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Molecular, cell biological and genetic aspects of diseases: The “three parent child” -Mitochondrial donation for prevention of mitochondrial disease – methods, technical and ethical concerns Abstract Iita Palosaari, Marika Pätsi Mitochondrial genome replacement techniques • • • • Mitochondrial replacement techniques (MRT) are designed to prevent the transmission of mitochondrial DNA (mtDNA) diseases from mother to child. The transmission of mtDNA mutations that potentially may cause disease has been estimated to be as high as one in every 200 newborns. MRT could satisfy the desire of women seeking to have a genetically related child without the risk of passing on mtDNA disease The goal of MRT is to prevent the transmission of these serious diseases by creating an embryo with nuclear DNA (nDNA) from the intended mother and mtDNA from a woman with nonpathogenic mtDNA through modification of either an oocyte (egg) or zygote (fertilized egg). Picture 1. A) Spindle Transfer involves isolation and transfer of a nuclear genetic material (spindle-chromosomal complex) from an unfertilized oocyte containing mutated mtDNA to the cytoplasm of another enucleated oocyte containing healthy mtDNA. The reconstructed oocyte is then fertilized and transplanted. (B) Pronuclear Transfer takes place after fertilization, at the one-cell embryo stage containing male and female pronuclei (zygote). Both pronuclei are isolated and transplanted into a cytoplasm of another enucleated zygote. Ethics • • • • • • • • • Germline therapy or not? - PNT and MST don’t (shouldn’t) act on nucleus - mtDNA is not modified; whole mitochondrial genomes replaced - though these genes will be incorporated to germline and passed on maternallyheritable, irreversible and affects every cell type of the child Identity - three genetic contributions confused self-image? - does the person seek for the bio-history, who was the donor? - issue of consent Three “parents”, two “mothers” - only 0.1 % from total DNA from donor Unnatural? Form of eugenics? - impact on persons with disabilities; pressure to mutated women to use the techniques? “Unmatched” nuclear and mitochondria genomes - takes several generations to see if the procedure has been safe Importance of giving information and counselling for donors and couples and long-term follow-up for children - status of the mitochondrial or sperm donor Current challenge is to chart a course that translates preclinical and clinical studies into clinical trials evaluating efficacy and safety - might be considered unethical to deny germline gene therapies for nuclear DNA diseases 2015 UK approved laws to permit procedure BUT doesn’t help with mitochondrial diseases connected to genes located in nucleus