the 32-item Motor Function Measure (MFM32, total score range 0–100), and the Revised Upper Limb Module (RULM, total score range 0–37). Invasive ventilation was defined as ( 1 ) tracheostomy or assisted ventilation for ≥ 16 hours per day continuously for more than 3 weeks or ( 2 ) continuous intubation for 3 weeks. Follow-up laboratory assessments were conducted to monitor adverse drug reactions, including hepatotoxicity, cardiac toxicity, and thrombocytopenia. Hepatotoxicity was classified as mild (≥ 3 to < 5 times the upper limit of normal [ULN]), moderate (≥ 5 to < 20 times ULN), or severe (≥ 20 times ULN). 21 Thrombocytopenia was defined as a platelet count less than 75 x 110 3 /L. 22 Cardiac troponin values greater than 0.05 ng/ml were considered elevated. 23 2.4 Statistical analysis Categorical data are displayed as counts and percentages, while continuous variables were first subjected to a normality test using the Shapiro–Wilk test. Continuous data are presented as the means with standard deviations or medians with ranges, depending on their distribution. Survival analysis was performed using the Kaplan–Meier method, and the data were compared with those of historical controls. All the statistical analyses were performed with IBM SPSS Statistics (version 26) and Stata 18. A p value less than 0.05 was considered to indicate statistical significance. 3. Results 3.1 Clinical characteristics Eight patients were treated with OA at Siriraj Hospital, Thailand, during the study period. Among these patients, five were diagnosed with SMA type 1, and three were diagnosed with SMA type 2 (Table 1 ). The median follow-up duration was 220 days. Table 1 Patient demographics and characteristics treated with onasemnogene abeparvovec for SMA type 1 (Patients 1–5) and type 2 (Patients 6–8) Patient Sex SMA Type SMN2 copy number Onset of Symptom (month) Age at Diagnosis (month) Age at treatment (month) Weight (kg) Respiratory Support Feeding Support CHOP-INTEND score Age at last follow up (month) Follow up time (days) Status 1 F 1 2 3 4.8 16.7 12.1 Invasive NG 4 24.7 249 Dead 2 M 1 2 1 4.5 18.5 14.3 Invasive GT 1 20.6 72 Dead 3 M 1 2 1 1.4 6.5 5 Invasive GT 5 28.1 660 Dead 4 F 1 2 4 15.3 24.9 12.3 Invasive NG 10 27.4 87 Dead 5 F 1 2 5 6.9 13.7 8.3 Invasive GT 6 16.4 90 Dead 6 M 2 3 8 18.1 19 10.4 No No 54 40.1 641 Alive 7 F 2 3 11 14.2 31.5 16.1 No No 28 49.6 547 Alive 8 F 2 3 7 13.7 20.3 6.9 No No 39 26.6 191 Alive Abbreviations : F, female; GT, gastrostomy tube; M, male; NG, nasogastric tube. Invasive ventilation: (1) tracheostomy or assisted ventilation for ≥ 16 hours per day continuously for more than 3 weeks or (2) continuous intubation for 3 weeks. The disease progression among the SMA type 1 patients is detailed in Fig. 1 . These patients experienced symptom onset at a median age of 3 months (range 1–5 months). They were diagnosed at approximately 4.8 months (range 1.4–15.3 months) and received treatment at an average age of 16.7 months (range 6.5–24.9 months). All patients with SMA type 1 had two copies of the SMN2 gene. The median weight at the time of OA administration was 12.1 kg (range 5–14.3 kg). The median CHOP-INTEND score at the baseline visit was 5 (range 1–10). Prior to treatment, all SMA type 1 patients required a tracheostomy for invasive respiratory support and non-oral feeding support via either gastrostomy or a nasogastric tube. The median age at the onset of invasive ventilation and non-oral feeding support was 5.1 months (range 0.4–16.4 months). None of the patients had received nusinersen or risdiplam before treatment with OA. For patients with SMA type 2, symptom onset occurred at a median age of 8 months (range 7–11 months). The patients were diagnosed at a median age of 14.2 months (range 13.7–18.1 months), and treatment was initiated at approximately 20.3 months (range 19–31.5 months). All patients with SMA type 2 had three copies of the SMN2 gene. Their median weight at the time of dosing was 10.4 kg (range 6.9–16.1 kg), and the median CHOP-INTEND score at baseline was 39 (range 28–54). None of the SMA type 2 patients required respiratory or feeding support before receiving treatment. 3.2 Motor outcome and survival status SMA type 1 A modest but gradual increase in the CHOP-INTEND score was noted for SMA type 1 patients (Fig. 2 ), although no new motor milestones were achieved during the follow-up period. Tragically, all patients with SMA type 1 died during the follow-up. The median age at death was 24.7 months (range 16.4–28.1 months). Three patients (Patients No. 2, 4, and 5) passed away 2.7 months after treatment with OA and during the tapering of prednisolone. These patients were found to be unresponsive and cyanotic at home and suffered cardiac arrest before reaching the hospital. Despite evidence of transaminitis in their last follow-up laboratory tests, which showed a decreasing trend, cardiac enzyme levels were not elevated. Another patient (Patient No. 1) died 8.4 months after treatment. The cause of death was suspected to be sepsis secondary to infectious gastroenteritis. Symptoms included mucus, bloody stools, and stupor before the patient passed away at home. The final patient (Patient No. 3) died 21.7 months after treatment from community-acquired pneumonia. No autopsies were conducted on any of the patients due to prevailing cultural beliefs in Thailand. The survival analysis contrasted the SMA type 1 patients treated with OA to the historical controls (Fig. 3 ). The median time to death for the treated group was 24.7 months (range 16.4–28.1 months). This duration did not significantly differ from that of the historical control group ( n = 21, median 13.5 months, range 3.6–65 months, p = 0.87). SMA type 2 For patients with SMA type 2, there was a gradual increase in motor scores (CHOP-INTEND, HFMSE, MFM32, and RULM) during the follow-up period (Fig. 4 ). All patients retained the ability to sit independently, and one patient progressed to standing with assistance 3 months posttreatment at the age of 2.6 years. Furthermore, all patients maintained normal oral and swallowing abilities. One patient required initiation of nighttime noninvasive ventilation support due to adenotonsillar hypertrophy, which led to severe obstructive sleep apnea. 3.3 Safety outcomes All patients experienced adverse events, with serious adverse events occurring in five patients (all SMA type 1). These serious events included the deaths of five patients during the follow-up period. Additionally, three patients (37.5%) developed pneumonia and were treated with intravenous antibiotics. Another two patients (25%) experienced emesis within the first 3 days following treatment. The vomiting was managed without the need for antiemetic medication or intravenous hydration. The most frequent adverse event observed was anicteric hepatitis, which affected every participant. Two distinct peaks of liver enzyme elevation were identified. The initial peak occurred between day 7 and day 14 posttreatment (AST median 90 U/L, range 50–319 U/L; ALT median 64 U/L, range 23–598 U/L). The second peak occurred at approximately 6 weeks posttreatment (AST median 90 U/L, range 34–301 U/L; ALT median 70 U/L, range 32–445 U/L). Importantly, no cases of coagulopathy, hepatic encephalopathy, severe hepatitis, or hepatic failure were reported in this cohort. Cardiac surveillance, including measurements of cardiac enzymes and echocardiograms, was conducted for all participants. Four patients were monitored using troponin-I, while the remaining four were assessed with troponin-T. Baseline cardiac enzyme levels were above the normal limits, with troponin-I levels at 51.4 ng/L (range 2.8–98.7 ng/L) and troponin-T levels at 52.8 ng/L (range 16.7–65.8 ng/L). Clinical evaluations and echocardiograms performed before treatment initiation showed that all the results were within normal ranges. Throughout the three-month follow-up, fluctuations in cardiac enzyme levels were noted, albeit without accompanying clinical symptoms. Additionally, all patients experienced a transient decrease in platelet counts approximately 7 days after dosing (median nadir platelet count 209 x 10 3 /L, range 129–252 x 10 3 /L). The decrease occurred without clinical bleeding, and the values returned to baseline by week 3. No instances of thrombocytopenia or thrombotic microangiopathy were observed in this study. 3.4 Corticosteroid adjustment A prednisolone regimen of 1 mg/kg daily was initiated for all patients, with a tapering schedule commencing after week 4, guided by liver enzyme levels. The median duration of prednisolone therapy was 75 days (range 57–146 days). None of the patients required an increase in the prednisolone dosage beyond 1 mg/kg per day or a transition to intravenous methylprednisolone. One patient discontinued prednisolone on day 90 postdosing; however, due to a rise in liver enzyme levels, the administration of the medication was resumed on day 134 and continued until day 190. 