AAV‐mediated gene therapy improving mitochondrial function provides benefit in age‐related macular degeneration models

Millington‐Ward, Sophia; Chadderton, Naomi; Finnegan, Laura K.; Post, Iris; Carrigan, Matthew; Gardiner, Tom; Peixoto, Elisa; Maloney, Daniel; Humphries, Marian M.; Stitt, Alan W.; Léveillard, Thierry; Humphries, Pete; Kenna, Paul F.; Palfi, Arpad; Farrar, G. Jane

doi:10.1002/ctm2.952

Cited by 5 publications

(19 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We recently reported that aged Cfh −/− mice displayed abnormal cone morphology, with disorganised outer segment membranes. Additionally, cone inner segments contained abnormal mitochondria that were irregular in shape and generally smaller than mitochondria in adjacent rod inner segments [ 38 ]. Others have shown that Cfh −/− mice have decreased plasma C3 levels [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to the Cfh −/− model of dry AMD, chemically-induced models of AMD such as the well-established sodium iodate (NaIO 3 )-induced model [ 41 , 42 , 43 , 44 ] do not require aging. NaIO 3 , a strong oxidising agent, causes catastrophic damage to the RPE, leading to photoreceptor loss and reduced retinal function, including reduced electroretinogram (ERG) amplitudes [ 38 , 43 , 45 , 46 , 47 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

“…Complex 1, a component of the mitochondrial electron transport chain (ETC), is a 45-subunit complex, 7 of which are mitochondrially encoded [ 51 ]. We have recently demonstrated significant therapeutic benefit in a variety of dry AMD models with a gene therapy, ophNdi1 [ 38 ]. OphNdi1 is a modified gene from S. cerevisiae , NDI1, which has been optimised to express more efficiently in mammalian cells (patent no.…”

Section: Introductionmentioning

confidence: 99%

“…Encoded by a single nuclear gene, NDI1 performs a similar function to mammalian mitochondrial complex 1. OphNdi1, delivered subretinally via recombinant adeno-associated virus 2/8 (AAV2/8), was shown to provide significant and robust benefit in the Cfh −/− and NaIO 3 -induced murine models and two cellular models of dry AMD [ 38 ]. The study was the first to show functional benefit in vivo in murine models of dry AMD, using a gene therapy which directly targets mitochondrial dysfunction.…”

Section: Introductionmentioning

confidence: 99%

“…VMD2-ophNdi1 was expressed from recombinant AAV2/8 (AAV2/8-VMD2-ophNdi1; Figure 1 ) and its therapeutic potential was investigated in the Cfh −/− genetic and NaIO 3 -induced murine models of AMD. Primary porcine RPE (pRPE) models of dry AMD were also utilised; these were either insulted with NaIO 3 [ 38 ] or loaded with retinylidene-N-retinylethanolamine (A2E) and insulted with blue light [ 47 ]. A2E is a toxic bisretinoid byproduct of the visual cycle and a major component of drusen, which is known to lead to RPE dysfunction and cell death in vitro and in vivo [ 47 , 54 , 55 , 56 ].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Millington‐Ward

Chadderton

Finnegan

et al. 2023

IJMS

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Millington‐Ward

Chadderton

Finnegan

et al. 2023

IJMS

View full text Add to dashboard Cite

show abstract

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

Chen,

Wang,

Dalal

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Loss of mitochondrial electron transport complex (ETC) function in the retinal pigment epithelium (RPE) in vivo results in RPE dedifferentiation and progressive photoreceptor degeneration, and has been implicated in the pathogenesis of age-related macular degeneration. Xenogenic expression of alternative oxidases in mammalian cells and tissues mitigates phenotypes arising from some mitochondrial electron transport defects, but can exacerbate others. We expressed an alternative oxidase from Ciona intestinalis (AOX) in ETC-deficient murine RPE in vivo to assess the retinal consequences of stimulating coenzyme Q oxidation and respiration without ATP generation. RPE-restricted expression of AOX in this context is surprisingly beneficial. This focused intervention mitigates RPE mTORC1 activation, dedifferentiation, hypertrophy, stress marker expression, pseudohypoxia, and aerobic glycolysis. These RPE cell autonomous changes are accompanied by increased glucose delivery to photoreceptors with attendant improvements in photoreceptor structure and function. RPE-restricted AOX expression normalizes accumulated levels of succinate and 2-hydroxyglutarate in ETC-deficient RPE, and counteracts deficiencies in numerous neural retinal metabolites. These features can be attributed to the activation of mitochondrial inner membrane flavoproteins such as succinate dehydrogenase and proline dehydrogenase, and alleviation of inhibition of 2-oxyglutarate-dependent dioxygenases such as prolyl hydroxylases and epigenetic modifiers. Our work underscores the importance to outer retinal health of coenzyme Q oxidation in the RPE and identifies a metabolic network critical for photoreceptor survival in the context of RPE mitochondrial dysfunction.

show abstract

Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies

Kitaeva,

Solovyeva,

Blatt

et al. 2024

IJMS

View full text Add to dashboard Cite

The improvement of human living conditions has led to an increase in average life expectancy, creating a new social and medical problem—aging, which diminishes the overall quality of human life. The aging process of the body begins with the activation of effector signaling pathways of aging in cells, resulting in the loss of their normal functions and deleterious effects on the microenvironment. This, in turn, leads to chronic inflammation and similar transformations in neighboring cells. The cumulative retention of these senescent cells over a prolonged period results in the deterioration of tissues and organs, ultimately leading to a reduced quality of life and an elevated risk of mortality. Among the most promising methods for addressing aging and age-related illnesses are pharmacological, genetic, and cellular therapies. Elevating the activity of aging-suppressing genes, employing specific groups of native and genetically modified cells, and utilizing senolytic medications may offer the potential to delay aging and age-related ailments over the long term. This review explores strategies and advancements in the field of anti-aging therapies currently under investigation, with a particular emphasis on gene therapy involving adeno-associated vectors and cell-based therapeutic approaches.

show abstract

AAV‐mediated gene therapy improving mitochondrial function provides benefit in age‐related macular degeneration models

Cited by 5 publications

References 10 publications

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

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

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

Eternal Youth: A Comprehensive Exploration of Gene, Cellular, and Pharmacological Anti-Aging Strategies

Contact Info

Product

Resources

About