Introduction: Choroideremia is an X-linked inherited retinal degeneration resulting from mutations in the CHM gene, encoding Rab escort protein-1 (REP1), a protein regulating intracellular vesicular transport. Loss-of-function mutations in CHM lead to progressive loss of retinal pigment epithelium (RPE) with photoreceptor and choriocapillaris degeneration, leading to progressive visual field constriction and loss of visual acuity. Three hundred and fifty-four unique mutations have been reported in CHM. While gene augmentation remains an ideal therapeutic option for choroideremia, other potential future clinical strategies may exist. Areas covered: The authors examine the pathophysiology and genetic basis of choroideremia. They summarize the status of ongoing gene therapy trials and discuss CHM mutations amenable to other therapeutic approaches including CRISPR/Cas-based DNA and RNA editing, nonsense suppression of premature termination codons, and antisense oligonucleotides for splice modification. The authors undertook a literature search in PubMed and NIH Clinical Trials in October 2020. Expert opinion: The authors conclude that AAV-mediated gene augmentation remains the most effective approach for choroideremia. Given the heterogeneity of CHM mutations and potential risks and benefits, genome-editing approaches currently do not offer significant advantages. Nonsense suppression strategies and antisense oligonucleotides are exciting novel therapeutic options; however, their clinical viability remains to be determined.
Expert Opin Orphan Drugs
13 - 24
AAV, CHM, CRISPR, Choroideremia, REP1, antisense oligonucleotides, gene therapy, nonsense suppression