Mutations in mitochondrial DNA lead to a spectrum of neurodegenerative diseases for which no effective treatment exists.This is a group of untreatable disorders affecting the eye, nervous system and heart, some clinically characterized over a century ago, but they are now known to be a spectrum of molecularly defined diseases. We had chosen to start with one of the most severe, the ATP6 mutation (T8993G) in mitochondrial (mt) DNA responsible for Maternally Inherited Leigh Syndrome (MILS), a neurologic disease renowned for causing blindness and rapidly fatal encephalomyelopathy in early childhood or Neurogenic Ataxia and Retinitis Pigmentosa in early adulthood. We have made major strides towards determining the pathogenesis and testing treatments for another common mitochondrial disorder Leber hereditary optic neuropathy (LHON). In this application, we propose to design, modify and test the efficacy and safety of a clinically relevant vector for the treatment of MILS and NARP caused by mutated ATP6.
Our Aims are: (1) To facilitate translational studies for MILS and NARP by developing an MTS AAV serotype 9 vector for intravenous use to deliver the normal ATP6 gene directly to the mitochondria and test expression to rescue respiration in cybrid cells with 100% mutated T8993G mitochondrial DNA. (2) To evaluate biological effects of intravenous delivery of MTS AAV9 vectors in normal mice that result in mitochondrial gene transfer without adverse effects.(3) To rescue visual loss, encephalomyelopathy and death in transgenic ATP6 mice. We hope to identify the conditions for long-term rescue of visual loss and encephalomyelopathy in mice, so that this approach can be tested in a phase I/II clinical designed to restore visual and neurologic function in MILS and NARP patients.

Public Health Relevance

Mutations in mitochondrial DNA lead to a spectrum of neurodegenerative diseases for which no effective treatment exists. We propose to use the AAV vector that has been safely tested in many human clinical trials, to deliver the affected gene to the mitochondria. The AAV cassette accommodates genes of up to approximately 3,300 nucleotides (self-complementary), thus providing a platform for introduction of almost any mitochondrial gene. Thus, our technology is also applicable to treatment of the myriad of diseases caused by mutated mitochondrial DNA included in the category of orphan diseases affecting approximately 25 million Americans.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY027414-01
Application #
9218874
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Agarwal, Neeraj
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
$383,750
Indirect Cost
$133,750
Name
University of Miami School of Medicine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146