Novel targets for gene therapy in diabetic retinopathy (DR)

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Diabetes affects 8.5% of adults over the age of 18 worldwide. One-third of these are diagnosed with diabetic retinopathy (DR), making it the leading cause of blindness in working-age adults. The underlying causes of DR are difficult to correct and require treatment for years or decades. The hallmarks of DR have recently been linked to early gliotic changes in Müller cells. These important retinal macroglial cells have many supportive functions for neurons and act as a central connecting element within the retinal neurovascular unit. In particular, they help maintain the blood-retinal barrier (BRB), which is impaired in DR, leading to the increased vascular permeability often observed. Therefore, gliotic changes in Müller cells are thought to promote the progression of DR. Since mouse models for DR lack important retinal structures such as the cone rich macular region, the pig offers a better translational model with a cone-rich central retinal area more acurately resembling the human anatomy. Moreover, the genetic insulin deficient INSC94Y model recapitulates key hallmarks of DR pathology and therefore we aim to restore the homeostatic functions of Müller cells in this large animal model of type I diabetes. The project will develop an AAV-based gene therapy approach to reprogram Müller cell metabolism and test it in vitro and in vivo in the INSC94Y pig. The dCas9-VPR-mediated overexpression of key metabolic genes in Müller cells is expected to enhance the homeostatic function of Müller glial cells in the diabetic retina, thereby improving neuronal survival and BRB integrity in DR.