Hematopoietic stem cell gene therapy (HSC GT) is an experimental treatment based on the transplantation of autologous hematopoietic precursor cells genetically modified to express high levels of ARSA enzyme. This treatment benefits late infantile and early juvenile MLD children if treated in the pre-symptomatic/early symptomatic stage of the disease but is less effective in MLD children treated in the progressive phase of disease, who experience severe neurological deterioration. In order to recognize the reasons behind this different clinical outcome we need a better understanding of the therapeutic mechanisms of correction of MLD neural cells by the progeny of transplanted hematopoietic cells that engraft in the brain.

In this project the investigators aim to fill this gap of knowledge taking advantage of unique and clinically relevant in vitro human disease models, i.e. neural and blood cells derived from healthy donors, untreated and gene therapy treated MLD patients. We expect to clarify how and to which extent the ARSA enzyme is transported from metabolically competent donor blood cells to MLD neurons and glia. Also, they will provide hints on the contribution of complementary mechanisms of correction that could be exploited to enhance the benefit of HSC GT and broaden its accessibility to larger cohorts of MLD patients who presently not meet the inclusion criteria of these experimental treatments.

Project financed by ELA up to: 60 000 €