Towards germline gene therapy of inherited mitochondrial diseases

Published on Oct 24, 2012in Nature 41.58
· DOI :10.1038/nature11647
Masahito Tachibana14
Estimated H-index: 14
(Oregon Health & Science University),
Paula Amato20
Estimated H-index: 20
(Oregon Health & Science University)
+ 17 AuthorsShoukhrat Mitalipov36
Estimated H-index: 36
(Oregon Health & Science University)
Abstract
Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg’s cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle–chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls. Mitochondrial DNA is localized in the cell’s cytoplasm, whereas chromosomal genes are confined to the nucleus. Each cell may have thousands of mtDNA copies, which may all be mutated (homoplasmy) or exist as a mixture (heteroplasmy). The clinical manifestations of mtDNA diseases vary, but often affect organs and tissues with the highest energy requirements, including the brain, heart, muscle, pancreas and kidney 1 . The expression and severity of disease symptoms depends on the specific mutation and heteroplasmy levels 1 .
  • References (24)
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References24
Published on Aug 1, 2008in American Journal of Human Genetics 8.86
Hannah R Elliott12
Estimated H-index: 12
(Newcastle University),
David C. Samuels40
Estimated H-index: 40
(Virginia Tech)
+ 2 AuthorsPatrick F. Chinnery83
Estimated H-index: 83
(Newcastle University)
Mitochondrial DNA (mtDNA) mutations are a major cause of genetic disease, but their prevalence in the general population is not known. We determined the frequency of ten mitochondrial point mutations in 3168 neonatal-cord-blood samples from sequential live births, analyzing matched maternal-blood samples to estimate the de novo mutation rate. mtDNA mutations were detected in 15 offspring (0.54%, 95% CI = 0.30–0.89%). Of these live births, 0.00107% (95% CI = 0.00087–0.0127) harbored a mutation no...
337 Citations Source Cite
Published on Mar 1, 2004in Nature 41.58
David M. Lee56
Estimated H-index: 56
,
Richard R. Yeoman22
Estimated H-index: 22
(Oregon Health & Science University)
+ 4 AuthorsDon P. Wolf43
Estimated H-index: 43
(Oregon Health & Science University)
Top of page Radiation and high-dose chemotherapy may render women with cancer prematurely sterile, a side-effect that would be avoided if ovarian tissue that had been removed before treatment could be made to function afterwards. Live offspring have been produced from transplanted ovarian tissue in mice1 and sheep2 but not in monkeys3 or humans4, 5, although sex steroid hormones are still secreted. Here we describe the successful transplantation of fresh ovarian tissue to a different site in a m...
159 Citations Source Cite
Published on Sep 1, 2000in Biology of Reproduction 3.18
Kazuhiro Kikuchi35
Estimated H-index: 35
,
Kunihiko Naito24
Estimated H-index: 24
(University of Tokyo)
+ 6 AuthorsYutaka Toyoda22
Estimated H-index: 22
(Obihiro University of Agriculture and Veterinary Medicine)
Abstract Deterioration in the quality of mammalian oocytes during the metaphase-II arrest period is well known as “oocyte aging.” Oocytes in which aging has occurred are called aged oocytes, and these oocytes show enhanced activation and higher fragmentation rates after parthenogenetic activation. Previously we showed that porcine aged oocytes had low maturation/M-phase promoting factor (MPF) activity, and we suggested that this low MPF activity contributed at least in part to the aging phenomen...
