Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases

Abstract

Mitochondrial dysfunction has been recognized as a significant cause of a number of serious multi-organ diseases. Tissues with a high metabolic demand such as brain, heart, muscle, CNS are often affected. Mitochondrial disease can be due to mutations in mitochondrial DNA (mtDNA) 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. Since mtDNA 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.

Achievements, sensations and problemsof molecular prenatal diagnostics

“…С этой целью ядро из яйцеклет-ки с дефектными митохондриями переносят в предварительно энуклеированную донорскую яйцеклетку, полученную от здоровой женщи-ны. После оплодотворения такой «гибридной» яйцеклетки возникает зародыш с нормальным митохондриальным геномом, полученным из яйцеклетки -донора ооплазмы [13].…”

Valoración ética de las nuevas opciones reproductivas en las enfermedades mitocondriales

“…El ADN mitocondrial (ADNMt) tiene su propio código genético y contiene 37 genes que codifican algunas de las proteínas que intervienen en la cadena respiratoria, y en la síntesis del ARN ribosomal y ARN de transferencia necesarios para la síntesis proteica en las mitocondrias (5). Los individuos normales tienen homoplasmía en sus mitocondrias, es decir, todas las mitocondrias tienen la misma información genética normal.…”

Trends in Mitochondrial Therapeutics for Neurological Disease

“…Moreover, PGD is not helpful when homoplasmic mutations or high levels of heteroplasmic mtDNA mutations are already present in oocytes [22]. Development of other options for preventing transmission of mtDNA disease has thus been actively explored, primarily nuclear genome transplantation into the healthy mtDNA background of donor zygotes/oocytes via pronuclear or spindle transfer techniques [23,24].…”