Subretinal gene therapy delays vision loss in a Bardet-Biedl Syndrome type 10 mouse model

Blindness in Bardet-Biedl syndrome (BBS) is caused by dysfunc-tion and loss of photoreceptor cells in the retina. BBS10, muta-tions of which account for approximately 21% of all BBS cases, encodes a chaperonin protein indispensable for the assembly of the BBSome, a cargo adaptor important for ciliary trafficking. The loss of BBSome function in the eye causes a reduced light sensitivity of photoreceptor cells, photoreceptor ciliary malfor-mation, dysfunctional ciliary trafficking, and photoreceptor cell death. Cone photoreceptors lacking BBS10 have congenitally low electrical function in electroretinography. In this study, we performed gene augmentation therapy by injecting a viral construct subretinally to deliver the coding sequence of the mouse Bbs10 gene to treat retinal degeneration in a BBS10 mouse model. Long-term efficacy was assessed by measuring the electrical functions of the retina over time, imaging of the treated regions to visualize cell survival, conducting visually guided swim assays to measure functional vision, and perform-ing retinal histology. We show that subretinal gene therapy slowed photoreceptor cell death and preserved retinal function in treated eyes. Notably, cone photoreceptors regained their elec-trical function after gene augmentation. Measurement of func-tional vision showed that subretinal gene therapy provided a sig-nificant benefit in delaying vision loss.