Intravitreal gene therapy for inherited retinal disease

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Project Summary/Abstract Inherited retinal diseases (IRDs) are a major source of blindness worldwide. These diseases are typically single-gene disorders that result in the degeneration of photoreceptor cells. Historically they have been classified based on the clinical phenotype and electrophysiological results, and then grouped into various disease entities. In the past three decades the genetic basis of many forms of inherited retinal diseases have been discovered leading to the identification of over 270 retinal disease genes. Importantly, the field of medicine and vision science has resulted in an FDA-approved viral mediated gene therapy for IRD associated with mutations in RPE65. Children with this condition are treated with AAV carrying RPE65 delivered to the macula in the subretinal space at the time of vitrectomy. Many other single gene disorders affecting the retina are currently being targeted in various clinical trials, mostly through similar strategies to deliver virus to the macula through the subretinal route. Viral mediated gene therapy administered in this fashion is limited by treatment of only the macular area. Furthermore, it requires intraocular surgery, detachment of the macula from the retinal pigmented epithelium, and carries the risk of sight-threatening surgical complications. Recent studies have demonstrated progressive macular atrophy (retinal cell death) at the site of the subretinal bleb in ~15% of patients receiving this gene therapy within the first year after treatment, suggesting subretinal gene therapy may ultimately cause more harm than good. Therapeutic administration via the intravitreal route is much less invasive, takes place in a clinical setting, and can potentially be repeated to achieve maximal therapeutic effect. However, intravitreal viral mediated gene therapy can be associated with increased inflammation. In addition, native AAVs do not penetrate the retinal layers to transduce photoreceptors efficiently. In this study, we will take advantage of non-human primates with a mutation in PDE6C, a key component of phototransduction, causing electrically silent cone photoreceptors. With a proven effective therapeutic AAV-PR1.7-PDE6C vector in hand, we will compare the efficacy of AAV delivered via the subretinal vs intravitreal route to rescue cone function. Furthermore, we will compare inflammatory reaction between these contexts, determine the active components of the immune system, and define the role of pre- existing anti-AAV antibodies in host animals. We will measure the degree to which the route of delivery and inflammation affects the physiologic rescue. This proposal will advance the field of intravitreal gene therapy for inherited retinal diseases. The aims of this proposal will determine the efficacy of intravitreal compared to subretinal gene therapy, the role of pre-existing circulating antibodies in the host that may mitigate the efficacy of treatment, and the degree to which ocular inflammation affects the visual rescue. Together, the aims of this study will advance the understanding of intravitreal gene therapy and its relationship with ocular inflammation and treatment efficacy.