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134th Annual Meeting Works in Progress Abstracts

Neurodegenerative diseases (NDD’s) such as Leber’s hereditary optic neuropathy (LHON), Leigh’s syndrome (LS) and Kearns-Sayres syndrome (KSS) can arise from point mutations (LHON, LS) or deletions (KSS) in mitochondrial DNA (mtDNA). In sporadically occurring NDD’s such as Alzheimer’s (sAD) and Parkinson’s (sPD), mtDNA abnormalities are suspected. Substantia nigra neurons from sPD brains show highly abundant, variably sized mtDNA deletions that contribute to bioenergetic failure. We have developed a protein-mediated transfection (“ProtoFection”) that uses recombinant human mitochondrial transcription factor A (rhTFAM) designed to pass through membranes and target the mitochondrial matrix, either alone or following complex formation with mtDNA. Exposure to rhTFAM -/ intact human mtDNA of LHON or sPD cybrids (based in SH-SY5Y cells), or LS or KSS fibroblasts increased respiration and mitochondrial biogenesis. Normal mice treated with weekly rhTFAM i.v. injections increased abundance of multiple electron transport chain proteins, mitochondrial respiration in brain and skeletal muscle and motor endurance, while showing reduced oxidative stress damage. ProtoFection using rhTFAM increases mitochondrial biogenesis and energetics. While much remains to be elucidated about its pharmacokinetics and pharmacodynamics, ProtoFection holds promise as a treatment for NDD’s characterized by mitochondrial energy failure.