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

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.

Genetic eye diseases encompass single gene disorders (retinitis pigmentosa, LHON) and polygenic diseases (AMD and glaucoma). 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 phase III clinical trials. In this proposal, we aim to bridge the gap between studies in small animal models and humans by assessing therapies in non-human primates (NHP), before moving into clinical trials.
Many novel genetic therapies specifically target human genes or human visual system. Primates are the only species with an anatomical macula, packed with cone photoreceptors that degenerate in AMD. Surgical techniques for delivering gene therapies also require optimisation in large animal models prior to first-in-human trials. Specifically, we aim to develop a surgical procedure using a robot to more effectively target the cells of the inner retina by direct infusion into the optic nerve of non-human primates which is currently not possible to perform manually in patients. Following this, we aim to optimise gene delivery platforms for mitochondrial targeting in LHON and ganglion cell delivery for optogenetic applications. The project also aims to develop a CRISPR/Cas gene editing system to knockout or edit human retinal disease-associated genes implicated in AMD and to assess the efficacy and safety of gene editing in the eye and the retinal immune responses to these new treatments.
Both applicants have recently been awarded clinician scientist fellowships to develop these novel genetic therapies in an NHP model and further MRC support for this key equipment is requested to help deliver the goals of the fellowships. The research platform will no doubt facilitate further academic and commercial collaborations and translation of other emerging genetic therapies, strengthening the UK's leading role in gene therapy development.