Gene augmentation therapies for hereditary retinal degenerations

Abstract

Hereditary retinal degenerations (RDs) caused by thousands of mutations distributed across more than 200 different genes demonstrate vision loss due to dysfunction and/or degeneration of photoreceptors. In ‘pure’ RD, the extent of vision loss is predictable from the loss of quantum catch secondary to the reduced number of photoreceptor cells with shorter outer segments. In complex RD, on the other hand, vision loss is substantially greater than that predicted from remaining photoreceptor structure. RPE65 form of Leber congenital amaurosis (LCA) is an example of a complex RD with a congenital biochemical defect and an onset retinal degeneration in early childhood. Since 2007 we have known that gene augmentation therapy can ameliorate the biochemical defect in patients with RPE65-LCA, result in substantial improvement in light sensitivity, and convert the complex disease more into a pure RD. Long term evaluation of the same patients, however, shows continued progression of retinal degeneration within treated retinal regions at a rate no different than the undisturbed natural history of the RPE65-LCA. These results suggest consideration of a combinatorial therapeutic strategy involving neuroprotective, prosurvival, or antiapoptotic factors or antioxidants together with gene augmentation therapy in order to not only improve function in the short term but also slow retinal degeneration in the long term.