First-in-human AAV Gene Therapy for Tay-Sachs Disease

First-in-human AAV Gene Therapy for Tay-Sachs Disease | 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 First-in-human AAV Gene Therapy for Tay-Sachs Disease Miguel Sena-Esteves, Terence Flotte, Oguz Cataltepe, Ajit Puri, and 24 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-195847/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Feb, 2022 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Abstract Tay-Sachs Disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Preclinical work demonstrated safety and efficacy of CNS gene therapy using AAVrh8-HEXA/HEXB. Here we describe an expanded access trial in two patients with infantile TSD (IND 18225). Case TSD-001 demonstrated neurodevelopmental regression by 8 months of age and severe seizures by 1 year was treated at 30 months. An equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB (now AXO-AAV-GM2) was administered intrathecally (IT), with 75% of the dose (1x1014vg) delivered to the cisterna magna and 25% at the thoraco-lumbar junction. The second patient (TSD-002) was treated at 7 months of age with 4.2x1013 vg by a combination of bilateral thalamic (0.18 mL; 1.5x1012vg per thalamus), and IT infusion (3.9x1013vg). Both patients underwent immunosuppression with sirolimus, corticosteroids, and rituximab. Injection procedures were well tolerated and have shown no vector-related adverse events to date. CSF HexA activity nearly doubled from baseline and remained stable. In TSD-002 (now 16 months of age), MRI showed stabilization of disease by 3 months post-injection and appeared to temporarily deviate from the natural history of infantile TSD but declined again 6 months post-treatment. TSD-001 (now 4.5 years of age remains seizure-free on the same anti-convulsant therapy as pre-therapy, but TSD-002 developed seizures between 13 and 17 months posttreatment (by 2 years of age). Administration of AXO-AAV-GM2 by IT and thalamic injections was safe, HexA activity increased in CSF and ongoing myelination was apparent in the younger patient treated at an early symptomatic stage. This study provides early safety and proof-of-concept in humans for treatment of TSD patients by AAV gene therapy. Neurology Neurobiology of Disease case report Tay Sachs disease gene therapy GM2 gangliosidosis AAV 25 adeno-associated virus clinical trial Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Published Journal Publication published 10 Feb, 2022 Read the published version in Nature Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-195847","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":11177846,"identity":"b4d40420-4b85-4375-8f04-a2b979467e7f","order_by":0,"name":"Miguel 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01:50:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-195847/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-195847/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41591-021-01664-4","type":"published","date":"2022-02-10T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":6102053,"identity":"7fae6be6-20da-499a-8ad5-aa8b5a32cf66","added_by":"auto","created_at":"2021-02-18 18:57:29","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":232538,"visible":true,"origin":"","legend":"Longitudinal safety and immunological studies. Serum levels of liver enzymes A)\n alanine aminotransferase (ALT) and B) aspartate aminotransferase (AST) enzymes in TSD-001\n and TSD-002 patients before treatment (Pre-TX), weeks 1, 2, and 3 (W1, 2, 3) and months 1, 2,\n3 and 6 (M1, 2, 3, 6). Shaded bars in A) and B) represent the normal interval for both assays.