July 15, 2015

expert reaction to study investigating the use of stem cells to correct mutations in mitochondrial DNA

Efforts to prevent mitochondrial diseases have led to the development of various techniques, and a team of researchers have described one such technique in the journal Nature based on the use of stem cells, though it has not yet been trialed in animals.

Prof. Robin Lovell- Badge, Group Leader and expert in Stem Cell Biology and Developmental Genetics, Francis Crick Institute, said:

This is an interesting and important paper for basic understanding of mitochondrial DNA dynamics and the etiology of mitochondrial disease. The authors have used two techniques to generate pluripotent stem cells from fibroblasts (skin cells) obtained from patients carrying abnormal mitochondrial DNA.

They show that it is possible to derive iPS cells from a patient who has a mix of mutant and normal mtDNA (is heteroplasmic), where the separate cell lines can have anything from 0 to 100 % mutant mtDNA, but the same nuclear DNA. They show, as expected, when they induce differentiation of the iPS cells into cell types most commonly affected by mitochondrial disease, notably muscle, heart and neurons, that defects in metabolism, gene expression, and cell viability correlate with the proportion of mutant mtDNA. However, using these cell lines it should be possible to determine in detail how the defects arise (which is difficult in patients), and perhaps how to alter the segregation of mutant versus normal mtDNA during cell division to eventually lessen the burden of abnormal mitochondria function.

The second method used somatic cell nuclear transfer (cloning techniques) to exchange all the mtDNA from the patient’s cells with normal mtDNA from an egg donor in order to derive embryonic stem cells that are patient-specific with respect to nuclear DNA, but “rescued” with respect to mtDNA. Unlike the iPS cell method, this technique can be used when the patient is homoplasmic, meaning all their mtDNA is abnormal. Critically they show that the ES cells and differentiated cell derivatives from them are normal with respect to energy production and gene expression. This is despite swapping the type of mtDNA, as there were many differences in sequence between the mtDNA of the patient and the egg donor (in addition to the mutation leading to mitochondrial disease). This implies that mitochondrial nuclear DNA interactions will not be compromised if techniques such as maternal spindle transfer or pronuclear transfer are used to avoid the transmission of mitochondrial disease (both now a clinical option in the UK), as had been suggested by some critics of these proposed methods.

The authors suggest that the availability of patient-specific pluripotent stem cells may provide options for treatments based on regenerative medicine. The problem here will be to devise methods to replace cells within the patient. This might be feasible for muscle, where there are stem cells that are responsible for cell turnover within the tissue, but it will be very difficult for heart and brain cells, where cell turnover is very low or non-existent. However, if it is possible to influence mtDNA segregation in vivo and to select against cells with a high load of mutant mtDNA, then this may be beneficial for young children, when there is still a lot of growth.

Dr Dusko Ilic, Reader in Stem Cell Science, King’s College London, said:

“This beautifully executed work describes two strategies for derivation of pluripotent stem cells with exclusively wild-type mitochondrial DNA from the patients with mitochondrial disease. Following this approach, theoretically, one might be able to generate eggs with all healthy mitochondria from the mitochondrial disease carrier and in such a way eliminate a need for the healthy donor mitochondria or “the third parent”. Given the complexity of the technology, costs and risks involved, the strategies described here will remain a proof-of-concept and unlikely see a practical use in clinical medicine.”

Prof. Darren Griffin, Professor of Genetics and Director of the Centre for Interdisciplinary Studies of Reproduction (CISoR), University of Kent, said:

“This is clearly a very exciting study that might pave the way to possible treatment of mitochondrial disorders. These diseases can be horrendous and any routes to therapy (including palliative care) is most welcome.  The authors have advised a very elegant system to correct the genetic defect in question. It will however be some time before it can be applied clinically given the need for clinical trials etc.”

‘Metabolic rescue in pluripotent cells from patients with mtDNA disease’ by Shoukhrat Mitalipov et al. published in Nature on Wednesday 15th July. 

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/tag/mitochondrial-dna/

The SMC produced a Factsheet on mitochondrial DNA which is attached and also available here: http://www.sciencemediacentre.org/mitochondrial-dna/

The SMC also produced a Factsheet on genome editing which is available here: http://www.sciencemediacentre.org/genome-editing/

Declared interests

Prof. Robin Lovell-Badge: “I am a member of the Scientific and Clinical Advances Advisory Committee of the HFEA, and have served on the HFEA’s panel looking at the science and safety of methods to avoid mitochondrial disease. I am familiar with the methods of deriving iPS cells and with nuclear transfer, however, I do not carry out research on mitochondria or mitochondrial disease.  I have no financial or other conflicts of interest with respect to this paper, apart from my role in giving scientific advice on the topic of mitochondrial disease to the HFEA and to policy makers.”

Dr Dusko Ilic and Prof. Darren Griffin: no conflicts of interest to declare