Genome editing in the treatment of ocular diseases

Abstract

Genome-editing technologies have ushered in a new era in gene therapy, providing novel therapeutic strategies for a wide range of diseases, including both genetic and nongenetic ocular diseases. These technologies offer new hope for patients suffering from previously untreatable conditions. The unique anatomical and physiological features of the eye, including its immune-privileged status, size, and compartmentalized structure, provide an optimal environment for the application of these cutting-edge technologies. Moreover, the development of various delivery methods has facilitated the efficient and targeted administration of genome engineering tools designed to correct specific ocular tissues. Additionally, advancements in noninvasive ocular imaging techniques and electroretinography have enabled real-time monitoring of therapeutic efficacy and safety. Herein, we discuss the discovery and development of genome-editing technologies, their application to ocular diseases from the anterior segment to the posterior segment, current limitations encountered in translating these technologies into clinical practice, and ongoing research endeavors aimed at overcoming these challenges.

Fig. 1. CRISPR‒Cas9-based genome-editing approaches.

a The CRISPR‒Cas9 system can introduce double-stranded breaks (DSBs) in target DNA. Cells have two repair mechanisms: nonhomologous end-joining (NHEJ) and homology-directed repair (HDR). NHEJ rejoins the cleaved ends of DNA, resulting in deletions or insertions. On the other hand, HDR relies on a template for repair. The template can be donor DNA or a sister chromatid, which is used as a template to copy the correct sequence into the cleaved ends. b Cytosine base editors (CBEs) and adenine base editors (ABEs) are genome-editing tools that introduce specific nucleotide changes without generating DSBs. CBEs result in a C•G to T•A conversion, and ABEs result in an A•T to G•C conversion. c Prime editors (PEs) utilize a Cas9 nickase fused with reverse transcriptase to introduce new DNA sequences at the target locus without generating DSBs. PegRNA, an extended sgRNA containing the template sequence for reverse transcription, directs nucleotide synthesis at the target locus.