Studying the role of microglia in the treatment of Metachromatic Leukodystrophy using human organoids

Metachromatic leukodystrophy is a neurodegenerative genetic autosomal disorder finally leading to the loss of myelin and eventually to death. Mutations on ARSA or PSAP genes are responsible for the accumulation of sulfatides which is the actual cause of myelin degradation and thus of this deadly disease. Microglia are brain resident immune cells having a crucial role in the pathogenesis of MLD, but, paradoxically, they are also essential in the resolution of this disorder. Until now, treatments have mainly focused on correcting the mutation of arylsulafatse A or of PSAP genes through the use of gene therapy or by the allogenic transplantation of healthy HSCs. This thesis paper studies the role of microglia in the disease development and it also examines the application of these cells in a possible symptomatic therapy to associate to other existing treatments, like Libmeldy and other gene therapies, which, instead, try to solve the main cause of MLD; this combination of treatment approaches aims to slow the disease advancement. In addition, this work investigates the consequences of non-human brain and human brain environments on the maturation and functioning of these immune cells. This further understanding could result in the amelioration and development of more effective MLD therapies.