Inherited retinal degenerations (IRDs), such as retinitis pigmentosa and multifactorial ocular diseases, such as AMD represent the most frequent cause of visual impairment in the developed world. For example, in Ireland, approximately 300,000 people are affected by these conditions. While the genetic cause is known for many of the ~300 forms of IRDs and in principle could be treated by individual gene therapies, this approach may not be feasible for many IRDs. Multifactorial diseases are influenced by multiple genetic and environmental risk factors, and therefore may not be readily amenable to targeted gene therapies.
Advances in understanding the pathomechanisms of ocular diseases has revealed common cellular pathways of disease that are shared between many forms of IRDs and multifactorial ocular diseases. Such pathways include oxidative stress, mitochondrial dysfunction and metabolic dysregulation, inflammation, among others. Targeting these pathways in a gene- agnostic (gene-independent) fashion enables broad applicability for multiple ocular conditions including multifactorial diseases, very rare IRDs and those with unresolved genetic causes.
The aim of this study is to explore novel gene-agnostic therapies focused on enhancing mitochondrial function in retinal cells for the treatment of both IRDs and common ocular diseases. We previously demonstrated significant benefit in a variety of AMD and glaucoma murine and cellular models with an AAV-Ndi1 gene therapy. We now propose to use AAV- Ndi1 in two murine models of IRDs. Additionally, modulation of mitochondrial biogenesis with an optimised AAV-PGC-1alpha in cell (including iPSC-derived RPE from AMD patients) and retinal organoid (from IRD patients) models, as well as, in three mouse models of AMD and IRDs is another strategy proposed in this application. While our main focus is to identify candidate gene therapies with high efficacy and broad applicability, we also plan to interrogate the therapeutic mechanisms of some of the proposed candidate therapies.