\n Dashed line in B) indicates the maximum value reported in TSD patients25. C) Total anti-AAVrh8\n IgG in serum quantified by ELISA. In C) the gray squares and lines represent anti-capsid IgG\n levels in serum of an ALS patient treated by IT AAV gene therapy. D) Neutralizing antibody titers\n to AAVrh8 capsid quantified by a transduction assay. Peripheral blood mononuclear cells\n(PBMCs) were isolated from TSD-001 and TSD-002 patients before treatment and at various time\n points thereafter to assess T-cell responses by interferon gamma ELISpot assays using\n stimulation with pools of overlapping peptides spanning E, F) AAVrh8 VP1, or G, H) human HEXA\n and HEXB proteins. Unstimulated or CD3/CD28-stimulated PBMCs were included in all assays\n as negative and positive controls. A-D) TSD-001 data is represented by blue circles and connecting lines, while TSD-002 data is represented by red triangles and connecting lines.","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-195847/v1/3b2d1372135d0506a278c367.png"},{"id":6102297,"identity":"9fe73863-35f3-47bd-9181-ed0f1049c5b1","added_by":"auto","created_at":"2021-02-18 19:00:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":351896,"visible":true,"origin":"","legend":"Longitudinal biochemical and neurological function outcome measures. HexA activity\n was measured in A) cerebral spinal fluid (CSF) and B) serum of TSD-001 (blue bars) and TSD-\n 002 (red bars) patients and non-TSD individuals (gray bars). CSF was collected on treatment\n day prior to infusion (D0), months 3 and 6 (M3, 6). Serum was collected at weeks 1, 2, 3 (W1-3),\n months 2, 3, and 6 (M2, M3, M6). The increase in HexA activity levels in CSF and serum post\ntreatment was statistically significant using a mixed effects model to adjust for repeated measures\n within individual. C) Mass spectrometry quantification of GM2 ganglioside species in CSF at day\n 0, months 3 and 6. TSD-001 data is represented by blue circles and connecting lines. TSD-002\n data is represented by red triangles and connecting lines. D) Western blot analysis of HEXA and\n HEXB protein expression in CSF of TSD-001 and TSD-002 patients at day 0 (D0), months 3 (M3)\n and 6 (M6). Transthyretin (TTR), which is the most abundant protein in CSF, was used as a\n loading control. Arrowheads indicate the location of the bands corresponding to the HEXA andHEXB proteins. E) CHOP-INTEND scores for patients TSD-001 and TSD-002 from 2 days prior\nto treatment until 6 months or 12 months post-treatment.","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-195847/v1/393698f4fb46516b3cc2b8eb.png"},{"id":6102054,"identity":"ff1a0152-4abe-418a-b891-909436ed80d6","added_by":"auto","created_at":"2021-02-18 18:57:29","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1171351,"visible":true,"origin":"","legend":"MRI findings in TSD patients treated with rAAVrh8.HEX/HEXB vectors. A) Thalamic\n targeting in TSD-002. T1 weighted coronal (left panel) and T2 weighted (T2) coronal and axial\n (middle and right panels) MRIs immediately after bilateral thalamic injection. Note injection\nlocations and fluid distribution (yellow arrows). B) Longitudinal MRIs from TSD-001 and TSD-002\n at the time of injection and at 3 and 6 months after treatment. T2 MRI of TSD-001 shows some\n unchanged cortical atrophy and ventricular enlargement and diffusely affected white matter over\n the 6 month period. Color map (CM) of the fractional anisotropy (FA) and radial diffusivity (RD)\n suggest a combination of hypomyelination and myelin loss. The pretreatment MRI for TSD-002\n shows incomplete myelination during infancy as posterior limbs of the internal capsule were not\n myelinated and lacked parietal and occipital myelination. After treatment, the degree of myelination, as shown by the darkening on T2 imaging (B) and FA metrics (C), suggest stabilization over time and potential improvement in the posterior corpus callosum.","description":"","filename":"Fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-195847/v1/58d20de088b36e777fb553d6.png"},{"id":19034963,"identity":"af20d695-89e7-498e-a9ab-eb8a3a8f0efe","added_by":"auto","created_at":"2022-03-09 18:54:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":17223960,"visible":true,"origin":"","legend":"","description":"","filename":"120520FlotteEtalREVISEDNatureMedicinelinenumbers.pdf","url":"https://assets-eu.researchsquare.com/files/rs-195847/v1_covered.pdf"},{"id":13590506,"identity":"3d7f157d-4a48-4ac1-8de2-a41c65e52e7f","added_by":"auto","created_at":"2021-09-17 