The decline of motor and cognitive function in aging finds an extreme manifestation in the form of sarcopenia and senile dementia, most commonly of the Alzheimer's type. Both are associated with mitochondrial dysfunction. In sarcopenia there is accumulation of mitochondrial DNA (mtDNA) deletions and loss of oxidative capacity in the muscle. In the Alzheimer's brain, there is accumulation of pathological forms of beta- amyloid and tau which suppress oxidative metabolism that eventually may cause loss of neurons. Experimental upregulation of oxidative metabolism in transgenic mice achieved by overexpression of the human mitochondrial transcription factor (TFAM) results in reduced brain aging, preservation of cognitive and cardiac function, motor performance and endurance and improved hippocampal LTP [Hayashi et al, 2008]. If mitochondrial oxidative capacity could be safely increased in aging, many of the phenotypes resulting from mitochondrial suppression could be mitigated. In conjunction with the Center for the Study of Neurodegenerative Disease (CSND) at the University of Virginia, in a Phase II STTR, Gencia Corporation successfully utilized an injectable recombinant human mitochondrial transcription factor A (rhTFAM) to treat mitochondrial dysfunction in aged mice. Data from the on-going Phase II studies show that aged mice treated over the course of 6 months (starting at 24 months) with rhTFAM therapy have improved motor function as well as lower incidence of liver neoplasms. At 30 months the treated mice have significantly increased motor performance and endurance (by 25% in rotarod testing) versus age-matched controls and reduced body weight (by 10%) despite increased food-intake (by nearly 200%) over the course of the 6 month study. Mitochondrial function and metabolism are significantly increased in animals treated with rhTFAM, without noticeable deleterious side-effects. This is the first mitochondrial therapeutic shown in normal aged animals to reverse age-related mitochondrial suppression and to improve correlates of mitochondrial function such as endurance. In this Phase II Continuation, Gencia Corporation and the CSND propose to conduct the following pre- clinical Investigational New Drug (IND)studies for the FDA/CDER (Center for Drug Evaluation and Research): (i) Rat CNS (Irwin study), respiratory, dose range finding, and repeat dose 1 month;(ii) Dog cardiovascular, dose range finding, repeat dose 1 month. Upon completion of the IND application and approval by CDER, Phase I clinical studies would begin in humans for the indications of AD and Sarcopenia. Given widespread mitochondrial dysfunction in aging, mitochondrial upregulation using rhTFAM may find additional applications in the treatment of type II diabetes, cancer, and Parkinson's disease.

Public Health Relevance

The proposal will support completion of a preclinical program and an IND filing with the FDA/CDER (Center for Drug Evaluation and Research) for the rhTFAM therapeutic as a treatment for Alzheimer's Disease(AD). AD is the most common form of dementia. In 2008, 5 million people are estimated to suffer from Alzheimer's disease in the US alone. The disease is incurable and represents the 6th leading cause of death in the United States. As a degenerative disease, AD places a significant burden on caregivers and is therefore, one of the most economically costly diseases to society. The potential impact on public health is significant.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Technology Transfer (STTR) Grants - Phase II (R42)
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Special Emphasis Panel (ZRG1-ETTN-H (13))
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Chen, Wen G
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Gencia Corporation
United States
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