Metachromatic Leukodystrophy (MLD): The Role Of Microglia

Prof. Biffi explains how microglial impairment in MLD contributes to neurodegeneration through mechanisms such as impaired lysosomal function, oxidative stress, accumulation of dysfunctional organelles, and chronic inflammation. These pathologies arise from the enzymatic deficiency in arylsulfatase A, leading to sulfatide accumulation. Microglia, due to their resident nature and long-term self-renewal capacity, become central players in either exacerbating or potentially modulating disease progression.

Traditional allogeneic hematopoietic stem cell transplantation (HSCT) has shown limited success in treating early-onset MLD due to the slow engraftment of donor-derived cells into the CNS—often occurring after significant neurodegeneration has already taken place. To overcome this delay, Prof. Biffi and others have explored gene therapy strategies that aim to enhance the metabolic capacity of microglia-like cells derived from transplanted hematopoietic stem cells.

She details preclinical and clinical efforts to optimize HSCT by enriching for hematopoietic progenitors with CNS engraftment potential and introducing gene therapy approaches that deliver functional ARSA. These strategies aim to produce donor-derived microglia-like cells that can perform necessary lysosomal functions, reduce inflammation, and promote neuroprotection.

The presentation also explores innovative approaches being investigated in the lab, including the use of gene editing, antibody-targeted conditioning, and intrathecal administration of hematopoietic cells to promote more rapid and targeted CNS engraftment.

Prof. Biffi concludes by emphasizing that therapeutic benefit from these advanced strategies strongly depends on the timing of intervention. The earlier the treatment—ideally in pre-symptomatic or very early symptomatic stages—the more likely it is to prevent or delay neurodegeneration. She also highlights the promise of cross-correction mechanisms, which enable enzyme transfer between cells, reinforcing the value of even partial microglial restoration.

The session underscores the importance of integrating molecular neuroscience with therapeutic innovation to advance care for patients with MLD.