Evaluation of the Toxicity and Efficacy of an Adeno-Associated Viral Vector Expressing BEST1 Delivered by Subretinal Injection in a Canine Model of Human Bestrophinopathy.

To treat patients affected with bestrophinopathies caused by mutations in the BEST1 gene, a recombinant adeno-associated virus vector (OPGx-BEST1 or rAAV2/2-VMD2-BEST1) is being developed. The vector construct includes the human BEST1 cDNA under control of the VMD2/BEST1 promoter and is packaged in an AAV2 capsid. This study evaluated the efficacy and toxicity of OPGx-BEST1 administered by subretinal injection in dogs that were homozygous mutant or compound heterozygotes for 3 naturally occurring mutations in BEST1. Twelve BEST1-mutant dogs were divided into 4 groups of 3 animals each, and they received in their left eye a subretinal injection of 0.15 mL of OPGx-BEST1 at 1 of 3 concentrations (9.5 × 109 vector genome [vg]/mL; 3.0 × 1010 vg/mL; or 3.0 × 1011 vg/mL) of OPGx-BEST1, resulting, respectively, in a low (1.4 × 109 vg), high (4.5 × 109 vg), and highest (4.5 × 1010 vg) dose or vehicle control. The right eyes were not injected. Subretinal injections were well tolerated and were not associated with any systemic or ocular toxicity. Electroretinography showed improved rod- and cone-mediated responses in eyes treated with OPGx-BEST1. Noninvasive retinal imaging by optical coherence tomography showed improved structural integrity with a reduction or prevention of appearance of vitelliform lesions and reversal of microdetachments in the retinal areas treated with OPGx-BEST1. These results support the use of OPGx-BEST1 in clinical studies with patients affected with bestrophinopathies and define the no-observed-adverse-effect level at 4.5 × 1010 vg/eye (0.15 mL, 3.0 × 1011 vg/mL).