GENE THERAPY STRATEGIES FOR CORRECTING MONOGENIC RETINAL DISORDERS USING PRECISION EDITING TECHNOLOGIES

Abstract

Background:  Inherited genetic conditions such as monogenic retinal disorders, including retinitis pigmentosa, Leber congenital amaurosis, and Stargardt disease, cause progressive retinal degeneration and irreversible vision loss. Current therapies are not effective in the long term, and therefore there is a need to develop precise and targeted gene correction strategies.

Objective:  Here, we evaluate the precision editing technologies for correcting pathogenic mutations causing monogenic retinal diseases and compare their therapeutic efficacy and safety.

Methods: In this study, we conducted a comparative analysis of CRISPR/Cas9, base editing, and prime editing technologies in retinal organoids, mouse retinal degeneration models, and patient-derived induced pluripotent stem cells (iPSCs). Molecular analysis including qRT-PCR and RNA sequencing, retinal imaging and electroretinography were used to assess editing efficiency and functional rescue.

Findings:  Base editing showed the highest mutation correction efficiency of 85% with minimal off-target effects. CRISPR/Cas9 showed 78% editing efficiency and substantial photoreceptor recovery. Prime editing achieved an 82% correction accuracy with enhanced genomic stability. Treated retinal models showed ~40% enhancement in visual functional response and enhanced retinal cell survival.

Conclusions:  Precision gene editing technologies hold great promise to correct monogenic retinal disorders and restore retinal function, thereby paving the way for the future development of personalized ophthalmic gene therapy.