141 Citations Source Cite
Published on Sep 1, 2011in Annals of Medicine 3.01
Jacques Donnez78
Estimated H-index: 78
(Cliniques Universitaires Saint-Luc),
Sherman J. Silber60
Estimated H-index: 60
(Mount Sinai St. Luke's and Mount Sinai Roosevelt)
+ 5 AuthorsMarie-Madeleine Dolmans45
Estimated H-index: 45
(Cliniques Universitaires Saint-Luc)
Abstract Introduction. Premature ovarian failure (POF) can occur naturally at an early age or be due to iatrogenic agents. Indeed, ovaries are very sensitive to cytotoxic treatment, especially to radiation and alkylating agents. Methods. Several options are currently available to preserve fertility in cancer patients and allow them to conceive when they have overcome their disease: embryo cryopreservation, oocyte cryopreservation, and ovarian tissue cryopreservation. Cryopreservation of ovarian ...
246 Citations Source Cite
J. Mandelbaum7
Estimated H-index: 7
,
O. Anastasiou1
Estimated H-index: 1
+ 3 AuthorsJean-Marie Antoine15
Estimated H-index: 15
Abstract The microtubular meiotic spindle of most mammals, including humans, is very sensitive to cooling [Hum. Reprod. 16 (2001) 2374; Fertil. Steril. 54 (1990) 102; Fertil. Steril. 75 (2001) 769; Zygote 3 (1995) 357] and is rapidly depolymerised even after a slight reduction in temperature to 33 °C. Spindle disassembly is dependent on the extent of temperature decrease and its duration. After rewarming, the recovery is far from complete. Cryoprotectants themselves may alter the spindle structu...
77 Citations Source Cite
Published on Mar 25, 2004in The New England Journal of Medicine 79.26
Chad A. Cowan37
Estimated H-index: 37
(Howard Hughes Medical Institute),
Irinha Klimanskaya1
Estimated H-index: 1
+ 8 AuthorsDoug Powers1
Estimated H-index: 1
This report, first published online on March 3, 2004, discusses the procedures used to develop 17 lines of human embryonic stem cells from the inner cell masses of blastocysts. These cell lines are available to researchers under a Material Transfer Agreement; according to current regulations, the cells cannot be used for research supported by federal funds. These cells are expected to facilitate research on a variety of serious chronic diseases.
849 Citations Source Cite
Published on Jun 1, 2010in Nature Protocols 12.42
Masahito Tachibana14
Estimated H-index: 14
(Oregon Health & Science University),
Michelle Sparman13
Estimated H-index: 13
(Oregon National Primate Research Center),
Shoukhrat Mitalipov36
Estimated H-index: 36
(Oregon National Primate Research Center)
In this article, we describe detailed protocols for the isolation and transfer of spindle–chromosomal complexes between mature, metaphase II-arrested oocytes. In brief, the spindle–chromosomal complex is visualized using a polarized microscope and extracted into a membrane-enclosed karyoplast. Chromosomes are then reintroduced into an enucleated recipient egg (cytoplast), derived from another female, by karyoplast–cytoplast membrane fusion. Newly reconstructed oocytes consist of nuclear genetic ...
24 Citations Source Cite
Published on Jul 1, 2001in Biology of Reproduction 3.18
Shoukhrat Mitalipov36
Estimated H-index: 36
,
Kevin D. Nusser6
Estimated H-index: 6
(Oregon Health & Science University),
Don P. Wolf43
Estimated H-index: 43
(Oregon Health & Science University)
Abstract This study determines the efficiency of sequential calcium treatments (electroporation or ionomycin) combined with protein synthesis (cycloheximide) or phosphorylation inhibitors (6-dimethylaminopurine) or the specific maturation promoting factor (MPF) inhibitor, roscovitine, in inducing artificial activation and development of rhesus macaque parthenotes or nuclear transfer embryos. Exposure of oocytes arrested at metaphase II (MII) to ionomycin followed by 6-dimethylaminopurine or to e...
