AAV8-PDE6B with 3’UTR provides rescue of photoreceptor structure and function in the rd10 mouse model of retinitis pigmentosa

Retinitis pigmentosa (RP), a leading cause of inherited blindness, results in a subset of cases from phosphodiesterase 6 (PDE6) deficiency. We evaluated a novel gene therapy construct, AAV8-RK-PDE6B-3'UTR, in the rd10 mouse model which has a homozygous missense variant that disrupts the function of the β-subunit of PDE6. The construct utilises a rhodopsin-kinase promoter, human PDE6B cDNA, and a PDE6B 3' untranslated region (3'UTR), which was delivered subretinally at postnatal day 12 (P12). Treated mice showed sustained preservation of retinal function and structure for up to 15 months, as confirmed by visual acuity (VA), electroretinography (ERG), optical coherence tomography (OCT), and immunohistochemistry. This represents the longest functional and structural follow-up reported for AAV-mediated PDE6B gene supplementation in the rd10 model. Inclusion of the PDE6B 3'UTR increased PDE6B expression in vitro and improved functional rescue in four week post-therapy testing. These data indicate that the combination described here of vector capsid type and promoter specific to photoreceptors, along with PDE6B 3'UTR sequence may provide benefit in therapeutic effect in PDE6B gene therapy.