Optimisation of AAV-NDI1 Significantly Enhances Its Therapeutic Value for Correcting Retinal Mitochondrial Dysfunction
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2023Access:
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Chadderton N, Palfi A, Maloney DM, Carrigan M, Finnegan LK, Hanlon KS, Shortall C, O'Reilly M, Humphries P, Cassidy L, Kenna PF, Millington-Ward S, Farrar GJ. Optimisation of AAV-NDI1 Significantly Enhances Its Therapeutic Value for Correcting Retinal Mitochondrial Dysfunction. Pharmaceutics. 2023 Jan 18;15(2):322Download Item:
Abstract:
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. Many ocular disorders have a mitochondrial involvement from
primary mitochondrial disorders such as Leber hereditary optic neuropathy (LHON), predominantly
due to mutations in genes encoding subunits of complex I, to Mendelian and multifactorial ocular
conditions such as dominant optic atrophy, glaucoma and age-related macular degeneration. In
this study, we have optimised the nuclear yeast gene, NADH-quinone oxidoreductase (NDI1),
which encodes a single subunit complex I equivalent, creating a candidate gene therapy to improve
mitochondrial function, independent of the genetic mutation driving disease. Optimisation of NDI1
(ophNdi1) substantially increased expression in vivo, protected RGCs and increased visual function,
as assessed by optokinetic and photonegative response, in a rotenone-induced murine model. In
addition, ophNdi1 increased cellular oxidative phosphorylation and ATP production and protected
cells from rotenone insult to a significantly greater extent than wild type NDI1. Significantly, ophNdi1
treatment of complex I deficient patient-derived fibroblasts increased oxygen consumption and ATP
production rates, demonstrating the potential of ophNdi1 as a candidate therapy for ocular disorders
where mitochondrial deficits comprise an important feature.
Sponsor
Grant Number
Science Foundation Ireland (SFI)
16/IA/4452
Author's Homepage:
http://people.tcd.ie/gjfarrarhttp://people.tcd.ie/phumphrs
Author: Farrar, Gwyneth; Humphries, Peter
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Pharmaceutics;15;
2;
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Full text availableKeywords:
retinal ganglion cell (RGC), mitochondrial dysfunction, LHON, Complex I deficiency, NDI1, Oxidative stress, Neuroprotection, AAV, Gene therapyDOI:
http://dx.doi.org/10.3390/pharmaceutics15020322Metadata
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