Many ocular disorders occur due to problems in the mitochondria, the “powerhouses” of the cell, who manage the production of energy. The retina is particularly susceptible to mitochondrial malfunction due to its high metabolic demand.
The study shows how the ophNdi1 gene therapy can boost the mitochondrial function in retinal ganglion cells, the cells dysfunctional in diseases such as glaucoma. The way this gene therapy works is by using the AAV-ophNdi1 virus to access the defective retinal cells and deliver the gene needed to enable mitochondria to generate extra energy and continue their function in supporting vision.
“Because a loss of retinal ganglion cells leads to sight loss in many conditions including inherited optic neuropathies and glaucoma, we are excited that this potential therapeutic approach could provide benefit to many patients in the future,” said Dr Naomi Chadderton, first author of the research article and a scientist in Trinity’s School of Genetics and Microbiology. “Our study shows that ophNdi1 is protective in three models of mitochondrial dysfunction. Notably, the optimisation of the therapy, which is outlined in the study, allows for use of a lower therapeutic dose.”
The experiments showed that it improved the sight in vision impaired mice and was efficient when tested in cells from LHON patients, meaning that it could be a candidate therapy for ocular disorders where mitochondrial deficits comprise an important feature. The results are consistent with previously published ones by the same group, showing benefit in age related macular degeneration (AMD) models and highlighting the potential value of ophNdi1 for multiple eye diseases.
The current therapy is not yet ready to be administered to patients but the researchers hope that with some further studies it can be applicable to humans as well. As they mention in the publication, “AAV gene therapy for ocular disease has become a reality with the market authorisation of LuxturnaTM for RPE65-linked inherited retinal degenerations and many AAV gene therapies currently undergoing phase III clinical trials.”
Professor Jane Farrar, senior author of the research article and Professor in Trinity’s School of Genetics and Microbiology, said: “Our work provides clear evidence supporting using this novel gene therapeutic approach for multiple eye disorders. It also suggests that the ophNdi1 therapeutic platform targeting mitochondrial dysfunction could have applications for other devastating conditions beyond the eye in which mitochondrial dysfunction is in play.”
This study was published in the journal Pharmaceutics and the research was funded by Science Foundation Ireland, the Health Research Board, Enterprise Ireland, Fighting Blindness Ireland and the Irish Research Council.