Gene Therapies for Metachromatic Leukodystrophy

Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder. It arises due to biallelic pathogenic variants in the arylsulfatase A(ARSA) gene, which leads to a deficiency of the lysosomal ARSA enzyme. This enzyme plays a crucial role in metabolizing sulfatides, a major component of myelin membranes in both the central and peripheral nervous system. When ARSA is deficient, undegraded sulfatides accumulate within the central and peripheral nervous system causing microglial damage, progressive demyelination, neurodegeneration, and ultimately resulting in the loss of motor and cognitive functions, often leading to early death –especially in patients with symptom onset before the age of 7 years. MLD subtypes are primarily defined based on age of symptom onset. The late infantile subtype is defined by symptom onset before 30 months of age while early juvenile subtype is defined by symptom onset between 30 months and 7 years of age. In late juvenile subtype, symptom onset is between 7 years and 16 years of age. Symptom onset after 16 years of age is defined as adult onset. Late infantile and early juvenile are the most severe subtypes. Prior to the approval of atidarsagene autotemcel, there were no approved treatments for MLD in the US. Allogeneic hematopoietic stem cell transplantation has shown benefit in some patients with late-onset MLD who are pre-symptomatic or minimally symptomatic at the time of transplant, but it offers little or no benefit in patients with late infantile or early juvenile MLD. Atidarsagene autotemcel is an autologous hematopoietic stem cell (HSC)-based gene therapy which adds functional copies of the ARSA gene into patients’ HSCs through transduction of autologous CD34+ cells with Lenti-D lentiviral vector. The genetically repaired cells are infused back into the individual, where, once engrafted, they differentiate into multiple cell types, some of which migrate across the blood-brain barrier into the central nervous system and express the functional enzyme.