This proposal aims at the (pre-)clinical validation of the novel Nuclear Transfer (NT) technology in assisted reproductive technology for two specific indications, being (1) female-related infertility and (2) mitochondrial DNA (mtDNA) diseases. The NT technology involves the transfer of the nuclear genome from a patient’s diseased or inferior quality oocyte or zygote to a healthy donor counterpart from which the nuclear genome was removed. The resulting NT embryos contain the nuclear DNA from both prospective parents and the cytoplasm, including the mtDNA, originating from the donor

This technology has already shown potential in overcoming transmission of mtDNA diseases, mostly in a research setting, as to date only one baby was born after NT to overcome transmission. More recently, the NT technology has also been proposed to overcome specific female-related infertility indications that could be attributed to inferior oocyte quality, for which generally oocyte donation is advised. NT could provide these patients still a chance to obtain their own genetic child. Both experimental evidence on animal and human models as well just recently published clinical data on a limited number of patients support the feasibility of this approach. The currently available (pre-)clinical data is however still insufficient to fully support clinical implementation of the technique, especially to overcome mtDNA disorders, because some of the mutant mtDNA which is still transferred with the nucleus, can take it over from the healthy donor mtDNA during life. As such, we first want to further validate the NT technology for specific infertility
disorders (failed fertilization and embryo developmental arrest) in a pre-clinical context, by extensive -omics analyses on the created NT embryos; and compare different NT strategies in patients with mtDNA diseases. Thereafter, NT will be clinically implemented, first for infertility, secondly for mitochondrial diseases.