Lentiviral Gene Therapy for MLD

Gene Therapy for Metachromatic Leukodystrophy (MLD) Using a Self-inactivating Lentiviral Vector (TYF-ARSA)

This is a Phase I/II clinical trial of gene transfer for treating Metachromatic leukodystrophy (MLD) using a safety and efficiency 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 gene transfer clinical protocol.

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 some 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 efficiency improved self-inactivating lentiviral vector carrying a functional MLD gene to correct the genetic defect by intracerebral injection to delivery the lentiviral vector carrying a normal ARSA gene to correct the pathogenic defect. The primary objectives are to evaluate the safety of the improved self-inactivating lentiviral vector TYF-ARSA, the in vivo gene transfer clinical protocol and the efficacy of degradative metabolite in patients at the time of treatment, assessment of vector integration sites, and finally the long-term correction of the related pathological symptoms.

Intracerebral LV gene therapy to deliver high level lenviral vectors which carry normal ARSA gene at 1-2×10^9 multiplicity of infection (moi)/ml per site.

Safety of intracerebral injection of lentiviral TYF-ARSA, determined by number of participants with treatment-related adverse events (AEs), according to scheduled assessments, vital signs, & physical examinations as assessed by CTCAE v4.0. AEs & clinically significant abnormalities (meeting grade 3, 4, or 5 criteria according to CTCAE) will be summarized by maximum intensity & relationship to study drug(s). Grade 1 & 2 AEs will be summarized if related to study therapy.

Inclusion Criteria: MLD patient age >= 0 year 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.