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Towards germline gene therapy of inherited mitochondrial diseases

Published on Jan 1, 2013in Nature 41.58
· DOI :10.1038/nature11647
Masahito Tachibana14
Estimated H-index: 14
(Oregon Health & Science University),
Paula Amato21
Estimated H-index: 21
(Oregon Health & Science University)
+ 17 AuthorsShoukhrat Mitalipov36
Estimated H-index: 36
(Oregon Health & Science University)
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)
  • Citations (218)
Published on Sep 1, 2012in Fertility and Sterility 4.80
Eric J. Forman16
Estimated H-index: 16
(Rutgers University),
Xinying Li1
Estimated H-index: 1
+ 3 AuthorsRichard T. Scott55
Estimated H-index: 55
(Rutgers University)
Objective To assess the impact of oocyte vitrification on aneuploidy and reproductive potential by comparing vitrified and control oocytes from a single patient within a single cycle and a single fresh transfer. Design Paired randomized controlled trial in which each patient's cohort of mature oocytes was divided into two even groups with half undergoing Cryotop vitrification and rapid warming and half serving as controls. Setting Academic center for reproductive medicine. Patient(s) Forty-four ...
75 Citations Source Cite
Published on Jun 1, 2012in Human Reproduction 4.99
Laura Rienzi40
Estimated H-index: 40
Ana Cobo28
Estimated H-index: 28
+ 6 AuthorsFilippo Maria Ubaldi40
Estimated H-index: 40
results: In 486 cycles performed in 450 couples, 2721 oocytes were warmed and 2304 of them survived cryopreservation (84.7%). Of the 2182 oocytes subjected to ICSI, the rates of fertilization and development to top-quality embryos were 75.2 and 48.1%, respectively. A total of 128 deliveries were obtained (26.3% per cycle and 29.4% per transfer) for 450 patients (28.4%) and 147 babies were live born from 929 embryos transferred (15.8%). The forward logistic regression analysis on a per patient ba...
150 Citations Source Cite
Published on May 1, 2012in Cell Reports 8.03
Hyo Sang Lee6
Estimated H-index: 6
(Oregon National Primate Research Center),
Hong Ma27
Estimated H-index: 27
(Oregon National Primate Research Center)
+ 10 AuthorsPaula Amato21
Estimated H-index: 21
(Oregon Health & Science University)
The timing and mechanisms of mitochondrial DNA (mtDNA) segregation and transmission in mammals are poorly understood. Genetic bottleneck in female germ cells has been proposed as the main phenomenon responsible for rapid intergenerational segregation of heteroplasmic mtDNA. We demonstrate here that mtDNA segregation occurs during primate preimplantation embryogenesis resulting in partitioning of mtDNA variants between daughter blastomeres. A substantial shift toward homoplasmy occurred in fetuse...
66 Citations Source Cite
Published on Sep 1, 2011in Annals of Medicine 3.01
Jacques Donnez79
Estimated H-index: 79
(Cliniques Universitaires Saint-Luc),
Sherman J. Silber61
Estimated H-index: 61
(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 ...
247 Citations Source Cite
Published on Jun 1, 2010in Nature Protocols 12.42
Masahito Tachibana14
Estimated H-index: 14
(Oregon Health & Science University),
Michelle Sparman14
Estimated H-index: 14
(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 ...
25 Citations Source Cite
Published on Sep 1, 2009in Nature 41.58
Masahito Tachibana14
Estimated H-index: 14
(Oregon Health & Science University),
Michelle Sparman14
Estimated H-index: 14
(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...
336 Citations Source Cite
Published on Aug 1, 2008in American Journal of Human Genetics 8.86
Hannah R Elliott13
Estimated H-index: 13
(Newcastle University),
David C. Samuels42
Estimated H-index: 42
(Virginia Tech)
+ 2 AuthorsPatrick F. Chinnery84
Estimated H-index: 84
(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...
345 Citations Source Cite
Published on Jan 1, 2008in Annals of Neurology 10.25
Andrew M. Schaefer23
Estimated H-index: 23
(Newcastle University),
Robert McFarland40
Estimated H-index: 40
(Newcastle University)
+ 5 AuthorsDouglass M. Turnbull93
Estimated H-index: 93
(Newcastle University)
Objective Diverse and variable clinical features, a loose genotype–phenotype relationship, and presentation to different medical specialties have all hindered attempts to gauge the epidemiological impact of mitochondrial DNA (mtDNA) disease. Nevertheless, a clear understanding of its prevalence remains an important goal, particularly about planning appropriate clinical services. Consequently, the aim of this study was to accurately define the prevalence of mtDNA disease (primary mutation occurs ...
386 Citations Source Cite
Published on Dec 1, 2007in Pediatrics 5.51
Richard H. Haas37
Estimated H-index: 37
(University of California, San Diego),
Sumit Parikh15
Estimated H-index: 15
(Cleveland Clinic)
+ 4 AuthorsBruce H. Cohen33
Estimated H-index: 33
(Cleveland Clinic)
Notorious variability in the presentation of mitochondrial disease in the infant and young child complicates its clinical diagnosis. Mitochondrial disease is not a single entity but, rather, a heterogeneous group of disorders characterized by impaired energy production due to genetically based oxidative phosphorylation dysfunction. Together, these disorders constitute the most common neurometabolic disease of childhood with an estimated minimal risk of developing mitochondrial disease of 1 in 50...
