Gene therapy strategies for usher syndrome type 1B

Abstract

Usher syndrome type 1B (Usher 1B) is an inherited deaf-blindness disorder, caused by mutations in the MYO7A gene. Newborns with Usher 1 are readily identified due to their congenital profound deafness. Thus, they are prime candidates for gene therapy to treat their ensuing progressive blindness. MYO7A functions in both the retinal pigment epithelium (RPE) and photoreceptor cells, and Myo7a-null mice demonstrate mutant phenotypes in both cell types. Preclinical studies have tested the efficacy of correcting these mutant phenotypes by delivering MYO7A cDNA with different lentiviral and adeno-associated viral vectors, following subretinal injections. Lentiviruses successfully delivered functional MYO7A to both RPE and photoreceptor cells, although the integrating viruses resulted in some variation in expression level, and thus efficacy, from cell to cell. The size of MYO7A cDNA is too large to be packaged by adeno-associated virus (AAV) without fragmentation; however, AAV delivery was nevertheless found to correct the mutant phenotypes. Therefore, although each viral approach has its own limitation, both vectors work to restore functional MYO7A in the mouse retina, and are realistic candidates for use in preventing blindness in Usher 1B patients. © 2012 Springer Science+Business Media, LLC.