RPE-Directed Gene Therapy Improves Mitochondrial Function in Murine Dry AMD Models

Abstract

Age-related macular degeneration (AMD) is the most common cause of blindness in the aged population. However, to date there is no effective treatment for the dry form of the disease, representing 85–90% of cases. AMD is an immensely complex disease which affects, amongst others, both retinal pigment epithelium (RPE) and photoreceptor cells and leads to the progressive loss of central vision. Mitochondrial dysfunction in both RPE and photoreceptor cells is emerging as a key player in the disease. There are indications that during disease progression, the RPE is first impaired and RPE dysfunction in turn leads to subsequent photoreceptor cell degeneration; however, the exact sequence of events has not as yet been fully determined. We recently showed that AAV delivery of an optimised NADH-ubiquinone oxidoreductase (NDI1) gene, a nuclear-encoded complex 1 equivalent from S. cerevisiae, expressed from a general promoter, provided robust benefit in a variety of murine and cellular models of dry AMD; this was the first study employing a gene therapy to directly boost mitochondrial function, providing functional benefit in vivo. However, use of a restricted RPE-specific promoter to drive expression of the gene therapy enables exploration of the optimal target retinal cell type for dry AMD therapies. Furthermore, such restricted transgene expression could reduce potential off-target effects, possibly improving the safety profile of the therapy. Therefore, in the current study, we interrogate whether expression of the gene therapy from the RPE-specific promoter, Vitelliform macular dystrophy 2 (VMD2), might be sufficient to rescue dry AMD models.

Age-Related Macular Degeneration and Mitochondria-Associated Autoantibodies: A Review of the Specific Pathogenesis and Therapeutic Strategies

“…At the same time, gene therapy targeting mitochondria has also come to our attention. A study used gene therapy to directly boost mitochondrial function via the adeno-associated virus delivery of an optimized NADH-ubiquinone oxidoreductase (NDI1) gene, which provided robust benefits in multiple murine and cellular models of dry AMD [133]. In vitro, with the rescue of mitochondrial morphology and function, the cellular ROS levels and cell viability of primary RPE cells were improved.…”

Alternative oxidase blunts pseudohypoxia and photoreceptor degeneration due to RPE mitochondrial dysfunction

“…Yeast Ndi1 can transfer electrons from NADH to coenzyme Q without proton pumping, thereby bypassing complex I defects in mammalian cells ( 22 , 23 ). Ndi1 expression has beneficial effects in rodent models of Parkinson disease, Leber hereditary optic neuropathy, multiple sclerosis, and AMD ( 24 – 30 ). Alternative oxidase (AOX) is ubiquitous in plants, but absent from mammals, and can transfer electrons from coenzyme Q to oxygen, bypassing the functions of complexes III and IV.…”