82 Citations Source Cite
Published on Sep 1, 2009in Nature 41.58
Masahito Tachibana14
Estimated H-index: 14
(Oregon Health & Science University),
Michelle Sparman13
Estimated H-index: 13
(Oregon Health & Science University)
+ 7 AuthorsShoukhrat Mitalipov36
Estimated H-index: 36
(Oregon Health & Science University)
Mitochondria are found in all eukaryotic cells and contain their own genome (mtDNA). Unlike the nuclear genome which is derived from both the egg and sperm at fertilization, the mtDNA in the embryo are derived almost exclusively from the egg, i.e. is of maternal origin. Mutations in mtDNA contribute to a diverse range of still incurable human diseases and disorders. To establish preclinical models for new therapeutic approaches, we demonstrate here that the mitochondrial genome can be efficientl...
327 Citations Source Cite
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Cited By208
Published on Aug 1, 2015in Colloids and Surfaces B: Biointerfaces 4.00
Ali Dehshahri10
Estimated H-index: 10
(Shiraz University of Medical Sciences),
Hossein Sadeghpour6
Estimated H-index: 6
(Shiraz University of Medical Sciences)
Abstract In recent years, the discovery of novel nucleic acid-based drug candidates ( e.g. , siRNA and miRNA) and the groundbreaking studies for somatic cell reprogramming into a state of pluripotency have led to reconsideration for the use of human gene therapy as a new paradigm with great therapeutic potential. However, the success of gene therapy is dependent on overcoming intra- and extracellular barriers hampering the efficient delivery of nucleic acid therapeutics into the target cells or ...
19 Citations Source Cite
Published on Jul 1, 2015in Journal of Inherited Metabolic Disease 4.09
Shamima Rahman23
Estimated H-index: 23
(Great Ormond Street Hospital)
Mitochondrial diseases are clinically, biochemically and genetically heterogeneous disorders of two genomes, for which effective curative therapies are currently lacking. With the exception of a few rare vitamin/cofactor responsive conditions (including ACAD9 deficiency, disorders of coenzyme Q10 biosynthesis, and Leigh syndrome caused by mutations in the SLC19A3 transporter), the mainstay of treatment for the vast majority of patients involves supportive measures. The search for a cure for mito...
17 Citations Source Cite
Kelly A. Turner1
Estimated H-index: 1
,
Francis Y.M. Choy13
Estimated H-index: 13
(University of Victoria)
It is estimated that mitochondrial diseases affect 1 in 5,000-10,000 live births. At present, there is no cure for a mitochondrial disease and current treatments are limited to reducing symptoms and slowing disease progression. The prevention of transmission of mitochondrial diseases is of vital importance to parents with a mitochondrial disease who wish to make informed reproductive decisions. This paper provides a critical evaluation of the various established and experimental techniques invol...
1 Citations Source Cite
Published on Nov 1, 2015in Clinical Genetics 3.51
Julie Steffann22
Estimated H-index: 22
(Necker-Enfants Malades Hospital),
Sophie Monnot11
Estimated H-index: 11
(Necker-Enfants Malades Hospital),
J-P. Bonnefont3
Estimated H-index: 3
(Necker-Enfants Malades Hospital)
Mitochondria are the largest generator of ATP in the cell. It is therefore expected that energy-requiring processes such as oocyte maturation, early embryonic or fetal development, would be adversely impacted in case of mitochondrial deficiency. Human mitochondrial DNA (mtDNA) mutations constitute a spontaneous model of mitochondrial failure and offer the opportunity to study the consequences of energetic defects over fertility and embryofetal development. This review provides an update on the m...
8 Citations Source Cite
Published on Apr 1, 2014in British Journal of Pharmacology 6.81
Marta Kanabus4
Estimated H-index: 4
(UCL Institute of Child Health),
S J Heales1
Estimated H-index: 1
(UCL Institute of Child Health),
Shamima Rahman23
Estimated H-index: 23
(UCL Institute of Child Health)
Mitochondrial diseases are an unusually genetically and phenotypically heterogeneous group of disorders, which are extremely challenging to treat. Currently, apart from supportive therapy, there are no effective treatments for the vast majority of mitochondrial diseases. Huge scientific effort, however, is being put into understanding the mechanisms underlying mitochondrial disease pathology and developing potential treatments. To date, a variety of treatments have been evaluated by randomized c...