4. Discussion This single-center, real-world observational study examined the outcomes of five SMA type 1 patients and three SMA type 2 patients who received OA gene replacement therapy over a three-year period. Our investigation predominantly addressed advanced-stage SMA type 1 patients whose treatment was delayed due to drug authorization and transportation issues. Unfortunately, all patients in this advanced group died, highlighting the critical need to reevaluate the timing and appropriateness of gene therapy in such patients. Symptom onset in our SMA type 1 patients occurred at 3 months, with diagnosis at approximately 4.8 months. These durations closely mirror those of the Pediatric Neuromuscular Clinical Research Network untreated cohort, which reported symptom onset at 3 months and diagnosis at 6 months. 2 However, there was a notable delay in diagnosis compared to the STR1VE study (symptom onset at 1.8 months and diagnosis at 2.2 months) and other treated cohorts. 10–13, 16 In addition, the age at treatment with OA in our SMA type 1 cohort was 16.7 months, with all patients in the advanced stage and needing invasive respiratory support and non-oral feeding. This marked a substantial delay in the treatment of patients and the severity of their condition at the time of treatment compared to the STR1VE study and other cohorts. 10–16 In contrast, for our patients with SMA type 2, symptoms began at 8 months, with diagnosis at 14.2 months. These values are consistent with those of the Pediatric Neuromuscular Clinical Research Network cohort for SMA type 2 (onset at 9.6 months and diagnosis at 13.2 months) and other treated cohorts. 13, 14, 16, 24 The age at treatment in our SMA type 2 group was 20.3 months, which represented a delay compared to other treated cohorts. 13–16 The delayed diagnosis and treatment of SMA in our cohort are attributable to several factors. Primarily, the absence of a national newborn screening protocol for SMA significantly hampers early detection, which is crucial for prompt intervention. Additionally, genetic testing for SMA in Thailand is largely limited to tertiary medical centers. It is also not included in Thailand’s Universal Coverage Scheme, necessitating referrals for definitive diagnosis and consequently prolonging the process. The introduction of SMA gene therapy in Thailand has also faced delays. They are chiefly due to the newness of the authorization process and the logistical challenges associated with the importation and distribution of the treatments. Moreover, other specific SMA treatments, such as nusinersen, are unavailable in Thailand, limiting therapeutic options for patients. These obstacles contribute to the progression of the disease to more advanced stages before effective treatment can be administered. Addressing these challenges involves enhancing early detection, expediting diagnosis, and improving the accessibility of treatments. Establishing a national newborn screening program for SMA, expanding genetic testing capabilities beyond tertiary centers, and integrating these services into the national Universal Coverage Scheme could significantly mitigate these delays and improve outcomes for SMA patients in Thailand. After receiving gene replacement therapy, our SMA type 1 patients demonstrated gradual improvements in CHOP-INTEND scores; however, no new motor milestones were attained postintervention. There was no statistically significant difference in survival outcomes compared to the historical controls 25 . Critically, all SMA type 1 patients suffered severe adverse events, including fatalities. In contrast, the STR1VE study and other treated cohorts reported enhancements in both motor scores and survival rates, accompanied by a considerably lower incidence of serious adverse events. 10–16 The treatment delays in our cohort, leading to advanced disease stages at the time of intervention, resulted in less favorable outcomes. These findings emphasize the vital importance of early treatment initiation in SMA patients to optimize its effectiveness and improve patient prognoses. All SMA type 1 patients in our study died during the follow-up period. Among these, one patient’s death was attributed to community-acquired pneumonia, but the specific causes of death for the other four patients remain unclear. Laboratory tests, including cardiac and liver enzyme tests, indicated no significant abnormalities prior to death. Infections and secretion obstructions are considered potential causes of death; however, the lack of autopsy reports precludes definitive conclusions about whether these were related to gene therapy complications or the natural progression of SMA. This situation underscores the need for healthcare systems that reimburse onasemnogene abeparvovec to acknowledge that, in addition to the lack of significant clinical improvement, serious adverse events such as death may occur. This study contributes to the growing body of evidence suggesting that gene therapy should not be administered to severely ill and intubated patients with SMA type 1, highlighting the complex risk-benefit considerations in this group. Several fatalities have also been reported in other studies involving OA. For instance, in the STR1VE study, which included 63 patients, two deaths occurred at 12 and 171 days posttherapy, both of which were due to respiratory failure. 10, 11 In the Global Managed Access Program, which involved 102 patients, three fatalities related to respiratory complications were recorded between 80 and 106 days after treatment, all related to respiratory complications. 22, 26 Importantly, these deaths were determined to be unrelated to the gene therapy itself. The SMA type 2 patients in our study exhibited more favorable outcomes, mirroring findings from other research. 13–16 Improvements in motor scores were observed over time, and notably, one patient achieved new motor milestones. Additionally, no serious adverse events were reported in these patients, aligning with outcomes documented in similar cohorts. Posttreatment monitoring in our cohort revealed common adverse events, including transient decreases in platelet counts and instances of hepatitis. The most frequently observed adverse event was mild to moderate anicteric hepatitis, characterized by two peaks of enzyme elevation that did not coincide with any clinical symptoms, consistent with previous studies. 10–16 No specific treatments were required apart from adjustments to the prednisolone dosage. Despite the observed decrease in platelet counts, none of our patients developed thrombocytopenia, a condition that has been reported in other studies with varying frequencies ranging from 9–78%. 10–16 This discrepancy highlights the variability in patient responses to gene therapy and underscores the importance of close clinical and laboratory monitoring to effectively manage and mitigate potential adverse effects. Furthermore, all patients in our study presented with abnormal baseline cardiac enzyme levels. Despite this, no increases in enzyme levels or clinical cardiac abnormalities were observed posttreatment, consistent with data from other treated cohorts. 12–16 Several studies have similarly reported elevated plasma levels of cardiac enzymes, including both troponin-I and troponin-T, among SMA patients without any overt cardiac symptoms. One study reported a median troponin-I level of 39.5 ng/L (range 4–1205 ng/L) and troponin-T levels that were 3–10 times greater in 16 SMA patients (80 ± 39 ng/L, range 43–143 ng/L), with the highest values noted in SMA type 1 patients. 27,28 Adult studies have indicated increased troponin-T in patients with muscle diseases, suggesting that cardiac troponin-T may be re-expressed during chronic skeletal muscle repair mechanisms. This hypothesis could explain the elevated cardiac enzymes observed in SMA patients despite the absence of cardiac abnormalities. 