title: Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases.
abstract: The exchange of nuclear genetic material between oocytes and embryos offers a novel reproductive option for the prevention of inherited mitochondrial diseases. Mitochondrial dysfunction has been recognized as a significant cause of a number of serious multiorgan diseases. Tissues with a high metabolic demand, such as brain, heart, muscle, and central nervous system, are often affected. Mitochondrial disease can be due to mutations in mitochondrial DNA or in nuclear genes involved in mitochondrial function. There is no curative treatment for patients with mitochondrial disease. Given the lack of treatments and the limitations of prenatal and preimplantation diagnosis, attention has focused on prevention of transmission of mitochondrial disease through germline gene replacement therapy. Because mitochondrial DNA is strictly maternally inherited, two approaches have been proposed. In the first, the nuclear genome from the pronuclear stage zygote of an affected woman is transferred to an enucleated donor zygote. A second technique involves transfer of the metaphase II spindle from the unfertilized oocyte of an affected woman to an enucleated donor oocyte. Our group recently reported successful spindle transfer between human oocytes, resulting in blastocyst development and embryonic stem cell derivation, with very low levels of heteroplasmy. In this review we summarize these novel assisted reproductive techniques and their use to prevent transmission of mitochondrial disorders. The promises and challenges are discussed, focusing on their potential clinical application.
authors.affiliation: Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon. Electronic address: amatop@ohsu.edu.
authors.forename: Paula
authors.initials: P
authors.lastname: Amato
authors.affiliation: Department of Obstetrics and Gynecology, South Miyagi Medical Center, Miyagi, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Tachibana
authors.affiliation: Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sparman
authors.affiliation: Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon.
authors.forename: Shoukhrat
authors.initials: S
authors.lastname: Mitalipov
mesh_terms: D000818:Animals; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods* / Q000639:trends; D015316:Genetic Therapy / Q000379:methods* / Q000639:trends; D006801:Humans; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000517:prevention & control*; D053652:Nuclear Transfer Techniques / Q000639:trends; D027724:Reproductive Techniques, Assisted / Q000639:trends
keywords: Mitochondria; gene replacement; nuclear transfer