Lentiviral Hematopoietic Stem Cell Gene Therapy for MLD

Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disease. This disease is an inherited single gene autosomal recessive defect. MLD is caused by a mutation in the ARSA gene encoding arylsulfatase A which leads to a deficiency in sulfatide degradation, resulting in its accumulation in oligodendrocytes, Schwann cells and neurons. A critical level of sulfatide storage can trigger demyelination, the hallmark of MLD, which results in multiple neurological symptoms. MLD has different onset ages including late infancy (1-2 years), adolescence (4 years-before sexual maturity) and adulthood (after sexual maturity). MLD patients are normally rescued by hematopoietic stem cell transplantation (HSCT) from a matched healthy donor. However, HSCT must be performed at a very early stage of the disease and carries a significant risk of graft-versus-host disease (GVHD), which restricts its therapeutic opportunities in MLD patients. This trial aims to treat MLD using an improved self-inactivating lentiviral vector (LV) carrying a functional ARSA gene to transduce patient-derived HSCs in culture, then delivering these genetically corrected HSCs carrying the normal ARSA gene to correct the genetic defect. The primary objectives are to evaluate the safety of the improved LV TYF-ARSA and the clinical protocol for gene therapy using the genetically modified HSCs, and the therapeutic efficacy in patients after treatment, assessment of vector integration sites, and finally the long-term correction of the pathological symptoms.