The Problem
Aging creates an accumulation of mutations in the DNA of our mitochondria, the organelles that create our energy supply on a molecular level. This impacts and impairs their ability to function correctly and creates a myriad of energy issues as we age. Testing potential therapies for use in humans requires a robust testing model that hasn’t yet been developed.
The Goal
Building upon a prior SRF program, the team engineered mice that have specific mutations in their mitochondrial DNA. They grow normally but show the defects common in humans with the same types of mutations.
The Status
Mouse models have been established for two of the thirteen mitochondrial genes successfully. This has led to functional testing of possible therapeutics in other Boominathan lab projects. More models are needed to continue developing further therapeutics for humans.
Allotopic Expression In Vivo
Mitochondrial mutations drive aging phenotypes and specific diseases of aging. The Boominathan lab has made substantial progress in the allotopic expression (AE) of mitochondrial genes from the nucleus as a mitochondrial gene therapy solution for this problem with their greatest success to date being the successful rescue of a patient cybrid cell line with a severe ATP8 mutation via AE ATP8 and ATP6. To implement AE as a therapeutic in aging people or as a treatment for congenital mitochondrial genetic diseases will require gene therapy. Gene therapy strategies utilizing viral vectors such as adeno- or lentiviruses are limiting in their cargo sizes and risk disrupting neighboring genes during random integration. To overcome the limits of these and other gene therapies, SRF funded the development of a mouse model in which the docking site for a phage integrase has been engineered into a well-characterized safe harbor locus in the mouse nuclear genome.
Using these mice, the Boominathan lab generated two transgenic mouse models expressing the AE ATP8 gene from this safe harbor locus. One line of such mice has wild-type mouse mitochondrial ATP8 genes, while the other has a mitochondrial ATP8 polymorphism (FVB) that has been reported to cause mild biochemical perturbations. This allowed for the assessment of both the potential of AE ATP8 to rescue the FVB polymorphism, and the risk that it might disrupt the normal functioning of the wild-type ATP8. Additional mouse lines are needed to continue testing in vivo the therapies generated by the Boominathan lab, and other mitochondria labs globally.
Team Members
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Amutha Boominathan, PhD
Principal Investigator
Funding
Annual Budget
50,000 USD
