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A4 - AAV Vectors - Preclinical and Proof-of-Concept In-Vivo Studies (Excluding Non-Human Primates)

19: GABA Selective AAV-Mediated Gene Therapy Provides Durable Seizure Protection in Multiple Refractory Epilepsy Models

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Vectors - Preclinical and Proof-of-Concept: Therapy Focus

Rationale: Epilepsy affects approximately 1% of the population, equating to 3 million individuals in the U.S. Nearly a third of epilepsy cases fail to respond to first- and second-line treatment, leaving patients with persistent and potentially disabling seizures. Antiseizure medications often exhibit a 'honeymoon period' of initial efficacy that diminishes over time and are associated with significant side effects, including organ toxicity, drowsiness, dizziness, and cognitive impacts. Consequently, there is an urgent unmet need for novel treatments to address refractory epilepsies. Genetic targeting of GABAergic neurons to enhance inhibition in an activity-dependent manner has the potential to restore excitatory-inhibitory balance in the brain and reduce seizure burden.
Methods: Using Encoded's vector engineering platform, we identified regulatory elements capable of driving cell-selective transgene expression within GABAergic inhibitory neurons. We coupled these GABA-selective AAV expression cassettes with effector genes with known roles in regulating neuronal excitability and/or neurotransmission. Candidates or vehicle were administered to wild-type mice via intracerebroventricular (ICV) injection on postnatal day 1 and seizure protection was evaluated 7-8 weeks later after chemical or electrical induction. In the 6-Hz model of focal seizures and refractory epilepsy, mice were administered an electric shock to induce seizures and protection was measured within 30 seconds of electrical stimulus. In the Pentylenetetrazole (PTZ) model for tonic-clonic seizures, mice were given a subcutaneous injection of PTZ to induce seizures and protection was measured over 30 minutes.
Results & Conclusions: The top candidate (Candidate 1) showed promising results in the 6-Hz and PTZ models, reducing both seizure incidence and severity. In the PTZ assay, Candidate 1 also prolonged the latency to first convulsive seizure. Our novel AAV-mediated GABA-selective gene therapy approach demonstrated in vivo efficacy across multiple epilepsy models, supporting its potential to provide durable seizure reduction in genetically heterogenous epilepsy populations.
Figure 1. Efficacy of gene therapy Candidate 1 in the PTZ and 6Hz electroshock seizure assay: PND1 ICV delivery of Candidate 1 significantly reduced seizure incidence (Panel A; p=0.0156, Wilson Signed Rank Test), increased latency to first tonic-clonic convulsion (panel B; p=0.0025, Mantel-Cox test), and reduced seizure severity score (Panel C; p=0.039, Mann-Whitney) in the PTZ assay at 7 weeks of age. Additionally, PND1 delivery of Candidate 1 in the 6Hz assay at 8 weeks of age resulted in a significant reduction in both seizure incidence (Panel D; p=0.0143, Chi-square) and seizure severity (Panel E; p=0.0128, Mann-Whitney) when compared with vehicle controls.

Brooke Babineau, Sheila Sears, Jennifer Su, Chao Tai, Keiko Takahashi, Adriana Gonzalez-Sandoval, Annie Tanenhaus, Pingping Jia, Rangoli Aeran, Tselmeg Amarlkhagva, Ming Chen, Dixon Hoffelt, Jason Le, Keith Place, Sammy Liang, Mark Elegue, Suresh Poda, Stephanie Tagliatela

Encoded Therapeutics, South San Francisco, CA"

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