Characterization of Immune Responses to rAAVrh8 Gene Therapy for GM2 Gangliosidosis in Phase 1/2 Trial

Characterization of Immune Responses to rAAVrh8 Gene Therapy for GM2 Gangliosidosis in Phase 1/2 Trial | 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 Characterization of Immune Responses to rAAVrh8 Gene Therapy for GM2 Gangliosidosis in Phase 1/2 Trial Allison Keeler, Terence Flotte, Meghan Blackwood, Motahareh Arjomandnejad, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6431041/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Understanding how the immune system responds to adreno-associated virus (AAV) gene therapy and potentially modulating that response is vital to their safety and ultimate success. However, the immune response in the central nervous system (CNS) to AAV gene therapy is still not well understood. Here, we characterized the immune responses to AAVrh8 vectors injected into the thalamus and cerebral spinal fluid (CSF) of Tay-Sachs (TSD) and Sandhoff (SD) disease patients. Nine patients in four dose cohorts were treated with gene therapy while being immunosuppressed with rituximab, sirolimus and prednisolone. Neutralizing antibodies against AAV capsid were detected in the serum of 9/9 patients and in the CSF of 7/9 patients. Specific T-cell responses against the AAV capsid were documented in all patients, with most patients developing responses at 2–3 weeks post-injection. Flow cytometry suggested the induction of capsid-specific regulatory T-cells in the periphery. Local immune responses were detected by cytokine analysis of the CSF along with upregulation of several chemokines, including CXCL8, CXCL9 and CXCL10. These Phase I/II clinical trial data provide valuable insights into how the human immune system responds to direct administration of AAV into the CNS and important assessments on the efficacy of the immune suppression regimen which can be used to inform future AAV clinical trials. Biological sciences/Immunology/Translational immunology Biological sciences/Neuroscience/Diseases of the nervous system Health sciences/Diseases/Neurological disorders/Paediatric neurological disorders Health sciences/Molecular medicine Full Text Additional Declarations There is NO Competing Interest. Ethical oversight of this study was provided by Western Institutional Review Board (Western IRB). The vector is being studied under IND #19314. All versions of the study as amended were approved by the Institutional Biosafety Committee of UMass Chan Medical School, WCG IRB, and Massachusetts General Hospital IRB. All patients were enrolled into this study after informed consent was obtained from their parents/guardians. These trials are registered on clinicaltrials.gov under identifiers NCT04669535 and NCT06614569. Supplementary Files NCOMMS2529701TnrreportingsummaryKeeler.pdf Cite Share Download PDF Status: Posted 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-6431041","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":461702053,"identity":"bc8b2827-4ee5-42ba-86af-843ef5cd591a","order_by":0,"name":"Allison 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