Abstract

Leber's hereditary optic neuropathy (LHON) is a genetic disease associated with mutations in mitochondrial DNA. The mutation has variable penetrance, but in many cases leads to severe and bilateral loss of vision in young adults. In this revision, the investigator and his senior collaborators propose to test the feasibility of delivering, expressing, and targeting normal gene products to mitochondria with the long-term objective of devising therapies for mitochondrial diseases. A recombinant adeno-associated virus (AAV) bearing a green fluorescent protein (GFP) gene and mitochondrion-specific targeting/processing signal sequences will be used to test whether proteins can be delivered safely, efficiently, and effectively into mitochondria in a cell culture system. This in vitro analysis will be followed by in vivo transduction experiments in which an attempt will be made to deliver a safe dose of a wild type NADH dehydrogenase to mitochondria in the retina and optic nerve of rats.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012355-03
Application #
6384776
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Hunter, Chyren
Project Start
1999-09-30
Project End
2003-08-31
Budget Start
2001-09-30
Budget End
2003-08-31
Support Year
3
Fiscal Year
2001
Total Cost
$356,288
Indirect Cost

  Institution

Name
University of Florida
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611

  Publications

Yu, Hong; Porciatti, Vittorio; Lewin, Alfred et al. (2018) Longterm Reversal of Severe Visual Loss by Mitochondrial Gene Transfer in a Mouse Model of Leber Hereditary Optic Neuropathy. Sci Rep 8:5587
Feuer, William J; Schiffman, Joyce C; Davis, Janet L et al. (2016) Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. Ophthalmology 123:558-70
Yu, Hong; Koilkonda, Rajeshwari D; Chou, Tsung-Han et al. (2015) Consequences of zygote injection and germline transfer of mutant human mitochondrial DNA in mice. Proc Natl Acad Sci U S A 112:E5689-98
Talla, Venu; Porciatti, Vittorio; Chiodo, Vince et al. (2014) Gene therapy with mitochondrial heat shock protein 70 suppresses visual loss and optic atrophy in experimental autoimmune encephalomyelitis. Invest Ophthalmol Vis Sci 55:5214-26
Koilkonda, Rajeshwari D; Yu, Hong; Chou, Tsung-Han et al. (2014) Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol 132:409-20
Qi, Xiaoping; Sun, Liang; Hauswirth, William W et al. (2007) Use of mitochondrial antioxidant defenses for rescue of cells with a Leber hereditary optic neuropathy-causing mutation. Arch Ophthalmol 125:268-72
Qi, Xiaoping; Lewin, Alfred S; Sun, Liang et al. (2007) Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 48:681-91
Qi, Xiaoping; Lewin, Alfred S; Sun, Liang et al. (2006) Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis. J Biol Chem 281:31950-62
Qi, Xiaoping; Lewin, Alfred S; Hauswirth, William W et al. (2003) Optic neuropathy induced by reductions in mitochondrial superoxide dismutase. Invest Ophthalmol Vis Sci 44:1088-96
Qi, Xiaoping; Lewin, Alfred S; Hauswirth, William W et al. (2003) Suppression of complex I gene expression induces optic neuropathy. Ann Neurol 53:198-205

Showing the most recent 10 out of 11 publications