Bridging the gap in mitochondrial disorder diagnosis and treatment by using human embryos and pluripotent stem cells

01 January 2017 → 31 December 2020
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Other biological sciences
    • Other natural sciences
Human embryos stem cells mitochondria
Project description

Mitochondrial DNA (mtDNA) diseases primarily originate from defects in the mtDNA, typically manifesting in a heteroplasmic manner with cells containing both wild-type and mutated mtDNA copies. The mutation load in cells represents the proportion of mutant-to-wild type mtDNA. In the absence of therapeutic treatment, overcoming transmission of mtDNA disorders is a must. Preimplantation genetic diagnosis allows for selection of embryos with no or low detectable mutation load. As a first objective, we will verify the efficiency of next generation sequencing for determining mutation load, as well as measuring mtDNA copy number in cells and embryos from patients with a known mtDNA mutation. At present, the mechanisms regulating mutant mtDNA variant segregation and progression remain largely unknown. Hence, we aim to derive induced pluripotent stem cells (iPSCs) from individuals with a known mitochondrial disorder, providing a unique and extremely valuable model for studying the pathophysiology of these disorders in vitro. We will explore the segregation pattern of wild-type and mutated mtDNA in iPSCs during self-renewal and differentiation. More specifically, we aim to verify how the mutation load affects the functionality of these cells, with a particular focus on differentiation potential and respiratory rates. Finally, we will evaluate the efficacy and safety of currently proposed nuclear transfer techniques to overcome transmission of mitochondrial diseases in humans.