Therapeutic activity of a haematopoietic stem cell delivered tissue penetrating peptide in a Friedreich’s ataxia mouse model

The idea behind this proposal is to restore the expression of the Frataxin protein in Friedreich’s patients by engineering a secreted, cell penetrating version of the molecule that will be delivered by haematopoietic stem cells (HSCs). The patient’s blood stem cells will be modified to carry a virus that produces the cell-penetrating Frataxin. The Frataxin-producing stem cells will be reinfused into patients, and they will be retained in the bone marrow. Modified haematopoietic cells circulating in the bloodstream will differentiate into macrophages, oligodendrocytes, and other terminally differentiated cells, which will deliver the therapeutic protein to the damaged tissues, hopefully resulting in a permanent treatment. The main goal of the study is to validate this concept using a mouse model of Friedrich’s ataxia called YG8XLR. YG8XLR mice show reduced expression of FXN and symptoms similar to those of patients. Dr. Sala and his collaborators will use this mouse model to investigate whether intravenous injections of HSCs modified to express Frataxin fused to a cell penetrating peptide ameliorate symptoms and restore normal organ systems functions. In parallel, they will carry out safety studies to gain proof of principle that expression of the therapeutic gene and lentivirus infections are well tolerated and do not result in genotoxicity in mice. If completed, this study should lead to the first cell and gene therapy trial for Friedrich’s ataxia.