Generation of MILS syndrome neurons to explore therapies for mitochondrial DNA disease

Funding Type: 
Basic Biology IV
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Mitochondria in our cells provide majority of cellular energy. Neuron and cardiomyocyte are sensitive to mitochondria failure due to their great energy demand. Mitochondria have their own DNA (mtDNA) to code for proteins essential for energy production, and each cell has several hundred copies of mtDNA subject to damage as we age. mtDNA mutations are implicated in common diseases, such as Parkinson’s disease, diabetes and autism. mtDNA mutation can be inherited from mother to offspring which can cause severe childhood neurological disorders. The therapeutic options are extremely limited because of poor understanding on mtDNA diseases. We can change the nuclear DNA but we don’t have similar technology with mtDNA. Therefore, the recent developed reprogramming technology that allows derivation of human induced pluripotent stem cells (hiPSC) from patients, which can then be differentiated into disease-specific neurons, can be the long-sought solution for mtDNA disease studies. In this proposal, we will derive hiPSC from mtDNA patients with Maternal Inherited Leigh’s Syndrome (MILS) and differentiate them into neurons, which will be analyzed with a series of functional and molecular tests to find out the reasons of patient neuron death and the potential rescue mechanism. We believe the findings made will have a significant clinical and scientific impact on understanding the molecular and pathological mechanism of mtDNA disease and drug screen.

Statement of Benefit to California: 

Maternal Inherited Leigh’s Syndrome (MILS) is the most common hereditary mitochondria DNA disease that causes severe childhood neurological disorders. In this study, we will generate hiPSC-derived neurons from patients with MILS, and then perform a series of functional and molecular analyses to determine the reason underlying the neuron cell death observed in MILS children. We believe patient neuron generated through iPSC technology will greatly advance the ability to perform future drug discovery and therapy evaluation as we will attempt in the study. It is estimated that 1 in 2000 individuals is affected by mitochondrial diseases; however, the exact prevalence of mitochondria DNA disease is hard to estimate due to the challenges of quantifying the mutations. In a recent clinical report in the Journal of American Medical Association, 2/10 autistic children were found to have mtDNA deletions and 5/10 had mtDNA replication defects, and moreover, widespread mtDNA heterogeneity has recently been found in normal human cells. Thus, mtDNA mutation is not as rare as believed, and its role in disease is underappreciated. MILS disease on its own is a rare disease, but it presents a severe form of general mitochondria dysfunction underling a much broader range of mtDNA diseases. Therefore, we believe that therapies resulting from these research findings will benefit the state of California and its citizens.