38 Citations Source Cite
Published on Jul 1, 2015in Protein & Cell 6.23
Si Wang4
Estimated H-index: 4
(Chinese Academy of Sciences),
Fei Yi18
Estimated H-index: 18
(Stanford University),
Jing Qu19
Estimated H-index: 19
(Chinese Academy of Sciences)
Nuclease-based gene editing technologies have opened up opportunities for correcting human genetic diseases. For the first time, scientists achieved targeted gene editing of mitochondrial DNA in mouse oocytes fused with patient cells. This fascinating progression may encourage the development of novel therapy for human maternally inherent mitochondrial diseases.
10 Citations Source Cite
Alexandra Reznichenko1
Estimated H-index: 1
(University of Pretoria),
Carin Huyser12
Estimated H-index: 12
(University of Pretoria),
Michael S. Pepper66
Estimated H-index: 66
(University of Pretoria)
Diseases resulting from mutations in mitochondrial DNA (mtDNA) are inherited by all offspring through the maternal lineage. Multiple organs are severely affected, no preventative treatments are available and most patients experience a poor quality of life or early death. With developments in mitochondrial transfer techniques, hope for preventing transmission of mutated mtDNA onto offspring is emerging. Many ethical issues have been raised regarding such treatments, which involve transfer of nucl...
3 Citations Source Cite
Published on Sep 1, 2015in Annals of the New York Academy of Sciences 4.28
H.J.M. Smeets39
Estimated H-index: 39
(Maastricht University),
Suzanne C.E.H. Sallevelt7
Estimated H-index: 7
(Maastricht University)
+ 2 AuthorsIrenaeus F.M. de Coo4
Estimated H-index: 4
(Boston Children's Hospital)
Mitochondrial disorders are among the most common inborn errors of metabolism; at least 15% are caused by mitochondrial DNA (mtDNA) mutations, which occur de novo or are maternally inherited. For familial heteroplasmic mtDNA mutations, the mitochondrial bottleneck defines the mtDNA mutation load in offspring, with an often high or unpredictable recurrence risk. Oocyte donation is a safe option to prevent the transmission of mtDNA disease, but the offspring resulting from oocyte donation are gene...
17 Citations Source Cite
Published on Aug 1, 2013in Molecular Reproduction and Development 3.11
Manuela Monti13
Estimated H-index: 13
,
CarloAlberto Redi6
Estimated H-index: 6
(University of Pavia)
SUMMARYThe egg, a fantastic little laboratory of molecular biology, has played a crucial role inredefining modern biology by moving it from the description of living things to thesynthesis of living things (synthetic biology). Over the centuries, many hypotheseshave been advanced concerning the egg’s role in reproduction from the preforma-tion theory until von Baer’s discovery to the present, with the 2012 Nobel Prize forPhysiologyorMedicinecelebratingtheeggasatotipotentstemcellabletoreprogramfu...
1 Citations Source Cite
Published on Aug 14, 2015in PLOS ONE 2.77
Thiago Simões Machado2
Estimated H-index: 2
(University of São Paulo),
Carolina Habermann Macabelli3
Estimated H-index: 3
(University of São Paulo)
+ 4 AuthorsMarcos Roberto Chiaratti15
Estimated H-index: 15
(University of São Paulo)
Mouse models are widely employed to study mitochondrial inheritance, which have implications to several human diseases caused by mutations in the mitochondrial genome (mtDNA). These mouse models take advantage of polymorphisms between the mtDNA of the NZB/BINJ and the mtDNA of common inbred laboratory (i.e., C57BL/6) strains to generate mice with two mtDNA haplotypes (heteroplasmy). Based on PCR followed by restriction fragment length polymorphism (PCR-RFLP), these studies determine the level of...
5 Citations Source Cite