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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Agarwal, Neeraj
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
Zip Code