29 Nonetheless, this study has limitations, particularly the small sample size, which limits the ability to widely generalize the findings. Moreover, no autopsies were performed on the deceased patients, which would have helped to definitively ascertain whether their deaths were related to the treatment or were a natural progression of the disease. This gap in data is due primarily to the cultural practices prevalent in Thailand. Given the uniformly fatal outcomes observed among the advanced SMA type 1 patients in this study, further research within this specific subgroup is not recommended at this time. Our findings underscore the need for careful patient selection and management in future clinical applications of gene therapy for SMA. The future of SMA management in Thailand hinges on early diagnosis, which is achievable through the development and implementation of a comprehensive newborn screening program. Further research into the outcomes of early intervention is crucial, as it represents a significant step toward integrating SMA treatment within Thailand’s Universal Coverage Scheme. This integration would enhance the quality of life for SMA patients and significantly reduce the overall burden of the disease on the nation. 5. Conclusion This study presents real-world outcomes of OA therapy in advanced SMA patients within the context of a developing country characterized by delayed diagnoses and restricted access to alternative treatments. Our findings revealed no substantial improvement in motor scores and no enhancement in survival rates, with all SMA type 1 patients succumbing to the disease. Therefore, this investigation underscores the imperative of initiating treatment early in the course of SMA and prompts a reevaluation of the use of OA in advanced SMA type 1 patients, particularly permanently ventilated patients. These results highlight the need for cautious and targeted application of gene therapy in this vulnerable patient population, ensuring that treatment approaches are timely and appropriate. Abbreviations Abbreviation Meaning AAV9 Adeno-associated virus serotype 9 CHOP-INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders HFMSE Hammersmith Functional Motor Scale–Expanded HINE-2 Hammersmith Infant Neurological Examination–Module 2 MFM32 32-item Motor Function Measure OA Onasemnogene abeparvovec RULM Revised Upper Limb Module SMA Spinal muscular atrophy SMN Survival motor neuron SMN1 Survival motor neuron 1 ULN Upper limit of normal Declarations Data Availability Statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Acknowledgments The authors gratefully acknowledge Dr Chulaluk Komoltri for her assistance with the statistical analyses, and Ms Tanaporn Netsuwan, Mr Cheewasan Apirukpanakhet, and Ms Naphat Maneesawat for their assistance with the data collection. CRediT Author Contribution Statement Peerada Pongsakornkullachart: Methodology, Data curation, Investigation, Formal analysis, Writing–original draft preparation. Pimchanok Kulsirichawaroj: Writing–review and editing. Ratcharin Kongkasuwan: Conceptualization, Methodology, Investigation, Formal analysis, Validation, Writing-review and editing. Prakarn Tovichien, Settapong Jitwongwai,Supaluck Kanjanauthai, Nutnicha Preeprem, Sivaporn Limpaninlachart, Nisasri Sermpon: Investigation. Oranee Sanmaneechai: Conceptualization, Methodology, Formal analysis, Validation, Writing–review and editing, Supervision, Project administration. All authors reviewed the results and approved the final version of the manuscript. Ethical Approval The study protocol was approved by the Siriraj Institutional Review Board (Si 405/2022), also the historical control data was approved by the Siriraj Institutional Review Board (Si 860/2021), and the research was conducted in accordance with the principles of the Declaration of Helsinki. Funding This study was funded by the Siriraj Research Department (R016631023) and the Health Systems Research Institute (R016741018). Conflict of Interest The authors declare that they have no conflicts of interest. References Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008 Jun 21;al371(9630):2120-33. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-7. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018 Feb 15;378(7):625-35. Gidaro T, Servais L. 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Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings. Gene Ther. 2023 Sep;30(9):685-97. Kaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012 Oct 30;79(18):1889-97. Sittiyuno P, Kulsirichawaroj P, Leelahavarong P, Sanmaneechai O. Survival analysis and life expectancy of pediatric patients with spinal muscular atrophy in Thailand. Heliyon. 2024 2024/06/15/;10(11):e32732. Chand DH, Mitchell S, Sun R, LaMarca N, Reyna SP, Sutter T. Safety of Onasemnogene Abeparvovec for Patients With Spinal Muscular Atrophy 8.5 kg or Heavier in a Global Managed Access Program. Pediatr Neurol. 2022 Jul;132:27-32. Johannsen J, Weiss D, Driemeyer J, et al. High-sensitive cardiac troponin I (hs-cTnI) concentrations in newborns diagnosed with spinal muscular atrophy. Front Pediatr. 2023;11:1259293. Ille A, van Egmond-Fröhlich A, Weiss S, et al. SMA THERAPIES II AND BIOMARKERS: P. 265Patients with spinal muscular atrophy without cardiac disease show elevated cardiac troponin T. Neuromuscular Disorders. 2018;28:S111-S2. du Fay de Lavallaz JA-O, Prepoudis AA-O, Wendebourg MA-O, et al. Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T. (1524-4539 (Electronic)). Additional Declarations There is NO conflict of interest to disclose. Supplementary Files FataloutcomefollowingOAinadvancedSMAsupgenetherapy1.docx FigureS1cmyk.jpg FigureS2cmyk.jpg FigureS3cmyk.jpg Cite Share Download PDF Status: Published Journal Publication published 23 Apr, 2025 Read the published version in Gene Therapy → Version 1 posted Editorial decision: revise 31 Oct, 2024 Review # 2 received at journal 22 Oct, 2024 Reviewer # 2 agreed at journal 09 Oct, 2024 Review # 1 received at journal 04 Aug, 2024 Reviewer # 1 agreed at journal 28 Jul, 2024 Reviewers invited by journal 23 Jul, 2024 Editor assigned by journal 10 Jun, 2024 Submission checks completed at journal 10 Jun, 2024 First submitted to journal 10 Jun, 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. 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12:39:12","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":686243,"visible":true,"origin":"","legend":"\u003cp\u003eCHOP-INTEND scores of SMA type 1 patients\u003c/p\u003e","description":"","filename":"Figure2cmyk.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4555695/v1/50efc28f30aa436a5a7cd12a.jpg"},{"id":63277774,"identity":"81cee923-f5bb-435d-a67d-39f25c0310d5","added_by":"auto","created_at":"2024-08-26 12:31:12","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":943928,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival status of SMA type 1 patients\u003c/p\u003e","description":"","filename":"Figure3cmyk.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4555695/v1/2f70e3b379cad20b925fb121.jpg"},{"id":63277778,"identity":"f3a1b478-8fa9-4db6-b87b-26a20edbc8dc","added_by":"auto","created_at":"2024-08-26 12:31:12","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1608561,"visible":true,"origin":"","legend":"\u003cp\u003eMotor function scores of SMA type 2 patients. \u003cstrong\u003e(A)\u003c/strong\u003e CHOP-INTEND score, \u003cstrong\u003e(B)\u003c/strong\u003e HFMSE score, \u003cstrong\u003e(C)\u003c/strong\u003e MFM32 score, \u003cstrong\u003e(D)\u003c/strong\u003e RULM score\u003c/p\u003e","description":"","filename":"Figure4cmyk.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4555695/v1/6fde4d2e34981914692e6d57.jpg"},{"id":81264426,"identity":"b35d082f-525c-4407-a9a0-086030cb59ab","added_by":"auto","created_at":"2025-04-24 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12:39:12","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1339296,"visible":true,"origin":"","legend":"","description":"","filename":"FigureS3cmyk.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4555695/v1/1468356f25c1f2b58070a1f2.jpg"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSpinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder marked by hypotonia, progressive muscle weakening, and areflexia. This condition stems from a homozygous deletion of the survival motor neuron 1 (\u003cem\u003eSMN1\u003c/em\u003e) gene, leading to diminished levels of functional survival motor neuron (SMN) protein.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSMA is categorized based on the age of onset and achieved motor milestones. Type I SMA, which constitutes 60\u0026ndash;70% of cases, typically appears within the first 6 months of life, and the severity of muscle weakness increases over time.\u003csup\u003e1\u003c/sup\u003e In the absence of intervention, patients with type 1 SMA generally need invasive ventilation by 11 months of age and often succumb to the disease before their second birthday.\u003csup\u003e2\u003c/sup\u003e Type 2 SMA, which is moderately severe, emerges between 6 and 18 months of age and is characterized by hypotonia and proximal muscle weakness, rendering patients unable to walk independently. Additionally, individuals with type 2 SMA frequently develop complications such as kyphoscoliosis and respiratory insufficiency, requiring positive pressure support.