TIMP3 mutations are associated with early-onset macular choroidal neovascularisation for which no treatment currently exists. CRISPR base editing, with its ability to irreversibly correct point mutations by chemical modification of nucleobases at DNA level, may be a therapeutic option. We report a bioinformatic analysis of potential therapeutic options in a patient presenting with Sorsby fundus dystrophy. Genetic testing in a 35-year-old gentleman with bilateral macular choroidal neovascularisation revealed the patient to be heterozygous for a TIMP3 variant c.610A>T, p.(Ser204Cys). Using a glycosylase base editor (GBE), another DNA-edit could be introduced that would revert the variant back to wild-type on amino acid level. Alternatively, the mutated residue could be changed to another amino acid that would be better tolerated, and for that, an available 'NG'-PAM site was found to be available for the SpCas9-based adenine base editor (ABE) that would introduce p.(Ser204Arg). In silico analyses predicted this variant to be non-pathogenic; however, a bystander edit, p.Ile205Thr, would be introduced. This case report highlights the importance of considering genetic testing in young patients with choroidal neovascularisation, particularly within the context of a strong family history of presumed wet age-related macular degeneration, and describes potential therapeutic options.
Keywords: CRISPR; TIMP3; age-related macular degeneration; base editing; genetics; inherited retinal dystrophy; macular choroidal neovascularisation.