A 1-Month Toxicology and Biodistribution NHP Pilot Study Evaluating a Single Subretinal Bilateral Administration of SPVN06 - A Novel AAV-Based Gene Therapy for the Treatment of Rod-Cone Dystrophies Agnostic of the Causative Mutation

Abstract

Purpose : Rod-Cone dystrophies (RCD) are inherited neurodegenerative diseases characterized by an initial loss of rod photoreceptors (rods) followed by loss of cone photoreceptors (cones) eventually causing blindness. Greater than 1.5 million individuals worldwide are affected by RCD with >65 genes identified. The NXNL1 gene encodes 2 proteins produced by rods, rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, also expressed by cones, that support cone survival by promoting glycolysis and preventing oxidative damage, respectively. SPVN06 is a novel AAV-based drug candidate encoding both human RdCVF and RdCVFL within the same vector. A single subretinal administration of SPVN06 is expected to protect against cone degeneration in RCD patients independent of the causative mutation. SPVN06 nonclinical safety was evaluated in a 1-month pilot toxicology and biodistribution study in non-human primates.

Methods : Four female cynomolgus monkeys received a bilateral subretinal injection of vehicle (n=1) or SPVN06 (n=3) at 1 x 10¹¹ vg/eye (100 μL). The animals were observed for one month. A limited toxicological assessment was conducted to assess systemic and ocular safety. Parameters evaluated included clinical observations, body weights, clinical pathology, organ weights and macroscopic observations. Ocular, brain, and liver tissues were microscopically assessed. A comprehensive ocular evaluation including indirect ophthalmoscopy, slit lamp biomicroscopy, intraocular pressure (IOP) measurements, fundus imaging, optical coherence tomography (OCT) and full-field electroretinography (ffERG) was conducted.

Results : There were no systemic effects on any of the parameters assessed. Ophthalmoscopic and microscopic observations were characterized by only minimal posterior uveitis and localized RPE hypertrophy confined to the dose site.

Conclusions : This one-month toxicology and biodistribution pilot study in NHP demonstrated that SPVN06 is well tolerated at 1 x 10¹¹ vg/eye, 100 µL, following subretinal administration. This study is informing the nonclinical development of SPVN06, a novel AAV-based drug candidate, expected to prevent cone degeneration in RCD patients independent of the causative mutation.

This is a 2021 ARVO Annual Meeting abstract.