\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSince 2016, the advent of targeted disease-modifying therapies has notably altered the trajectory of SMA. These treatments include nusinersen (Spinraza), risdiplam (Everydi), branaplam (LMI070), and a gene replacement therapy (onasemnogene abeparvovec, Zolgensma), each contributing to significant clinical improvements.\u003csup\u003e3\u0026ndash;9\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOnasemnogene abeparvovec (OA) is a single-dose intravenous gene therapy engineered to introduce a functional copy of the human \u003cem\u003eSMN\u003c/em\u003e gene via the adeno-associated virus serotype 9 (AAV9) vector.\u003csup\u003e9\u003c/sup\u003e Approved by the United States Food and Drug Administration in 2019, OA is indicated for the treatment of SMA patients under 2 years of age with biallelic mutations in the \u003cem\u003eSMN1\u003c/em\u003e gene.\u003csup\u003e5\u003c/sup\u003e The efficacy of this therapy was underscored by results from phase 3 clinical trials, such as the STR1VE-US study. That study demonstrated a significant improvement in clinical outcomes: 91% of enrolled SMA type 1 patients survived without permanent ventilation at 14 months of age, compared to only 26% in the untreated cohort from the Pediatric Neuromuscular Clinical Research Network.\u003csup\u003e2, 10, 11\u003c/sup\u003e However, due to a scarcity of supporting data, the use of OA is currently limited in advanced SMA patients who are already permanently ventilated.\u003csup\u003e9\u003c/sup\u003e Most clinical and observational studies have concentrated on SMA patients under 2 years of age who maintain adequate respiratory and bulbar functions, whether they are treatment-naive or have previously received nusinersen.\u003csup\u003e10\u0026ndash;16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn Thailand, SMA ranks as the second most common neuromuscular disorder among children.\u003csup\u003e17, 18\u003c/sup\u003e Despite its prevalence, diagnosing SMA in Thailand poses significant challenges. This is primarily due to the lack of a national newborn screening program and limited access to genetic testing. Genetic testing is available only in tertiary medical centers and is not covered by the Universal Coverage Scheme (a government health insurance program). These constraints impede the timely diagnosis of SMA across the country. Previously, specific treatments for SMA were neither approved nor available in Thailand. The care of SMA patients has traditionally depended on supportive interventions, including physical therapy, occupational therapy, and respiratory and nutritional support, which aligns with the most recent guidelines.\u003csup\u003e19, 20\u003c/sup\u003e However, the approval of specific SMA treatments in Thailand, including OA and risdiplam, marked a major advancement in the therapeutic options available for SMA patients.\u003c/p\u003e \u003cp\u003eThis real-world observational study aimed to evaluate the outcomes and safety of OA, including in advanced SMA patients in Thailand, and to compare the survival status of these patients with that of historical controls within the Thai context. In this study, OA was provided through the Zolgensma Accelerated Access Program and the Global Managed Access Program to five SMA type 1 patients and three SMA type 2 patients.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and patient population\u003c/h2\u003e \u003cp\u003eThis observational cohort study included all SMA patients who were treated with OA between May 2019 to April 2022 at Siriraj Hospital, Mahidol University, Thailand. All patients were confirmed to have genetic biallelic mutations in exons 7 and 8 of the \u003cem\u003eSMN1\u003c/em\u003e gene, were under the age of 2 years at the time of program registration, and had no contraindications for OA.\u003csup\u003e9\u003c/sup\u003e Risks and benefits were thoroughly discussed with the parents, and informed consent was obtained before treatment. No exclusion criteria were applied.\u003c/p\u003e \u003cp\u003eAdditionally, our study incorporated a historical control group comprising 21 patients who were diagnosed with SMA type 1, had not received any specific treatment, and were under follow-up at Siriraj Hospital from 2006 to 2021. This group was used for comparative analysis. The study protocol was approved by the Siriraj Institutional Review Board (Si 405/2022), also the historical control data was approved by the Siriraj Institutional Review Board (Si 860/2021), and the research was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Procedure\u003c/h2\u003e \u003cp\u003eBaseline laboratory evaluations were conducted within 2 weeks before drug administration. These tests were comprehensive: a complete blood count, liver function tests, cardiac enzymes (troponin-I or troponin-T), blood chemistry, and coagulogram. In scenarios where troponin-T was unavailable, troponin-I was utilized as an alternative for monitoring cardiac enzyme levels. Additionally, pretreatment echocardiography was performed to assess cardiac function.\u003c/p\u003e \u003cp\u003eThe patients were admitted to the hospital 1 day before the infusion and were transferred to the pediatric critical care unit on the day of infusion. OA was delivered as a single 60-minute intravenous infusion at a dosage of 1.1 \u0026times; 10\u003csup\u003e14\u003c/sup\u003e vector genomes per kilogram (vg/kg) of body weight through a peripheral vein.\u003csup\u003e9\u003c/sup\u003e Following infusion, patients were observed in the critical care unit for 4 hours before being moved to a general department, where they remained for 48 hours of inpatient monitoring prior to discharge.\u003c/p\u003e \u003cp\u003eAll patients received prednisolone starting 24 hours before the infusion at a daily dose of 1 mg/kg. It was continued for at least 30 days postinfusion, with dosage adjustments and tapering based on liver function test results. Clinical and laboratory evaluations were also integral to the posttreatment follow-up. Patients underwent weekly laboratory tests for the first month postinfusion, followed by tests every 2 weeks for at least another 3 months.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Functional and laboratory outcomes\u003c/h2\u003e \u003cp\u003eMotor function was systematically assessed prior to treatment initiation and subsequently every 3 months until the final follow-up. For patients under 2 years of age, motor function was measured using the Children\u0026rsquo;s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND, total score range 0\u0026ndash;64) and the Hammersmith Infant Neurological Examination\u0026ndash;Module 2 (HINE-2, total score range 0\u0026ndash;26). Patients aged 2 years or older or those who achieved the maximum score on the CHOP-INTEND were evaluated using the Hammersmith Functional Motor Scale\u0026ndash;Expanded (HFMSE, total score range 0\u0026ndash;66), the 32-item Motor Function Measure (MFM32, total score range 0\u0026ndash;100), and the Revised Upper Limb Module (RULM, total score range 0\u0026ndash;37). Invasive ventilation was defined as (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) tracheostomy or assisted ventilation for \u0026ge;\u0026thinsp;16 hours per day continuously for more than 3 weeks or (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) continuous intubation for 3 weeks.\u003c/p\u003e \u003cp\u003eFollow-up laboratory assessments were conducted to monitor adverse drug reactions, including hepatotoxicity, cardiac toxicity, and thrombocytopenia. Hepatotoxicity was classified as mild (\u0026ge;\u0026thinsp;3 to \u0026lt;\u0026thinsp;5 times the upper limit of normal [ULN]), moderate (\u0026ge;\u0026thinsp;5 to \u0026lt;\u0026thinsp;20 times ULN), or severe (\u0026ge;\u0026thinsp;20 times ULN).\u003csup\u003e21\u003c/sup\u003e Thrombocytopenia was defined as a platelet count less than 75 x 110\u003csup\u003e3\u003c/sup\u003e/L.\u003csup\u003e22\u003c/sup\u003e Cardiac troponin values greater than 0.05 ng/ml were considered elevated.