New genetic therapy approaches for inherited retinal diseases

Inherited retinal diseases, including retinitis pigmentosa and Leber congenital optic neuropathy (LHON) are the leading cause of untreatable blindness in the younger 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 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. Lastly, the project aims to explore the possibility of using an innovative gene editing technique called CRISPRa, to activate patients' own copies of genes and make them express light-detecting proteins in surviving retinal cells with potential to restore vision.

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.

Inherited retinal diseases, including retinitis pigmentosa and Leber congenital optic neuropathy (LHON) are the leading cause of blindness in the younger population in developed countries. Retinitis pigmentosa is caused my mutations in genes in outer retinal cells that ultimately lead to the loss of photoreceptors but the inner retinal cells, such as retinal ganglion cells (RGCs) remain intact. LHON is caused by mutations in mitochondrial genes that primarily affect the ganglion cells. There is no cure for these diseases. After loss of photoreceptors, optogenetic therapy aims to introduce light sensitive proteins to surviving cells of the retina, including RGCs, and confer ability to detect light. For patients with LHON, a promising strategy for the treatment of mitochondrial mutations in RGCs is allotopic expression-based gene therapy via intravitreal delivery of adeno-associated viral (AAV) vectors. However, efficient targeting of RGCs with therapeutic vectors has not been achieved to date.

Herein, we aim to develop a surgical procedure using a robot to more effectively target the cells of the inner retina. The procedure will involve robot-assisted 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 AAV gene delivery platforms by optimising mitochondrial delivery for LHON applications and by restricting transgene expression to soma and dendrites of RGCs, for optogenetic applications. Lastly, we aim to explore the possibility of activating endogenous opsins in RGCs using a gene editing tool, CRISPRa, as an alternative novel strategy for optogenetic therapy. The approaches have potential to lead to treatment of optic neuropathies and any late stage retinal degeneration.