Charles T. Roberts, Jr.(ONPRC), Shoukhrat Mitalipov (ONPRC), and the OHSU Strategic Communications Media Team

Primates Paved the Way to Egg Manipulation for Treatment of Mitochondrial Disease: Gene-based cures for human diseases are now on the horizon

Mitochondrial diseases represent devastating human disorders for which there is no current therapy or preventative approaches. These diseases are evident at or soon after birth and can affect multiple organ systems to cause diabetes, deafness, blindness, dementia, epilepsy, multiple sclerosis-like symptoms, etc. In the United States, 1,000 to 4,000 children are born with mitochondrial DNA disease each year. Although mitochondrial disease sometimes results from mutations in nuclear genes, maternally inherited mitochondrial disease is the result of mutations in the mitochondrial genome (mtDNA) of an egg. Thus, replacement of dysfunctional mitochondria in the egg of a woman who has previously had a child with a mitochondrial disease would offer the chance of having a normal child subsequently.

This concept, termed mitochondrial replacement therapy (MRT) was first established in principle in nonhuman primates by Shoukhrat Mitalipov, Ph.D., at the ONPRC, who demonstrated the feasibility of replacing an entire mtDNA complement in an egg with donor mitochondria from another egg [1], followed by in vitro fertilization and the development of normal offspring [2]. Based upon the success of these pre-clinical studies, this approach is now poised for use in humans. MRT also allows replacement of deficient cytoplasm in eggs from women of advanced maternal age, with the expectation of high pregnancy rates following in vitro fertilization [3].

A new study led by Dr. Mitalipov and Hong Ma, M.D., Ph.D., at ONPRC and the Center for Embryonic Cell and Gene Therapy at Oregon Health & Science University has revealed the first critical step in developing novel gene and stem cell therapies for patients who are already born with mitochondrial disease.

This breakthrough, published in July 2015 in the journal Nature [4], sets the stage for replacing diseased tissue in patients and opens the door to a world of regenerative medicine where doctors are able to treat human diseases that are currently incurable. Drs. Mitalipov and Ma successfully used mitochondrial replacement to create embryonic stem cells with healthy mitochondria from a patient’s skin cells containing mitochondrial DNA mutations. In this study, skin cells were collected from research subjects suffering from mitochondrial DNA disease. Next, the nucleus was isolated from the skin cells and transferred into egg cells from a healthy donor with normal mitochondria and from which the egg cell’s nucleus had been removed. This produced stem cells derived from the patient who had mitochondrial disease but that now had healthy mitochondria.

In May 2013, Dr. Mitalipov and his colleagues were the first in the world to demonstrate the successful use of somatic cell nuclear transfer to produce human embryonic stem cells from a research subject’s skin cells [5]. That breakthrough followed a six-year chain of discoveries that included his 2007 work demonstrating the nuclear transfer method to create embryonic stem cells from a nonhuman primate [6]. This research included what may be a new technique to help families prevent inherited mitochondrial disease in future generations.

“To families with a loved one born with a mitochondrial disease waiting for a cure, today we can say that a cure is on the horizon. Over the past several years, we have been working to generate stem cells for use in combating disease. This critical first step toward treating these diseases using gene therapy will put us on the path to curing them,” said Mitalipov. “And, unlike unmatched tissue or organ donations, combined gene and cell therapy will allow us to create the patients’ own healthy tissue that will not be rejected by their bodies.”

“This is an important advancement by Drs. Mitalipov and Ma in the quest to develop treatments and cures for those affected by mitochondrial disease,” said Philip Yeske, Ph.D., Science and Alliance Officer for the United Mitochondrial Disease Foundation. “Mitochondrial replacement holds great therapeutic potential, and the patient community looks forward to further progress on the path toward clinical applications.”

Scientists hope to use this technique to replace diseased tissue in the future by removing one cell, correcting the mutations, multiplying the cells and reinserting the genetically correct cells into the patient to replace diseased tissue. The nuclear transfer technique is more precise than classical gene therapy. Rather than inserting synthetic genes into patients delivered by viruses, nuclear transfer uses donated healthy mitochondrial genes.

“Regenerative technologies offer the prospect of transformative solutions to correct tissue defects in disease. Current care for mitochondrial diseases is limited to addressing patient symptoms, but falls short from providing a definitive cure,” said Andre Terzic, M.D., Ph.D., Michael S. and Mary Sue Shannon Family Director of the Center for Regenerative Medicine at Mayo Clinic and study co-author. “Resetting or replacing disease-corrupted mitochondria to produce healthy patient derived stem cells paves the way towards targeting the root cause of the problem. The present study exemplifies how synergy of multidisciplinary teams advances the field.”