05:04:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":17219042,"visible":true,"origin":"","legend":"","description":"","filename":"120520FlotteEtalREVISEDNatureMedicinelinenumbers.pdf","url":"https://assets-eu.researchsquare.com/files/rs-195847/v1_covered.pdf"},{"id":6102583,"identity":"8eea609a-fee0-4477-864c-8da38502faf4","added_by":"auto","created_at":"2021-02-18 19:03:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":17082238,"visible":true,"origin":"","legend":"","description":"","filename":"120520FlotteEtalREVISEDNatureMedicinelinenumbers.pdf","url":"https://assets-eu.researchsquare.com/files/rs-195847/v1_stamped.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"First-in-human AAV Gene Therapy for Tay-Sachs Disease","fulltext":[{"header":"Full Text","content":"\u003cp\u003eThis preprint is available for \u003ca href='/article/rs-195847/latest.pdf' target='_blank'\u003edownload as a PDF\u003c/a\u003e.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"case report, Tay Sachs disease, gene therapy, GM2 gangliosidosis, AAV, 25 adeno-associated virus, clinical trial","lastPublishedDoi":"10.21203/rs.3.rs-195847/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-195847/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Tay-Sachs Disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Preclinical work demonstrated safety and efficacy of CNS gene therapy using AAVrh8-HEXA/HEXB. Here we describe an expanded access trial in two patients with infantile TSD (IND 18225).\r\nCase TSD-001 demonstrated neurodevelopmental regression by 8 months of age and severe seizures by 1 year was treated at 30 months. An equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB (now AXO-AAV-GM2) was administered intrathecally (IT), with 75% of the dose (1x1014vg) delivered to the cisterna magna and 25% at the thoraco-lumbar junction. The second patient (TSD-002) was treated at 7 months of age with 4.2x1013 vg by a combination of bilateral thalamic (0.18 mL; 1.5x1012vg per thalamus), and IT infusion (3.9x1013vg). Both patients underwent immunosuppression with sirolimus, corticosteroids, and rituximab.\r\nInjection procedures were well tolerated and have shown no vector-related adverse events to date. CSF HexA activity nearly doubled from baseline and remained stable. In TSD-002 (now 16 months of age), MRI showed stabilization of disease by 3 months post-injection and appeared to temporarily deviate from the natural history of infantile TSD but declined again 6 months post-treatment. TSD-001 (now 4.5 years of age remains seizure-free on the same anti-convulsant\r\ntherapy as pre-therapy, but TSD-002 developed seizures between 13 and 17 months posttreatment (by 2 years of age).\r\nAdministration of AXO-AAV-GM2 by IT and thalamic injections was safe, HexA activity increased in CSF and ongoing myelination was apparent in the younger patient treated at an early symptomatic stage. This study provides early safety and proof-of-concept in humans for treatment of TSD patients by AAV gene therapy.","manuscriptTitle":"First-in-human AAV Gene Therapy for Tay-Sachs Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-02-18 18:57:27","doi":"10.21203/rs.3.rs-195847/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e65cfc0e-d198-40a6-9d0a-ec0b92b7f40c","owner":[],"postedDate":"February 18th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":2492077,"name":"Neurology"},{"id":2492078,"name":"Neurobiology of Disease"}],"tags":[],"updatedAt":"2022-03-09T18:54:42+00:00","versionOfRecord":{"articleIdentity":"rs-195847","link":"https://doi.org/10.1038/s41591-021-01664-4","journal":{"identity":"nature-medicine","isVorOnly":false,"title":"Nature Medicine"},"publishedOn":"2022-02-10 05:00:00","publishedOnDateReadable":"February 10th, 2022"},"versionCreatedAt":"2021-02-18 18:57:27","video":"","vorDoi":"10.1038/s41591-021-01664-4","vorDoiUrl":"https://doi.org/10.1038/s41591-021-01664-4","workflowStages":[]},"version":"v1","identity":"rs-195847","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-195847","identity":"rs-195847","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}