Robust Comparative Gene Therapy Biodistribution Study Demonstrates Delivery Approach is Important Factor for Optimal CNS Targeting

Results Show ICV and ICM Routes Achieve Broad and Comparable CNS Biodistribution; IT Lumbar, IV Achieve Meaningfully Lower Vector CNS Biodistribution

Study Presented at ASGCT 2021 Underscores Neurogene’s Commitment to Optimize AAV Delivery to Augment Gene Therapy Safety and Efficacy in Neurological Disease

Neurogene Inc., a company founded to bring life-changing genetic medicines to patients and families affected by rare neurological diseases, today announced results of a well-controlled non-human primate study, which demonstrate that route of adeno-associated virus (AAV) administration plays a critical role in optimizing gene therapy delivery to key regions of the central nervous system. These results underscore that the route of delivery is an essential factor in developing effective treatments for genetic neurological diseases. Data were presented virtually today at the 24^th annual meeting of American Society of Gene & Cell Therapy.

The study evaluated the biodistribution of AAV9 in non-human primates in the central and peripheral nervous system, comparing three intra-cerebrospinal fluid (CSF) routes of administration and systemic administration. The study also assessed three ocular delivery approaches. The AAV9 product and the dose were controlled across the delivery groups.

Results demonstrated that choice of delivery method has important implications for AAV9 biodistribution. Notably, intracerebroventricular (ICV) and intracisternal magna (ICM) achieved broad and comparable distribution across most brain regions, as measured by copies of vector DNA in brain tissue. In contrast, intrathecal-lumbar (IT-L) and intravenous (IV) delivery achieved approximately 10-100-fold lower levels of AAV product to these same brain regions. Additional findings in the spinal cord demonstrated that all intra-CSF delivery methods achieved comparable AAV levels, while IV delivery resulted in approximately 100-fold lower AAV levels. Finally, all delivery approaches achieved comparable AAV levels to peripheral nerves. All delivery approaches were well tolerated across treatment groups.

“Further confirming ICV and ICM routes of administration are the most effective approaches for broad targeting of the nervous system has important implications for AAV-based gene therapy delivery choices,” stated Bryan Pukenas, M.D., Assistant Professor of Radiology and a consultant for Neurogene. “These study results contribute to a growing body of data on the influence of delivery choice in the gene therapy field.”

“These data underscore the importance in gene therapy of matching the right route of administration to address the underlying biology of the specific disease to ensure that delivery method achieves optimal vector distribution, while minimizing unnecessarily high doses,” said Rachel McMinn, Ph.D., Founder and CEO of Neurogene. “These findings are good news for patients and families and will help inform the optimal route of administration for specific programs within our portfolio.”

About the Study

The study was conducted in cynomolgus macaques and compared AAV9 biodistribution in the central and peripheral nervous system of four delivery routes (ICV, ICM, IT-L and IV). Biodistribution for three delivery routes (bilateral intravitreal (IVT), suprachoroidal (SCh), or subretinal (SR) injections) were compared in the eye in a separate subset of animals. The study compared the transduction efficiency of a single AAV9 product (AAV9-CLN5) across these different nervous system domains. For the central and peripheral assessments, a dose of 1.1E13vg was administered to each group (N=3 per cohort). A fifth cohort also examined the variable of volume in the delivery. For the ocular routes, a dose of 2.8E11 vg was administered to both eyes (N=2 per cohort). Vector distribution was measured 30 days post AAV administration, using qPCR for central and peripheral tissue and RNAscope^TM for ocular tissue. Results were presented as a digital poster by Suzanne Burstein, Ph.D., Neurogene, Abstract #347. Title: Comparative Non-Human Primate Study to Assess Routes of Administration Targeting AAV9 to Key Nervous System and Ocular Regions.

About Neurogene

Neurogene Inc. is focused on developing life-changing genetic medicines for patients and their families affected by rare, devastating neurological diseases. We partner with leading academic researchers, patient advocacy organizations and caregivers to bring therapies to patients that address the underlying genetic cause of a broad spectrum of neurological diseases where no effective treatment options currently exist. Our lead programs use adeno-associated virus (AAV) vector-based gene therapy technology to deliver a normal gene to patients with a dysfunctional gene. Neurogene is also developing novel gene therapy technologies to advance treatments for complex neurological diseases that conventional gene therapy cannot successfully address. For more information, visit www.neurogene.com.

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