Cure MERRF: from fibroblasts to organoids speeding basic science into clinical trials for mitochondrial diseases

Diseases determined by mitochondrial DNA (mtDNA) mutations are individually rare but as a whole they are the most frequent genetic disorders in humans. They may affect infants and adults, ranging from milder forms with only one organ affected, leading to isolated blindness or deafness, to complex and devastating syndromes leading to death. Over 30 years of studies provided a number of potential therapies for these patients, however a major obstacle remains the ability to generate animal models due to the peculiar mtDNA genetic rules. Thus, translation of therapeutic strategies into clinical trials with patients is hampered.

This proposal has the ambition to establish and validate a new disease model, using an innovative technology that allows to reprograming pluripotent stem cells (hiPSCs) from patients, and then develop in a dish miniaturized organs, those which are affected in the living patient. These mini-organs reproduce most of the disease features, allowing to refine the mechanisms leading to clinical phenotype and, ultimately, to testing therapies. Two major advantages are reached by this approach: first the lack of animal models for diseases associated with mtDNA mutations is overcome, and second we tailor the therapy testing to the individual patient, applying a precision medicine approach. The disease we will tackle with this project is Myoclonus, Epilepsy, Ragged-Red-Fibers syndrome also known as MERRF, a paradigm for the so-called mitochondrial encephalomyopathies. We will test drugs that may be repurposed like rapamycin, new molecules and gene therapy, all approaches for which there are already promising results.