Stem cells offer alternative approach to develop therapies for inherited mitochondrial disorders

Genetically corrected stem cells derived from patients with inherited mitochondrial disorders offer a new approach to developing therapies for these incurable diseases, according to a study published in Nature. Using skin cells from patients with mitochondrial encephalomyopathy and stroke-like episodes (MELAS) and Leigh syndrome, diseases caused by mitochondrial mutations, the authors generated genetically corrected pluripotent stem cells which can be converted to any cell type in the body. Currently the only way to prevent inherited mitochondrial disorders is the controversial mitochondrial replacement procedure, so called ‘3-person IVF’, recently approved for clinical application in the United Kingdom.


Dr. David Valle, Henry J. Knott Professor and Director, McKusick-Nathans Institute  of Genetic Medicine, The Johns Hopkins School of Medicine (webpage): 

Expertise: clinical, biochemical, molecular and therapeutic aspects of specific  human genetic diseases; genetic factors in neuropsychiatric disease; Inborn errors of metabolism; medical sequencing, genome sequencing and  comparative genomics

“There are hundreds to thousands of mitochondria each with many mitochondrial genomes in most cells in our body. Mutations that cause disease may be present in all of mitochondrial genomes, referred to as homoplasmy, or may be present in a fraction of mitochondrial genomes, referred to as heteroplasmy. We know that the severity of the disease correlates roughly with the percentage of abnormal genomes. This observation has led to the idea that if we could somehow influence the fraction of heteroplasmy in favorable ways (more normal and fewer mutant genomes) we should be able to reduce the severity or even “cure” the disease.

“The investigators in this study cultured skin cells from patients who have heteroplasmy for a mitochondrial genome mutation and converted these cells to induced pluripotent stem (iPS) cells through a well established procedure. They found when they isolated single cell colonies from individual iPS cells that the mitochondria in some of them were completely free of the mutation (i.e. homoplasmic normal) while in other colonies all the mitochondria had the mutation (homoplasmic abnomal). They also did functional studies to show that the iPS cells homoplasmic for the mutation had the expected abnormalities in mitochondrial function.

“They then make the leap of faith that we can now use these corrected iPS cells to treat or cure the patient.There are, however, many hurdles before that can be achieved, some of which may be difficult if not impossible to cross. For example we don’t really understand which kind of cells in the brains of patients with MELAS syndrome have abnormalities  that lead to strokes. Going from a flask of cells in the lab to neurons or blood vessel cells in the brain is very difficult. There are many other such practical questions that must be answered  including what effects introducing these cells into the body may have and whether culturing these cells through many generations in the laboratory may introduce other mutations. Treating these patients would be a lifetime not a short time experiment.

“On the other hand these are very severe disorders and the available therapies available are supportive and not particularly effective so it is important to consider any new avenue. It is also important to be realistic about what it takes to develop a meaningful treatment because the families who have children or relatives with these disorders are desperate for some kind of treatment. So they are extremely vulnerable to any promise that treatment is “just around the corner”. I would say the work in this paper is an early step in a very long path towards providing effective therapy for these complicated and potentially devastating disorders.”


Metabolic rescue in pluripotent cells from patients with mtDNA disease‘ by Hong et al., published in Nature on July 15, 2015


Declared interests (see GENeS register of interests policy):

No interests declared

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