Human mitochondrial DNA (mtDNA) encodes 37 genes in a small genome of 16,569 bp, whichaccounts for 0.005% of the total human genome size. Despite the small size of this geneticinformation, mtDNA is indispensable to human cells. As mitochondria are critical for cellularrespiration and ATP production, mitochondria are often referred to as "the Powerhouses of thecell". Because of their importance, mutations in mtDNA can cause severe diseases anddisorders in humans. These include but are not limited to muscular/neurodegenerative anddevelopmental disorders such as Kearns-Sayre syndrome (KSS), Leber's Hereditary OpticNeuropathy (LHON) and MELAS disorders. Mutations in mtDNA are also suggested tocorrelate with a predisposition for common diseases like diabetes, Alzheimer's disease,Parkinson's disease and even aging. Although the causal relationships between certainmutations in mtDNA and their corresponding diseases were reported decades ago, cures havenot been realized due to the difficulty in accessing the sub-cellular structures in vivo. Also,CRISPR technology has not been applicable to mitochondria until recently and correspondinggene therapy of mtDNA still remains challenging in humans.The major challenge of mitochondrial gene editing is the lack of DNA transformation approachesfor human mitochondria. No selectable marker gene has been developed that enablesmitochondrial transformation in human cells. As part of our efforts for mitochondrialtransformation in crop plants, we have used a novel selectable marker gene to develop amethod that has shown good efficacy in rice and yeast. In this proposed project, we will applythis method to human mitochondria. A successful demonstration will be a major advancementfor the application of our organelle gene editing technology to human mitochondrial DNA, whichwill facilitate future gene therapy treatments for the repair of mtDNA mutations in patientssuffering from severe mitochondrial diseases.
Public Health Relevance Statement: Project Narrative
Using our proprietary CRISPR organelle gene editing and transformation technologies,
we aim to enable correction of human mitochondrial DNA mutations, which are the
causes of a number of severe human genetic diseases and also predispose for
Parkinson's and Alzheimer's diseases as well as the aging process. This first-phase
project will apply our novel selection method to the transformation of human
mitochondrial DNA, thereby providing a highly desired research technology to the
scientific community. This advance will open new opportunities both in developing
mitochondrial gene therapy and also in advancing basic research of mitochondria, the
powerhouses of cells.
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