831 Adeno-associated virus gene therapies in neurology: an update on the need for consistent safety monitoring of a promising treatment

Abstract

<h3></h3> A Systematic Review of Adeno-Associated Virus Gene Therapies in Neurology: An Update on The Need for Consistent Safety Monitoring of a Promising Treatment. Objective: Adeno-Associated Virus (AAV) gene therapies are generating much excitement in the rare disease field, particularly for previously untreatable neurological conditions. Efficacy has been claimed for several gene therapy products and the number of trials is rapidly increasing. However, reports of serious treatment-related adverse reactions are emerging, including death. Thrombotic Microangiopathy is now a recognised risk of these therapies, but its prevention and treatment remain incompletely understood. Other emerging adverse events are even less well characterised and information on prevention, monitoring and treatment is urgently needed. We therefore undertook to systematically review publicly available data on AAV gene therapies for neurological disorders in order to collate existing information on both safety and efficacy. <h3>Methods</h3> We searched Ovid Medline, Ovid Embase and Cochrane CENTRAL. The protocol is registered on PROSPERO, CRD- 42021226944. We also performed hand searches including forward and backward reference searching, and searching for relevant indexed studies on clinicaltrials.gov between December 2020 and April 2021. The initial search was conducted on 16.12.2020, and an updated version was conducted on 26.03.2020. A repeat search on clinicaltrials.gov was conducted on 06/04/2021 and again on 16/08/2021. Experts were consulted. Titles and abstracts were independently screened for inclusion by R.H.H and D.S. A risk of bias assessment was performed using the tool from the American Academy of Neurology. The search and results will be updated prior to presentation at the conference. <h3>Results</h3> Overall, we identified 61 trials for 52 AAV gene therapy products delivered systemically or directly into the CNS which met our inclusion criteria. Serious adverse events have been reported with 13 products, including seven deaths of four different suspected causes with four of these products. Most of these were not published or systematically appraised in peer review journals and information about monitoring, prevention and treatment remains incomplete. <h3>Conclusions</h3> The mechanisms of the serious treatment associated adverse events remain incompletely understood. As more trials emerge and participants are dosed, there is a real risk of further potentially fatal harm. There is therefore an urgent need to collaborate across sponsors in order to better understand, treat and prevent significant adverse events.