“Induced pluripotent stem cell and somatic cell nuclear transfer are two complementary cell reprogramming strategies that hold great potential for patient specific cell replacement therapies,” said Jun Wu, Ph.D., senior postdoctoral researcher in the laboratory of Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies and study co-author. “Both technologies have been successfully harnessed in our study for eliminating mutant mitochondrial DNAs, offering an important step forward toward therapeutic interventions for patients with mitochondrial diseases.”

Although the subject of controversy and described in the press somewhat erroneously as producing “3-parent” babies [3], the MRT has recently been approved by the UK Parliament, and approval for the technique has been requested in the United States.

References Cited:

1. Tachibana M, Amato P, Sparman M, Woodward J, Sanchis DM, Ma H, Gutierrez NM, Tippner-Hedges R, Kang E, Lee HS, Ramsey C, Masterson K, Battaglia D, Lee D, Wu D, Jensen J, Patton P, Gokhale S, Stouffer R, Mitalipov S. Towards germline gene therapy of inherited mitochondrial diseases. Nature. 2013 Jan 31;493(7434):627-31. PMID: 23103867

2. Tachibana M, Sparman M, Sritanaudomchai H, Ma M, Clepper L, Woodward J, Li Y, Ramsey C, Kolotushkina O & Mitalipov S. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature. 2009 Sep 17;461(7262):367-72. Epub 2009 Aug 26. PMID: 19710649

3. Wolf DP, Mitalipov N, Mitalipov S. Mitochondrial replacement therapy in reproductive medicine. Trends Mol Med. 2015;21(2):68-76. doi: 10.1016/j.molmed.2014.12.001. PubMed PMID: 25573721; PubMed Central PMCID: PMCPMC4377089.

4. Ma H, Folmes CD, Wu J, Morey R, Mora-Castilla S, Ocampo A, et al. Metabolic rescue in pluripotent cells from patients with mtDNA disease. Nature. 2015;524(7564):234-8. doi: 10.1038/nature14546. PubMed PMID: 26176921

5. Tachibana M, Amato P, Sparman M, Gutierrez NM, Tippner-Hedges R, Ma H, et al. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell. 2013;153(6):1228-38. doi: 10.1016/j.cell.2013.05.006. PubMed PMID: 23683578; PubMed Central PMCID: PMCPMC3772789.

6. Byrne JA, Pedersen DA, Clepper LL, Nelson M, Sanger WG, Gokhale S, et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature. 2007;450(7169):497-502. doi: 10.1038/nature06357. PubMed PMID: 18004281.

Recent NPRC Publications

There are currently 44 publications available for mitochondrial disease.

2018

McGill TJ, Stoddard J, Renner LM, Messaoudi I, Bharti K, Mitalipov S, Lauer A, Wilson DJ, Neuringer M
Allogeneic iPSC-Derived RPE Cell Graft Failure Following Transplantation Into the Subretinal Space in Nonhuman Primates.
Invest. Ophthalmol. Vis. Sci. 2018 Mar; 59(3): 1374-1383.

Xu J, Lawson MS, Mitalipov SM, Park BS, Xu F
Stage-specific modulation of antimüllerian hormone promotes primate follicular development and oocyte maturation in the matrix-free three-dimensional culture.
Fertil. Steril. 2018 Nov; 110(6): 1162-1172.

2017

Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, Koski A, Ji D, Hayama T, Ahmed R, Darby H, Van Dyken C, Li Y, Kang E, Park AR, Kim D, Kim ST, Gong J, Gu Y, Xu X, Battaglia D, Krieg SA, Lee DM, Wu DH, Wolf DP, Heitner SB, Belmonte JCI, Amato P, Kim JS, Kaul S, Mitalipov S.
Correction of a pathogenic gene mutation in human embryos.
Nature 2017 Aug; 548(7668): 413-419.

Ma H, O'Neil RC, Marti Gutierrez N, Hariharan M, Zhang ZZ, He Y, Cinnioglu C, Kayali R, Kang E, Lee Y, Hayama T, Koski A, Nery J, Castanon R, Tippner-Hedges R, Ahmed R, Van Dyken C, Li Y, Olson S, Battaglia D, Lee DM, Wu DH, Amato P, Wolf DP, Ecker JR, Mitalipov S.
Functional Human Oocytes Generated by Transfer of Polar Body Genomes.
Cell Stem Cell 2017 Jan; 20(1): 112-119.

Wolf DP, Hayama T, Mitalipov S.
Mitochondrial genome inheritance and replacement in the human germline.
EMBO J. 2017 Aug; 36(15): 2177-2181.

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