Transduction of gluconeogenic enzymes prolongs cone photoreceptor survival and function in models of retinitis pigmentosa

Abstract

The hereditary nature of many retinal degenerative disorders makes them potentially amenable to corrective gene therapies. Numerous clinical trials are ongoing with the goal to rectify the genetic defect in the afflicted cell types. However, the personalized nature of these approaches excludes many patients for whom the underlying mutation is not mapped, or the number of affected individuals is too few to develop a commercially viable therapy (vide infra). Thus, a therapy that can delay visual impairment irrespective of the underlying genetic etiology can satisfy this unmet medical need. Here, we demonstrate the utility of such an approach in retinitis pigmentosa (RP) by promoting survival of cone photoreceptors by targeting metabolic stress. These cells are not primarily affected by the inherited mutation, but their non-autonomous demise leads to a decline in daylight vision, greatly reducing the quality of life. We designed adeno-associated virus (AAV) vectors that promote gluconeogenesis- a pathway found in the liver which produces glucose in response to hypoglycemia. Retinal transduction with these vectors resulted in improved cone survival and delayed a decline in visual acuity in three different RP mouse models. Because this approach extended visual function independent of the primary mutation, therapies emanating from this approach could be used as a treatment option for a genetically heterogenous cohort of patients.