ICF - Optogenetic gene therapy for restoring vision in retinal degeneration

Inherited retinal diseases (IRDs), including retinitis pigmentosa are the leading cause of untreatable blindness in the working-age population in developed countries. They are caused by genetic mutations that lead to premature loss of cells in the retina that are important for vision. In retinitis pigmentosa, light detecting cells called photoreceptors are lost, but other retinal cells that transmit impulses to the brain remain intact. Significant advances have been made in research to develop genetic treatments for these diseases, and we now have an approved gene therapy treatment, Luxturna, for one rare form of the disease caused by mutations in RPE65 gene, representing 2% of IRDs. Gene therapy treatments aim to replace the mutated genes by healthy copies at early stages of degeneration, using adeno-associated viral (AAV) vectors to deliver these genes to the retina. However, approximately 40% of IRD patients have unknown mutations and 30% present late with photoreceptor loss, so gene replacement may not be possible. In these patients, optogenetic therapy is a promising strategy where light sensitive proteins called opsins are expressed in surviving cells of the retina, such as ON-bipolar cells, to enable them to detect light and restore vision. In this proposal we aim to develop an optogenetic gene therapy product which can be used in a clinical trial and ultimately to treat patients with advanced stage IRDs. To this end, we will draw together our extensive work to date on the three key components of this product (the AAV capsid, the minimal promoter, and the therapeutic gene) to design and validate our optimal therapeutic vector combination. We will test several validated AAV-based vectors, ON- bipolar cell specific promoters and human visual opsins to determine a combination which gives optimal gene expression in our target cells in several preclinical models of healthy and diseased retinas. In addition, we will compare in vivo function of several rhodopsins, which we have modified in structure, and select the one which has greatest ability to follow flickering light stimulation. This has potential to lead to improved quality of the visual scene for the patient, compared to the native rhodopsin protein. Importantly, we will perform studies to demonstrate safety of the therapeutic vector and determine the vector dose for clinical use. Achieving our research objectives has potential to lead to a new optogenetic therapy and ultimately restore vision in patients who are blind from retinal degeneration. The therapy has several advantages over current approaches using microbial channelrhodopsins. Rhodopsin is native to human retina and reduces the risk of any potential toxicity associated with activation of channelrhodopsins. In addition, human opsins operate under physiological light levels so there would be no need to use external goggle devices to deliver special high-intensity light (also potentially toxic to cells) or process images. If successful, this optogenetic therapy could become a universal treatment and restore vision in any patient with advanced retinal degeneration irrespective of genetic cause, with initial market size at conservative estimate around £2 billion/year, with significant growth potential as adoption increases and the therapy demonstrates efficacy and safety. The therapy could also be applicable for more common blinding conditions, such as age-related macular degeneration, which affects 196 million people worldwide. Furthermore, the therapy has potential to act as a platform technology and could target other high burden diseases such as cancer.