Researchers from Trinity College in Dublin have found that optimizing NDI1 (ophNdi1), a new potential gene therapy, could be beneficial for multiple eye diseases with mitochondrial deficiencies, including age-related macular degeneration (AMD), glaucoma, and Leber hereditary optic neuropathy (LHON).
Give me some background first.
A previous study conducted by the same group showed the benefit of adeno-associated virus (AAV)-delivered NDI1 by intravitreal injection to protect retinal ganglion cells in a rotenone-induced mouse model of optic neuropathy.
What role does mitochondria play into this?
Mitochondria are membrane-bound organelles known to manage energy production in cells and contain their own DNA (inherited from only the mother). In this study, investigators found that their performance was dampened in patients diagnosed with neurodegenerative disorders inclusive of the retina and optic nerve-related diseases.
Talk about this study.
The research team used silico analyses to modify a total of 329 codons of the yeast-derived NDI1 gene to optimize expression in mammalian cells and codon substitutions to prevent potential immunogenicity, which, as a result, create ophNdi1.
How does ophNdi1 work?
The gene therapy accesses cells where mitochondria failed to deliver a code that revitalized the mitochondria, enhancing energy output and the ability to support visual functions.
What else did they do?
Researchers looked at the effect of AAV-ophNdi1 on patient-derived fibroblasts taken from the biopsies of three male LHON patients. These were compared to sex- and age-matched control fibroblast cell lines of individuals with no history of mitochondrial or visual dysfunction.
What did they find?
When compared to NDI1, ophNdi1 more efficiently decreased reactive oxygen species (ROS) and increased cellular bioenergetics in vitro—counteracting two key causes behind mitochondrial dysfunction.
Evaluation in a mouse model found that intravitreal injection of AAV-ophNdi1 substantially reduced retinal ganglion cell death and, as a result, led to a significant preservation of retinal function.
Anything else?
AAV-ophNdi1 also rescued and reduced adenosine triphosphate (ATP) and oxygen consumption rates observed in LHON patient-derived fibroblasts, showcasing the potential of ophNdi1 as a candidate genetic therapy for ocular diseases associated with mitochondrial deficiencies.
Significance?
Study authors stated their findings support the use of ophNdi1 as a novel gene therapeutic approach for treating multiple eye diseases, as well as suggest that ophNdi1’s therapeutic platform could be a target treatment for other eye diseases plagued by mitochondrial dysfunction.
Further, this could be the next of many logical steps towards the potential development of personalized genetic therapies.