Direct Lentiviral Injection 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 thus restricting its therapeutic opportunies in MLD patients. This trial aims to treat MLD using a safety and efficacy improved self-inactivating lentiviral vector (LV) carrying a functional MLD gene to correct the genetic defect by intrathecal (IT) and intravenous (IV) injections to delivery the lentiviral vector carrying a normal ARSA gene to correct the genetic defect. The primary objectives are to evaluate the safety of the improved LV TYF-ARSA and the direct injection gene transfer clinical protocol, the efficacy of degradative metabolite in patients after treatment, vector integration profile, and finally the long-term correction of the related pathological symptoms.

Inclusion criteria

• MLD patient age >= 1 month
• ARSA gene sequence analysis to confirm MLD mutations
• Scoring system for brain MR Imaging confirmed MLD
• Parent / guardian / patient signing informed consent
• Patients and their families have a strong willingness to participate in clinical trials, and are willing to bear all the consequences caused by the failure of the trial, and sign an informed consent form

Exclusion criteria

• HIV positive patients
• Patients who are experiencing uncontrolled viral, bacterial or fungal infections, malignant tumors, heart abnormalities, liver dysfunction, or renal insufficiency
• Cannot perform an MRI
• Infection or dermatosis at pre-injection site
• Any condition that may increase the subjects' risk or interfere with the results of the trial. In addition to MLD, there are other neurological disorders.