September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Mitochondria targeted gene therapy for Leber Hereditary Optic Neuropathy (LHON).
Author Affiliations & Notes
  • John Guy
    Bascom Palmer Eye Institute, Miami, Florida, United States
  • Footnotes
    Commercial Relationships   John Guy, inventor (P)
  • Footnotes
    Support  Funding/Support: Supported by the National Eye Institute, National Institutes of Health, Department of Health and Human Services. Grant numbers: 1U10EY023558-01A1, 1U10EY024247-01, R01 EY017141 EY012355
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      John Guy; Mitochondria targeted gene therapy for Leber Hereditary Optic Neuropathy (LHON).. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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

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Presentation Description : Our laboratory has developed techniques and animal models directed towards treating patients with visual loss from Leber hereditary optic neuropathy caused by the G11778A mutation in mitochondrial DNA. Since there had been no way to import DNA into the mitochondria we adopted an approach coined “allotopic expression” for the nuclear approach.For the nuclear approach we used the allotopic technology of recoding a mitochondrial gene in the nuclear genetic code and redirecting the cytoplasmically synthesized protein to the mitochondria. This was necessary because the technology to introduce DNA to mitochondria did not exist. Recoding the ND4 gene was necessary because using the mitochondrial gene specifying the ND4 subunit of complex I expressed in the nucleus and cytoplasm would result in a short polypeptide of approximately 10 amino acids as the TGA encoding for tryptophan in the mitochondria is a stop codon in the nucleus. The ND4 protein is composed of 340 amino acids. This approach is now in phase I clinical trials.
We later developed an entirely independent way to express genes in the mitochondria by developing the technology to actually import DNA into mitochondria.Vector production targeted to the mitochondria utilizes a modified AAV (VP2) capsid into which a mitochondrial targeting sequences is added to the viral shell to deliver its gene a normal ND4 into the mitochondria. Translation is driven by a mitochondrial heavy strand promoter (HSP). Using this technology we developed transgenic mice expressing the mutant G11778A ND4 and reversed visual loss with injection of the wild-type allele. Our gene therapy approaches may some day prove useful to LHON patients.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.


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