\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eCategorical data are displayed as counts and percentages, while continuous variables were first subjected to a normality test using the Shapiro\u0026ndash;Wilk test. Continuous data are presented as the means with standard deviations or medians with ranges, depending on their distribution. Survival analysis was performed using the Kaplan\u0026ndash;Meier method, and the data were compared with those of historical controls. All the statistical analyses were performed with IBM SPSS Statistics (version 26) and Stata 18. A \u003cem\u003ep\u003c/em\u003e value less than 0.05 was considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003e3.1 Clinical characteristics\u003c/h2\u003e\n \u003cp\u003eEight patients were treated with OA at Siriraj Hospital, Thailand, during the study period. Among these patients, five were diagnosed with SMA type 1, and three were diagnosed with SMA type 2 (Table\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e). The median follow-up duration was 220 days.\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003ePatient demographics and characteristics treated with onasemnogene abeparvovec for SMA type 1 (Patients 1\u0026ndash;5) and type 2 (Patients 6\u0026ndash;8)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"21\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSMA Type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eSMN2 copy number\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOnset of Symptom (month)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge at Diagnosis (month)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge at treatment (month)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eWeight\u003c/p\u003e\n \u003cp\u003e(kg)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRespiratory Support\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eFeeding Support\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eCHOP-INTEND score\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAge at last follow up (month)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eFollow up time (days)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStatus\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e24.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e249\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e20.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e28.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e660\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e27.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInvasive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e16.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eDead\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e40.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e641\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e49.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e547\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e26.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e191\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eAlive\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e F, female; GT, gastrostomy tube; M, male; NG, nasogastric tube.\u003c/p\u003e\n \u003cp\u003eInvasive ventilation: (1)\u0026nbsp;tracheostomy or assisted ventilation for\u0026nbsp;\u0026ge;\u0026nbsp;16 hours per day continuously for more than 3 weeks or\u0026nbsp;(2)\u0026nbsp;continuous intubation for 3 weeks.\u003c/p\u003e\n \u003cp\u003eThe disease progression among the SMA type 1 patients is detailed in Fig.\u0026nbsp;\u003cspan\u003e1\u003c/span\u003e. These patients experienced symptom onset at a median age of 3 months (range 1\u0026ndash;5 months). They were diagnosed at approximately 4.8 months (range 1.4\u0026ndash;15.3 months) and received treatment at an average age of 16.7 months (range 6.5\u0026ndash;24.9 months). All patients with SMA type 1 had two copies of the \u003cem\u003eSMN2\u003c/em\u003e gene. The median weight at the time of OA administration was 12.1 kg (range 5\u0026ndash;14.3 kg). The median CHOP-INTEND score at the baseline visit was 5 (range 1\u0026ndash;10). Prior to treatment, all SMA type 1 patients required a tracheostomy for invasive respiratory support and non-oral feeding support via either gastrostomy or a nasogastric tube. The median age at the onset of invasive ventilation and non-oral feeding support was 5.1 months (range 0.4\u0026ndash;16.4 months). None of the patients had received nusinersen or risdiplam before treatment with OA.\u003c/p\u003e\n \u003cp\u003eFor patients with SMA type 2, symptom onset occurred at a median age of 8 months (range 7\u0026ndash;11 months). The patients were diagnosed at a median age of 14.2 months (range 13.7\u0026ndash;18.1 months), and treatment was initiated at approximately 20.3 months (range 19\u0026ndash;31.5 months). All patients with SMA type 2 had three copies of the \u003cem\u003eSMN2\u003c/em\u003e gene. Their median weight at the time of dosing was 10.4 kg (range 6.9\u0026ndash;16.1 kg), and the median CHOP-INTEND score at baseline was 39 (range 28\u0026ndash;54). None of the SMA type 2 patients required respiratory or feeding support before receiving treatment.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\"\u003e\n \u003ch2\u003e3.2 Motor outcome and survival status\u003c/h2\u003e\n \u003cp\u003e\u003cem\u003eSMA type 1\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eA modest but gradual increase in the CHOP-INTEND score was noted for SMA type 1 patients (Fig.\u0026nbsp;\u003cspan\u003e2\u003c/span\u003e), although no new motor milestones were achieved during the follow-up period. Tragically, all patients with SMA type 1 died during the follow-up. The median age at death was 24.7 months (range 16.4\u0026ndash;28.1 months). Three patients (Patients No. 2, 4, and 5) passed away 2.7 months after treatment with OA and during the tapering of prednisolone. These patients were found to be unresponsive and cyanotic at home and suffered cardiac arrest before reaching the hospital. Despite evidence of transaminitis in their last follow-up laboratory tests, which showed a decreasing trend, cardiac enzyme levels were not elevated. Another patient (Patient No. 1) died 8.4 months after treatment. The cause of death was suspected to be sepsis secondary to infectious gastroenteritis. Symptoms included mucus, bloody stools, and stupor before the patient passed away at home. The final patient (Patient No. 3) died 21.7 months after treatment from community-acquired pneumonia. No autopsies were conducted on any of the patients due to prevailing cultural beliefs in Thailand.\u003c/p\u003e\n \u003cp\u003eThe survival analysis contrasted the SMA type 1 patients treated with OA to the historical controls (Fig.\u0026nbsp;\u003cspan\u003e3\u003c/span\u003e). The median time to death for the treated group was 24.7 months (range 16.4\u0026ndash;28.1 months). This duration did not significantly differ from that of the historical control group (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21, median 13.5 months, range 3.6\u0026ndash;65 months, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.87).\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eSMA type 2\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eFor patients with SMA type 2, there was a gradual increase in motor scores (CHOP-INTEND, HFMSE, MFM32, and RULM) during the follow-up period (Fig.\u0026nbsp;\u003cspan\u003e4\u003c/span\u003e). All patients retained the ability to sit independently, and one patient progressed to standing with assistance 3 months posttreatment at the age of 2.6 years. Furthermore, all patients maintained normal oral and swallowing abilities. One patient required initiation of nighttime noninvasive ventilation support due to adenotonsillar hypertrophy, which led to severe obstructive sleep apnea.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\"\u003e\n \u003ch2\u003e3.3 Safety outcomes\u003c/h2\u003e\n \u003cp\u003eAll patients experienced adverse events, with serious adverse events occurring in five patients (all SMA type 1). These serious events included the deaths of five patients during the follow-up period. Additionally, three patients (37.5%) developed pneumonia and were treated with intravenous antibiotics. Another two patients (25%) experienced emesis within the first 3 days following treatment. The vomiting was managed without the need for antiemetic medication or intravenous hydration.\u003c/p\u003e\n \u003cp\u003eThe most frequent adverse event observed was anicteric hepatitis, which affected every participant. Two distinct peaks of liver enzyme elevation were identified. The initial peak occurred between day 7 and day 14 posttreatment (AST median 90 U/L, range 50\u0026ndash;319 U/L; ALT median 64 U/L, range 23\u0026ndash;598 U/L). The second peak occurred at approximately 6 weeks posttreatment (AST median 90 U/L, range 34\u0026ndash;301 U/L; ALT median 70 U/L, range 32\u0026ndash;445 U/L). Importantly, no cases of coagulopathy, hepatic encephalopathy, severe hepatitis, or hepatic failure were reported in this cohort.