FIGURE 4.

Summary diagram of gene-based therapies currently in clinical use or clinical trials for inherited retinal diseases. (1) AAV-mediated gene replacement therapy is currently the predominant modality, and delivers replacement transgenes (e.g., RPE65), or transgene fragments (dual AAV systems) to produce a functional protein in biallelic autosomal recessive IRDs; (2) CRISPR/Cas9 genome editing requires delivery of CRISPR/Cas9 constructs, most commonly with AAV vector systems, and enables site-directed editing or mutagenesis of IRD target genes (e.g., CEP290); (3) ADAR-mediated RNA editing is used to perform sequence-specific RNA nucleotide edits by utilizing guide DNA or RNA and an ADAR recruitment domain, with either endogenous ADAR or transduced and overexpressed exogenous ADAR enzyme; (4) Antisense oligonucleotides (ASOs) induce sequence specific gene silencing via RNAi, RNase H-mediated mRNA knockdown, or targeted exon skipping (e.g., USH2A exon 13); (5) Optogenetics delivers an engineered phototransducing opsin to a specific retinal cell type (e.g., ganglion cells) to render the cell photosensitive and capable of replacing the light-responsive function of degenerating photoreceptor cells in IRDs.