title: Live birth derived from oocyte spindle transfer to prevent mitochondrial disease.
abstract: Mutations in mitochondrial DNA (mtDNA) are maternally inherited and can cause fatal or debilitating mitochondrial disorders. The severity of clinical symptoms is often associated with the level of mtDNA mutation load or degree of heteroplasmy. Current clinical options to prevent transmission of mtDNA mutations to offspring are limited. Experimental spindle transfer in metaphase II oocytes, also called mitochondrial replacement therapy, is a novel technology for preventing mtDNA transmission from oocytes to pre-implantation embryos. Here, we report a female carrier of Leigh syndrome (mtDNA mutation 8993T > G), with a long history of multiple undiagnosed pregnancy losses and deaths of offspring as a result of this disease, who underwent IVF after reconstitution of her oocytes by spindle transfer into the cytoplasm of enucleated donor oocytes. A male euploid blastocyst wasobtained from the reconstituted oocytes, which had only a 5.7% mtDNA mutation load. Transfer of the embryo resulted in a pregnancy with delivery of a boy with neonatal mtDNA mutation load of 2.36-9.23% in his tested tissues. The boy is currently healthy at 7 months of age, although long-term follow-up of the child's longitudinal development remains crucial.
authors.affiliation: New Hope Fertility Center, Punto Sao Paulo, Lobby Corporativo, Américas 1545 Providencia, Guadalajara, Mexico; New Hope Fertility Center, 4 Columbus Circle, New York, NY 10019, USA. Electronic address: johnzhang211@gmail.com.
authors.forename: John
authors.initials: J
authors.lastname: Zhang
authors.affiliation: New Hope Fertility Center, 4 Columbus Circle, New York, NY 10019, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Luo
authors.affiliation: New Hope Fertility Center, 4 Columbus Circle, New York, NY 10019, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Lu
authors.affiliation: New Hope Fertility Center, Punto Sao Paulo, Lobby Corporativo, Américas 1545 Providencia, Guadalajara, Mexico.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Chávez-Badiola
authors.affiliation: New Hope Fertility Center, 4 Columbus Circle, New York, NY 10019, USA.
authors.forename: Zitao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: New Hope Fertility Center, 4 Columbus Circle, New York, NY 10019, USA.
authors.forename: Mingxue
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Division of Reproductive Biology, NYU School of Medicine, 180 Varick Street, New York, NY 10014, USA.
authors.forename: Zaher
authors.initials: Z
authors.lastname: Merhi
authors.affiliation: Infertility Center of St Louis, St Luke's Hospital, St Louis, MO 63017, USA.
authors.forename: Sherman J
authors.initials: SJ
authors.lastname: Silber
authors.affiliation: Reprogenetics, 3 Regent Street, Livingston, NJ 07078, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Munné
authors.affiliation: Reprogenetics, 3 Regent Street, Livingston, NJ 07078, USA.
authors.forename: Michalis
authors.initials: M
authors.lastname: Konstantinidis
authors.affiliation: Reprogenetics, 3 Regent Street, Livingston, NJ 07078, USA.
authors.forename: Dagan
authors.initials: D
authors.lastname: Wells
authors.affiliation: Department of Obstetrics and Gynecology, The Mount Sinai Hospital, E 101(st) Street, New York, NY 10029, USA.
authors.forename: Jian J
authors.initials: JJ
authors.lastname: Tang
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA. Electronic address: Taosheng.Huang@cchmc.org.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
mesh_terms: D004272:DNA, Mitochondrial / Q000737:chemistry; D005260:Female; D005307:Fertilization in Vitro; D006579:Heterozygote; D006801:Humans; D007888:Leigh Disease / Q000235:genetics / Q000517:prevention & control*; D050498:Live Birth; D000072741:Maternal Inheritance; D008928:Mitochondria; D000069321:Mitochondrial Replacement Therapy; D018587:Oocyte Donation; D009865:Oocytes / Q000648:ultrastructure*; D010375:Pedigree; D011247:Pregnancy; D019836:Preimplantation Diagnosis; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial
keywords: Cytoplasm; Leigh syndrome; Meiotic spindle; Mitochondria; Nuclear transfer; Oocyte