\u003c/p\u003e\n \u003cp\u003eCardiac surveillance, including measurements of cardiac enzymes and echocardiograms, was conducted for all participants. Four patients were monitored using troponin-I, while the remaining four were assessed with troponin-T. Baseline cardiac enzyme levels were above the normal limits, with troponin-I levels at 51.4 ng/L (range 2.8\u0026ndash;98.7 ng/L) and troponin-T levels at 52.8 ng/L (range 16.7\u0026ndash;65.8 ng/L). Clinical evaluations and echocardiograms performed before treatment initiation showed that all the results were within normal ranges. Throughout the three-month follow-up, fluctuations in cardiac enzyme levels were noted, albeit without accompanying clinical symptoms.\u003c/p\u003e\n \u003cp\u003eAdditionally, all patients experienced a transient decrease in platelet counts approximately 7 days after dosing (median nadir platelet count 209 x 10\u003csup\u003e3\u003c/sup\u003e/L, range 129\u0026ndash;252 x 10\u003csup\u003e3\u003c/sup\u003e/L). The decrease occurred without clinical bleeding, and the values returned to baseline by week 3. No instances of thrombocytopenia or thrombotic microangiopathy were observed in this study.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003e3.4 Corticosteroid adjustment\u003c/h2\u003e\n \u003cp\u003eA prednisolone regimen of 1 mg/kg daily was initiated for all patients, with a tapering schedule commencing after week 4, guided by liver enzyme levels. The median duration of prednisolone therapy was 75 days (range 57\u0026ndash;146 days). None of the patients required an increase in the prednisolone dosage beyond 1 mg/kg per day or a transition to intravenous methylprednisolone. One patient discontinued prednisolone on day 90 postdosing; however, due to a rise in liver enzyme levels, the administration of the medication was resumed on day 134 and continued until day 190.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis single-center, real-world observational study examined the outcomes of five SMA type 1 patients and three SMA type 2 patients who received OA gene replacement therapy over a three-year period. Our investigation predominantly addressed advanced-stage SMA type 1 patients whose treatment was delayed due to drug authorization and transportation issues. Unfortunately, all patients in this advanced group died, highlighting the critical need to reevaluate the timing and appropriateness of gene therapy in such patients.\u003c/p\u003e \u003cp\u003eSymptom onset in our SMA type 1 patients occurred at 3 months, with diagnosis at approximately 4.8 months. These durations closely mirror those of the Pediatric Neuromuscular Clinical Research Network untreated cohort, which reported symptom onset at 3 months and diagnosis at 6 months.\u003csup\u003e2\u003c/sup\u003e However, there was a notable delay in diagnosis compared to the STR1VE study (symptom onset at 1.8 months and diagnosis at 2.2 months) and other treated cohorts.\u003csup\u003e10\u0026ndash;13, 16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn addition, the age at treatment with OA in our SMA type 1 cohort was 16.7 months, with all patients in the advanced stage and needing invasive respiratory support and non-oral feeding. This marked a substantial delay in the treatment of patients and the severity of their condition at the time of treatment compared to the STR1VE study and other cohorts.\u003csup\u003e10\u0026ndash;16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn contrast, for our patients with SMA type 2, symptoms began at 8 months, with diagnosis at 14.2 months. These values are consistent with those of the Pediatric Neuromuscular Clinical Research Network cohort for SMA type 2 (onset at 9.6 months and diagnosis at 13.2 months) and other treated cohorts.\u003csup\u003e13, 14, 16, 24\u003c/sup\u003e The age at treatment in our SMA type 2 group was 20.3 months, which represented a delay compared to other treated cohorts.\u003csup\u003e13\u0026ndash;16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe delayed diagnosis and treatment of SMA in our cohort are attributable to several factors. Primarily, the absence of a national newborn screening protocol for SMA significantly hampers early detection, which is crucial for prompt intervention. Additionally, genetic testing for SMA in Thailand is largely limited to tertiary medical centers. It is also not included in Thailand\u0026rsquo;s Universal Coverage Scheme, necessitating referrals for definitive diagnosis and consequently prolonging the process.\u003c/p\u003e \u003cp\u003eThe introduction of SMA gene therapy in Thailand has also faced delays. They are chiefly due to the newness of the authorization process and the logistical challenges associated with the importation and distribution of the treatments. Moreover, other specific SMA treatments, such as nusinersen, are unavailable in Thailand, limiting therapeutic options for patients. These obstacles contribute to the progression of the disease to more advanced stages before effective treatment can be administered.\u003c/p\u003e \u003cp\u003eAddressing these challenges involves enhancing early detection, expediting diagnosis, and improving the accessibility of treatments. Establishing a national newborn screening program for SMA, expanding genetic testing capabilities beyond tertiary centers, and integrating these services into the national Universal Coverage Scheme could significantly mitigate these delays and improve outcomes for SMA patients in Thailand.\u003c/p\u003e \u003cp\u003eAfter receiving gene replacement therapy, our SMA type 1 patients demonstrated gradual improvements in CHOP-INTEND scores; however, no new motor milestones were attained postintervention. There was no statistically significant difference in survival outcomes compared to the historical controls\u003csup\u003e25\u003c/sup\u003e. Critically, all SMA type 1 patients suffered severe adverse events, including fatalities. In contrast, the STR1VE study and other treated cohorts reported enhancements in both motor scores and survival rates, accompanied by a considerably lower incidence of serious adverse events.\u003csup\u003e10\u0026ndash;16\u003c/sup\u003e The treatment delays in our cohort, leading to advanced disease stages at the time of intervention, resulted in less favorable outcomes. These findings emphasize the vital importance of early treatment initiation in SMA patients to optimize its effectiveness and improve patient prognoses.\u003c/p\u003e \u003cp\u003eAll SMA type 1 patients in our study died during the follow-up period. Among these, one patient\u0026rsquo;s death was attributed to community-acquired pneumonia, but the specific causes of death for the other four patients remain unclear. Laboratory tests, including cardiac and liver enzyme tests, indicated no significant abnormalities prior to death. Infections and secretion obstructions are considered potential causes of death; however, the lack of autopsy reports precludes definitive conclusions about whether these were related to gene therapy complications or the natural progression of SMA. This situation underscores the need for healthcare systems that reimburse onasemnogene abeparvovec to acknowledge that, in addition to the lack of significant clinical improvement, serious adverse events such as death may occur. This study contributes to the growing body of evidence suggesting that gene therapy should not be administered to severely ill and intubated patients with SMA type 1, highlighting the complex risk-benefit considerations in this group.\u003c/p\u003e \u003cp\u003eSeveral fatalities have also been reported in other studies involving OA. For instance, in the STR1VE study, which included 63 patients, two deaths occurred at 12 and 171 days posttherapy, both of which were due to respiratory failure.\u003csup\u003e10, 11\u003c/sup\u003e In the Global Managed Access Program, which involved 102 patients, three fatalities related to respiratory complications were recorded between 80 and 106 days after treatment, all related to respiratory complications.\u003csup\u003e22, 26\u003c/sup\u003e Importantly, these deaths were determined to be unrelated to the gene therapy itself.\u003c/p\u003e \u003cp\u003eThe SMA type 2 patients in our study exhibited more favorable outcomes, mirroring findings from other research.\u003csup\u003e13\u0026ndash;16\u003c/sup\u003e Improvements in motor scores were observed over time, and notably, one patient achieved new motor milestones. Additionally, no serious adverse events were reported in these patients, aligning with outcomes documented in similar cohorts.