Development of gene editing, optogenetic therapy and robotic eye surgery in large animal models

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Genetic eye diseases include retinitis pigmentosa, age-related macular degeneration (AMD) and optic neuropathies. Together, they account for the majority of irreversible sight loss worldwide. At Oxford, we are developing a range of pioneering retinal gene therapies, several of which have reached advanced clinical trials, to treat these blinding diseases by addressing the underlying genetic causes. In this project, we aim to bridge the vital gap between studies in small animal models and humans by investigating these therapies in non-human primates (NHPs), before moving into clinical trials.In retinitis pigmentosa and AMD, light detecting cells called photoreceptors are lost, but other retinal cells such as ganglion cells that transmit impulses to the brain remain intact. In LHON, mutations in mitochondrial genes affect the ganglion cells first, so the signal from the retina cannot be sent to the brain. 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 form of the disease caused by mutations in a specific gene. Gene therapy treatments aim to replace the mutated genes by healthy copies. However, for many patients, mutations are not known and for those who present late, where the photoreceptors have already been loss, gene replacement may not be possible. In these patients, optogenetic therapy is a very promising strategy where light sensitive proteins are expressed in surviving cells of the retina, including ganglion cells, to make them able to detect light and restore vision. However, efficient targeting of these cells with genetic therapies has not been achieved to date. Moreover, as the mitochondria in ganglion cells are affected in LHON, if we can deliver healthy genes to these cells, and in particular to the mitochondria, then there is potential to slow down ganglion cell degeneration and associated loss of vision.In this project we aim to develop a surgical procedure using a robot to more effectively deliver genetic therapies to retinal ganglion cells. The procedure will involve robot-assisted direct infusion into the optic nerve in an animal model, which is currently not possible to perform manually in patients. Having achieved this, we then aim to develop applications for this technique including optogenetic applications and for the treatment of optic neuropathies in future human clinical trials. In addition, the project aims to develop a gene editing system called CRISPR/Cas to knockout or edit human retinal disease-associated genes implicated in AMD. Lastly we aim to assess the efficacy and safety of gene editing in the eye and the immune responses to these new treatments. The approaches have potential to lead to the treatment of a much broader range of blinding diseases. Optogenetic therapy could become a universal treatment and restore vision in any late stage retinal degeneration irrespective of genetic cause. Improved targeting of retinal ganglion cells could lead to potential treatments of LHON and other optic neuropathies including glaucoma, the most common cause of irreversible blindness worldwide. In addition, improved mitochondrial targeting may have implications for treatment of other inherited mitochondrial disease that lead to systemic diseases and involve organs other than the eye.In summary, project will establish the first in UK ocular NHP facility to carry out retinal gene therapy work on par with US and European counterpart academic institutions and facilitate translation of many emerging ocular genetic therapies. This unique platform will enable a wide range of high impact research projects, collaborations both within the UK and internationally, and strengthening the UK's leading role in gene therapy development.