CRISPR VISION Program: Nonviral Genome Editing to Treat Congenital Blindness

Abstract

Purpose : Advances in genetic screening have revolutionized the identification of genetic causes of visual impairment. However, most of these causes are not actionable in the clinic. CRISPR genomic medicine is a rapidly evolving area of biomedical research, with its first clinical approval in 2023. We present our collaborative CRISPR VISION Program for the nonviral delivery of CRISPR-based genome editors to treat a form of Leber Congenital Amaurosis (LCA) and BEST disease as models to facilitate translational research.

Methods : We established a collaborative academic-industry partnership supported by the US National Institutes of Health. We identified three key projects using genomic editing for a KCNJ13 mutation causing LCA16 and BEST1 mutations causing autosomal dominant BEST vitelliform macular degeneration. Delivery of the genomic medicine will be accomplished through nonviral nanoparticle or non-packaged delivery formulations. Two cores are evaluating the safety and efficacy of these formulations within models spanning human bioengineered cell culture systems and non-human primate models. Finally, a regulatory core aims to share our interactions with the FDA and the larger field to accelerate the development of an investigational new drug application for clinical trials by 2028.

Results : Synthetic nonviral delivery of adenosine base editor (ABE) corrected KCNJ13 disease mutation and restored the encoding inwardly rectifying potassium (Kir7.1) channel function. Functional restoration was demonstrated in vitro in retinal pigment epithelium (RPE) derived from human induced pluripotent stem cells (hiPSCs). In mouse models, sustained visual function was observed after subretinal injection of the nanoparticles, with normal electroretinogram wave responses and preserved retinal structure. Furthermore, a distinct nonviral formulation of engineered ribonucleoproteins (eRNPs) resulted in robust editing in the RPE after subretinal injection. . Finally, we registered calcium-activated chloride channel current in Best disease patient hiPSC-RPE as a functional outcome of our genome editing strategy.

Conclusions : We are moving the CRISPR-based medicines into the eye to treat inherited retinal disorders. Our Program could accelerate the development of mutation-specific treatment interventions to match the speed of genetic variant discovery.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.