\u003c/p\u003e \u003cp\u003ePosttreatment monitoring in our cohort revealed common adverse events, including transient decreases in platelet counts and instances of hepatitis. The most frequently observed adverse event was mild to moderate anicteric hepatitis, characterized by two peaks of enzyme elevation that did not coincide with any clinical symptoms, consistent with previous studies.\u003csup\u003e10\u0026ndash;16\u003c/sup\u003e No specific treatments were required apart from adjustments to the prednisolone dosage. Despite the observed decrease in platelet counts, none of our patients developed thrombocytopenia, a condition that has been reported in other studies with varying frequencies ranging from 9\u0026ndash;78%.\u003csup\u003e10\u0026ndash;16\u003c/sup\u003e This discrepancy highlights the variability in patient responses to gene therapy and underscores the importance of close clinical and laboratory monitoring to effectively manage and mitigate potential adverse effects.\u003c/p\u003e \u003cp\u003eFurthermore, all patients in our study presented with abnormal baseline cardiac enzyme levels. Despite this, no increases in enzyme levels or clinical cardiac abnormalities were observed posttreatment, consistent with data from other treated cohorts.\u003csup\u003e12\u0026ndash;16\u003c/sup\u003e Several studies have similarly reported elevated plasma levels of cardiac enzymes, including both troponin-I and troponin-T, among SMA patients without any overt cardiac symptoms. One study reported a median troponin-I level of 39.5 ng/L (range 4\u0026ndash;1205 ng/L) and troponin-T levels that were 3\u0026ndash;10 times greater in 16 SMA patients (80\u0026thinsp;\u0026plusmn;\u0026thinsp;39 ng/L, range 43\u0026ndash;143 ng/L), with the highest values noted in SMA type 1 patients.\u003csup\u003e27,28\u003c/sup\u003e Adult studies have indicated increased troponin-T in patients with muscle diseases, suggesting that cardiac troponin-T may be re-expressed during chronic skeletal muscle repair mechanisms. This hypothesis could explain the elevated cardiac enzymes observed in SMA patients despite the absence of cardiac abnormalities.\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNonetheless, this study has limitations, particularly the small sample size, which limits the ability to widely generalize the findings. Moreover, no autopsies were performed on the deceased patients, which would have helped to definitively ascertain whether their deaths were related to the treatment or were a natural progression of the disease. This gap in data is due primarily to the cultural practices prevalent in Thailand.\u003c/p\u003e \u003cp\u003eGiven the uniformly fatal outcomes observed among the advanced SMA type 1 patients in this study, further research within this specific subgroup is not recommended at this time. Our findings underscore the need for careful patient selection and management in future clinical applications of gene therapy for SMA.\u003c/p\u003e \u003cp\u003eThe future of SMA management in Thailand hinges on early diagnosis, which is achievable through the development and implementation of a comprehensive newborn screening program. Further research into the outcomes of early intervention is crucial, as it represents a significant step toward integrating SMA treatment within Thailand\u0026rsquo;s Universal Coverage Scheme. This integration would enhance the quality of life for SMA patients and significantly reduce the overall burden of the disease on the nation.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study presents real-world outcomes of OA therapy in advanced SMA patients within the context of a developing country characterized by delayed diagnoses and restricted access to alternative treatments. Our findings revealed no substantial improvement in motor scores and no enhancement in survival rates, with all SMA type 1 patients succumbing to the disease. Therefore, this investigation underscores the imperative of initiating treatment early in the course of SMA and prompts a reevaluation of the use of OA in advanced SMA type 1 patients, particularly permanently ventilated patients. These results highlight the need for cautious and targeted application of gene therapy in this vulnerable patient population, ensuring that treatment approaches are timely and appropriate.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"624\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAbbreviation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeaning\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eAAV9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eAdeno-associated virus serotype 9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eCHOP-INTEND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eChildren\u0026rsquo;s Hospital of Philadelphia Infant Test of Neuromuscular Disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eHFMSE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eHammersmith Functional Motor Scale\u0026ndash;Expanded\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eHINE-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eHammersmith Infant Neurological Examination\u0026ndash;Module 2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eMFM32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003e32-item Motor Function Measure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eOA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eOnasemnogene abeparvovec\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eRULM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eRevised Upper Limb Module\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eSMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eSpinal muscular atrophy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eSMN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eSurvival motor neuron\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003e\u003cem\u003eSMN1\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eSurvival motor neuron 1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.391025641025642%\"\u003e\n \u003cp\u003eULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"80.60897435897436%\"\u003e\n \u003cp\u003eUpper limit of normal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u0026nbsp;Acknowledgments\u003cbr\u003e\u0026nbsp;\u003c/strong\u003eThe authors gratefully acknowledge Dr Chulaluk Komoltri for her assistance with the statistical analyses, and Ms\u0026nbsp;Tanaporn Netsuwan, Mr Cheewasan Apirukpanakhet, and Ms Naphat Maneesawat for their assistance with the data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT Author Contribution Statement\u003c/strong\u003e\u003cbr\u003ePeerada Pongsakornkullachart:\u0026nbsp;Methodology, Data curation, Investigation, Formal analysis, Writing\u0026ndash;original draft preparation.\u0026nbsp;Pimchanok Kulsirichawaroj:\u0026nbsp;Writing\u0026ndash;review and editing.\u0026nbsp;Ratcharin Kongkasuwan:\u0026nbsp;Conceptualization, Methodology, Investigation, Formal analysis, Validation, Writing-review and editing.\u0026nbsp;Prakarn Tovichien, Settapong Jitwongwai,Supaluck Kanjanauthai, Nutnicha Preeprem, Sivaporn Limpaninlachart, Nisasri Sermpon:\u0026nbsp;Investigation.\u0026nbsp;Oranee Sanmaneechai:\u0026nbsp;Conceptualization, Methodology, Formal analysis, Validation, Writing\u0026ndash;review and editing, Supervision, Project administration.\u0026nbsp;All authors reviewed the results and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Siriraj Institutional Review Board (Si\u0026nbsp;405/2022), also the historical control data was approved by the Siriraj Institutional Review Board (Si\u0026nbsp;860/2021), and the research was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cbr\u003eThis study was funded by the Siriraj Research Department (R016631023)\u0026nbsp;and the Health Systems Research Institute (R016741018).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003cbr\u003eThe authors declare that they have no conflicts of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008 Jun 21;al371(9630):2120-33.\u003c/li\u003e\n\u003cli\u003eFinkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014 Aug 26;83(9):810-7.\u003c/li\u003e\n\u003cli\u003eMercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018 Feb 15;378(7):625-35.\u003c/li\u003e\n\u003cli\u003eGidaro T, Servais L. Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps. Dev Med Child Neurol. 2019 Jan;61(1):19-24.\u003c/li\u003e\n\u003cli\u003eนMendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1713-22.\u003c/li\u003e\n\u003cli\u003eMessina S, Sframeli M. New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges. J Clin Med. 2020 Jul 13;9(7).\u003c/li\u003e\n\u003cli\u003eRatni H, Ebeling M, Baird J, et al. Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Aug 9;61(15):6501-17.\u003c/li\u003e\n\u003cli\u003eCheung AK, Hurley B, Kerrigan R, et al. Discovery of Small Molecule Splicing Modulators of Survival Motor Neuron-2 (SMN2) for the Treatment of Spinal Muscular Atrophy (SMA). J Med Chem. 2018 Dec 27;61(24):11021-36.\u003c/li\u003e\n\u003cli\u003eZolgensma prescribing information 2019 [database on the Internet]2019 [cited November 2020]. Available from: https://www.novartis.com/us-en/sites/novartis_us/files/zolgensma.pdf.\u003c/li\u003e\n\u003cli\u003eMercuri E, Muntoni F, Baranello G, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Oct;20(10):832-41.\u003c/li\u003e\n\u003cli\u003eDay JW, Finkel RS, Chiriboga CA, et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Apr;20(4):284-93.\u003c/li\u003e\n\u003cli\u003eBitetti I, Lanzara V, Margiotta G, Varone A. Onasemnogene abeparvovec gene replacement therapy for the treatment of spinal muscular atrophy: a real-world observational study. Gene Ther. 2023 Aug;30(7-8):592-7.\u003c/li\u003e\n\u003cli\u003eMatesanz SE, Battista V, Flickinger J, Jones JN, Kichula EA. Clinical Experience With Gene Therapy in Older Patients With Spinal Muscular Atrophy. Pediatr Neurol. 2021 May;118:1-5.\u003c/li\u003e\n\u003cli\u003eWei\u0026szlig; C, Ziegler A, Becker LL, et al. Gene replacement therapy with onasemnogene abeparvovec in children with spinal muscular atrophy aged 24 months or younger and bodyweight up to 15 kg: an observational cohort study. (2352-4650 (Electronic)).\u003c/li\u003e\n\u003cli\u003eStettner GM, Hasselmann O, Tscherter A, Galiart E, Jacquier D, Klein A. Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study. BMC Neurol. 2023 Feb 28;23(1):88.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Silva AM, Holland S, Kariyawasam D, et al. Onasemnogene abeparvovec in spinal muscular atrophy: an Australian experience of safety and efficacy. Ann Clin Transl Neurol. 2022 Mar;9(3):339-50.\u003c/li\u003e\n\u003cli\u003eSanmaneechai O. Pediatric Neuromuscular Diseases Prevalence in Siriraj Hospital, Thailand\u0026apos;s Largest Tertiary Referral Hospital. Siriraj Medical Journal. 2020 04/27;72:125-31.\u003c/li\u003e\n\u003cli\u003eJongpiputvanich S, Norapucsunton T Fau - Shuangshoti S, Shuangshoti S. Muscle disorders in pediatric patients in King Chulalongkorn Memorial Hospital. (0125-2208 (Print)).\u003c/li\u003e\n\u003cli\u003eMercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018 Feb;28(2):103-15.\u003c/li\u003e\n\u003cli\u003eFinkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018 Mar;28(3):197-207.\u003c/li\u003e\n\u003cli\u003eChand D, Mohr F, McMillan H, et al. Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy. J Hepatol. 2021 Mar;74(3):560-6.\u003c/li\u003e\n\u003cli\u003eDay JW, Mendell JR, Mercuri E, et al. Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug Saf. 2021 Oct;44(10):1109-19.\u003c/li\u003e\n\u003cli\u003eChand DH, Sun R, Diab KA, Kenny D, Tukov FF. Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings. Gene Ther. 2023 Sep;30(9):685-97.\u003c/li\u003e\n\u003cli\u003eKaufmann P, McDermott MP, Darras BT, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012 Oct 30;79(18):1889-97.\u003c/li\u003e\n\u003cli\u003eSittiyuno P, Kulsirichawaroj P, Leelahavarong P, Sanmaneechai O. Survival analysis and life expectancy of pediatric patients with spinal muscular atrophy in Thailand. Heliyon. 2024 2024/06/15/;10(11):e32732.\u003c/li\u003e\n\u003cli\u003eChand DH, Mitchell S, Sun R, LaMarca N, Reyna SP, Sutter T. Safety of Onasemnogene Abeparvovec for Patients With Spinal Muscular Atrophy 8.5 kg or Heavier in a Global Managed Access Program. Pediatr Neurol. 2022 Jul;132:27-32.\u003c/li\u003e\n\u003cli\u003eJohannsen J, Weiss D, Driemeyer J, et al. High-sensitive cardiac troponin I (hs-cTnI) concentrations in newborns diagnosed with spinal muscular atrophy. Front Pediatr. 2023;11:1259293.\u003c/li\u003e\n\u003cli\u003eIlle A, van Egmond-Fr\u0026ouml;hlich A, Weiss S, et al. SMA THERAPIES II AND BIOMARKERS: P. 265Patients with spinal muscular atrophy without cardiac disease show elevated cardiac troponin T. Neuromuscular Disorders. 2018;28:S111-S2.\u003c/li\u003e\n\u003cli\u003edu Fay de Lavallaz JA-O, Prepoudis AA-O, Wendebourg MA-O, et al. Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T. (1524-4539 (Electronic)).\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"gene-therapy","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"gt","sideBox":"Learn more about [Gene Therapy](http://www.nature.com/gt/)","snPcode":"41434","submissionUrl":"https://mts-gt.nature.com/cgi-bin/main.plex","title":"Gene Therapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Gene therapy, Onasemnogene abeparvovec, Spinal muscular atrophy","lastPublishedDoi":"10.21203/rs.3.rs-4555695/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4555695/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eSupported by encouraging trial outcomes, onasemnogene abeparvovec (OA) was authorized for treating spinal muscular atrophy (SMA) in children under 2 years of age. Nevertheless, the efficacy of OA in advanced SMA patients remains underexplored. This investigation assessed the clinical effectiveness and adverse effects of OA in a patient cohort including those with advanced SMA, and compared these outcomes to historical survival data for SMA type 1 patients in Thailand.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted an observational cohort study at Siriraj Hospital, Thailand, from May 2019 to April 2022. The study enrolled eight SMA patients receiving OA therapy. We monitored safety through laboratory tests and clinical evaluations. Patient outcomes, such as motor scores, motor milestones, and survival status, were analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe cohort comprised five SMA type 1 patients treated at median age of 16.7 months (6.5\u0026ndash;24.9 months) and three SMA type 2 patients treated at median age of 20.3 months (19\u0026ndash;31.5 months). Before receiving OA, all type 1 patients needed invasive ventilation and nutritional support by feeding tubes. Posttreatment, these patients did not achieve new motor milestones, their survival rates remained static, and each patient experienced severe adverse events, including fatalities. Conversely, type 2 patients exhibited improved motor scores without experiencing serious adverse events.\u003c/p\u003e\u003ch2\u003eInterpretation:\u003c/h2\u003e \u003cp\u003eThis real-world evaluation revealed that OA did not significantly improve outcomes or survival rates among advanced SMA type 1 patients, with all such cases resulting in mortality. These findings suggest the need for additional caution and revised guidelines when administering OA to this subgroup.\u003c/p\u003e","manuscriptTitle":"Fatal outcomes following onasemnogene abeparvovec in advanced-stage spinal muscular atrophy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-26 12:31:07","doi":"10.21203/rs.3.rs-4555695/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-10-31T10:08:25+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-10-22T18:55:13+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-10-10T03:22:49+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-08-04T15:25:42+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-07-29T01:19:13+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-07-23T11:07:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-10T10:47:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-10T10:46:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Gene Therapy","date":"2024-06-10T04:24:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"gene-therapy","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"gt","sideBox":"Learn more about [Gene Therapy](http://www.nature.com/gt/)","snPcode":"41434","submissionUrl":"https://mts-gt.nature.com/cgi-bin/main.plex","title":"Gene Therapy","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"69a6af12-fa11-4d99-b31c-07f34fbff3d5","owner":[],"postedDate":"August 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-04-24T07:10:41+00:00","versionOfRecord":{"articleIdentity":"rs-4555695","link":"https://doi.org/10.1038/s41434-025-00535-8","journal":{"identity":"gene-therapy","isVorOnly":false,"title":"Gene Therapy"},"publishedOn":"2025-04-23 04:00:00","publishedOnDateReadable":"April 23rd, 2025"},"versionCreatedAt":"2024-08-26 12:31:07","video":"","vorDoi":"10.1038/s41434-025-00535-8","vorDoiUrl":"https://doi.org/10.1038/s41434-025-00535-8","workflowStages":[]},"version":"v1","identity":"rs-4555695","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4555695","identity":"rs-4555695","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}