Overview
This is a Phase I/II clinical trial of gene therapy for treating Metachromatic leukodystrophy (MLD) using a safety and efficacy improved self-inactivating lentiviral vector TYF-ARSA to functionally correct the genetic defect. The primary objectives are to evaluate the safety and efficacy of the direct gene transfer clinical protocol.
Description
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.
Eligibility
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.