Gene Therapies for Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the arylsulfatase A (ARSA) gene, resulting in ARSA enzyme deficiency. ARSA is essential for metabolizing sulfatides, a major myelin component. ARSA deficiency leads to sulfatide accumulation in the central and peripheral nervous systems, causing progressive demyelination, neurodegeneration, and loss of motor and cognitive functions, often leading to early death. MLD subtypes are defined by age of symptom onset: late infantile (before 30 months), early juvenile (30 months to 7 years), late juvenile (7 to 16 years), and adult (after 16 years), with late infantile and early juvenile being the most severe. Atidarsagene autotemcel is an autologous hematopoietic stem cell-based gene therapy that introduces functional ARSA copies into CD34+ cells via Lenti-D lentiviral vector. Once engrafted, corrected cells differentiate and migrate across the blood-brain barrier to express functional ARSA in the central nervous system.