June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Gene Therapy for Leber Hereditary Optic Neuropathy
Author Affiliations & Notes
  • Patrick Yu-Wai-Man
    Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, United Kingdom
    Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
  • Footnotes
    Commercial Relationships   Patrick Yu-Wai-Man Chiesi, Code C (Consultant/Contractor), GenSight Biologics, Code C (Consultant/Contractor), Transine Therapeutics, Code C (Consultant/Contractor), Stoke Therapeutics, Code C (Consultant/Contractor)
  • Footnotes
    Support  NIHR Grant NIHR301696
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1345. doi:
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      Patrick Yu-Wai-Man; Gene Therapy for Leber Hereditary Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1345.

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      © ARVO (1962-2015); The Authors (2016-present)

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Presentation Description : Leber hereditary optic neuropathy (LHON) is an important cause of blindness among young adult men. Three pathogenic mitochondrial DNA (mtDNA) variants, namely m.3460G>A (MT-ND1), m.11778G>A (MT-ND4) and m.14484T>C (MT-ND6), account for about 90% of cases, with all of them affecting key subunits of the mitochondrial respiratory chain complex I. The m.11778G>A variant is by far the most common and depending on the population surveyed, it accounts for 60-90% of patients presenting with a LHON phenotype. Gene replacement is an obvious treatment strategy for this classical mitochondrial optic neuropathy, but it has proven challenging due to the difficulty in importing genetic material directly into the mitochondrial compartment. The breakthrough came with the development of allotopic gene expression, which combined with the use of a mitochondrial targeting sequence (MTS), allows the mitochondrial import of a nuclear-encoded protein of the gene of interest. Successful validation of this approach in cellular and animal LHON models led to the launch of clinical studies, including three pivotal phase III randomised controlled trials of rAAV2/2-ND4 gene therapy in patients carrying the m.11778G>A variant and duration of visual loss ≤1 year (RESCUE (NCT02652767), REVERSE (NCT02652780) and REFLECT (NCT03293524)). Treated patients showed a significant improvement in vision to a greater extent than what would be expected based on the natural history of MT-ND4 LHON. Rather unexpectedly, the untreated eye in patients receiving a uniocular intravitreal injection of rAAV2/2-ND4 showed a similar degree and pattern of visual improvement to the treated eye. A non-human primate study found evidence of transfer of viral vector DNA from the injected eye to the non-injected eye, including the anterior segment, retina and optic nerve. Further experimental work is ongoing to explore the contralateral effect observed in clinical trials. Looking towards the future, other therapeutic approaches are being actively considered for LHON, including mutation-independent gene therapy and gene editing.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.


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