183 Citations Source Cite
Published on Jan 1, 2007in BMC Developmental Biology 2.43
Jörg Patrick Burgstaller4
Estimated H-index: 4
(University of Veterinary Medicine Vienna),
Pamela Schinogl4
Estimated H-index: 4
(University of Veterinary Medicine Vienna)
+ 2 AuthorsRalf Steinborn22
Estimated H-index: 22
(University of Veterinary Medicine Vienna)
Background The mitochondrial DNA (mtDNA) of the cloned sheep "Dolly" and nine other ovine clones produced by somatic cell nuclear transfer (SCNT) was reported to consist only of recipient oocyte mtDNA without any detectable mtDNA contribution from the nucleus donor cell. In cattle, mouse and pig several or most of the clones showed transmission of nuclear donor mtDNA resulting in mitochondrial heteroplasmy. To clarify the discrepant transmission pattern of donor mtDNA in sheep clones we analysed...
31 Citations Source Cite
Cited By218
Published on Apr 30, 2019in Scientific Reports 4.12
Justin C. St. John32
Estimated H-index: 32
(Monash University, Clayton campus),
Yogeshwar Makanji17
Estimated H-index: 17
(Monash University, Clayton campus)
+ 7 AuthorsPeter Temple-Smith24
Estimated H-index: 24
(Monash University, Clayton campus)
Many women suffer from either failed fertilisation or their embryos arrest early during development. Autologous mitochondrial supplementation has been proposed as an assisted reproductive technology to overcome these problems. However, its safety remains to be tested in an animal model to determine if there are transgenerational effects. We have supplemented oocytes with autologous populations of mitochondria to generate founders. We mated the female founders and their offspring to produce three...
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Published on Jun 3, 2019in Nature Medicine 32.62
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Published on Jun 1, 2019in Biological Reviews 11.70
Geoffrey E. Hill66
Estimated H-index: 66
(Auburn University),
Justin C Havird1
Estimated H-index: 1
(University of Texas at Austin)
+ 3 AuthorsDamian K. Dowling25
Estimated H-index: 25
(Monash University, Clayton campus)
Author(s): Hill, Geoffrey E; Havird, Justin C; Sloan, Daniel B; Burton, Ronald S; Greening, Chris; Dowling, Damian K | Abstract: Metazoans exist only with a continuous and rich supply of chemical energy from oxidative phosphorylation in mitochondria. The oxidative phosphorylation machinery that mediates energy conservation is encoded by both mitochondrial and nuclear genes, and hence the products of these two genomes must interact closely to achieve coordinated function of core respiratory proce...
2 Citations Source Cite
Published on May 1, 2019in Mitochondrion 3.23
M. Aravintha Siva (Shanmugha Arts, Science), R. Mahalakshmi (Shanmugha Arts, Science)+ 1 AuthorsGunjan Guha18
Estimated H-index: 18
(Shanmugha Arts, Science)
Abstract In the recent years, the reported cases of mitochondrial disorders have reached a colossal number. These disorders spawn a sundry of pathological conditions, which lead to pernicious symptoms and even fatality. Due to the unpredictable etiologies, mitochondrial diseases are putatively referred to as “mystondria” (mysterious diseases of mitochondria). Although present-day research has greatly improved our understanding of mitochondrial disorders, effective therapeutic interventions are s...
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Published on Apr 30, 2019
Yehezkel Margalit2
Estimated H-index: 2
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Published on Mar 29, 2019in Open Biology 3.29
Anna Klucnika (University of Cambridge), Hansong Ma (University of Cambridge)
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Published on Mar 1, 2019in Journal of Assisted Reproduction and Genetics 2.79
Marybeth A. Pompei1
Estimated H-index: 1
(College of Health Sciences, Bahrain),
Francesco Pompei8
Estimated H-index: 8
The purpose of the paper is to explore novel means to overcome the controversial ban in the USA against mitochondrial replacement therapy, a form of IVF, with the added step of replacing a woman’s diseased mutated mitochondria with a donor’s healthy mitochondria to prevent debilitating and often fatal mitochondrial diseases. Long proven effective in non-human species, MRT recently performed in Mexico resulted in the birth of a healthy baby boy. We explore the ethics of the ban, the concerns over...
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Published on Feb 1, 2019in Science and Engineering Ethics 1.86
Abdul Halim Ibrahim1
Estimated H-index: 1
(University of Malaya),
Noor Naemah Abdul Rahman4
Estimated H-index: 4
(University of Malaya)
+ 1 AuthorsMadiha Baharuddin (University of Malaya)
Tri-parent baby technology is an assisted reproductive treatment which aims to minimize or eliminate maternal inheritance of mutated mitochondrial DNA (mtDNA). The technology became popular following the move by the United Kingdom in granting license to a group of researchers from the Newcastle Fertility Centre, Newcastle University to conduct research on the symptoms of defective mtDNA. This technology differs from other assisted reproductive technology because it involves the use of gamete com...
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