Direct Lentiviral Injection Gene Therapy for MLD

Shenzhen Geno-Immune Medical Institute

Status: Enrolling

Conditions: Metachromatic Leukodystrophy (MLD)

Treatments: Genetic: Intrathecal and intravenous LV gene therapy

Study type: Interventional

Funder types: Other

Identifiers

NCT03725670

GIMI-IRB-18005

Details and patient eligibility

About

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.

Full 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.

Enrollment: 10 estimated patients

Sex: All

Ages: 1 month to 50 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. MLD patient age >= 1 month
2. ARSA gene sequence analysis to confirm MLD mutations
3. Scoring system for brain MR Imaging confirmed MLD
4. Parent / guardian / patient signing informed consent
5. 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

1. HIV positive patients
2. Patients who are experiencing uncontrolled viral, bacterial or fungal infections, malignant tumors, heart abnormalities, liver dysfunction, or renal insufficiency
3. Cannot perform an MRI
4. Infection or dermatosis at pre-injection site
5. 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.

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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10 participants in 1 patient group

Lentivirus-mediated delivery of ARSA to the CNS and the body

Experimental group

Description:

Intrathecal and intravenous injections with lentiviral TYF-ARSA vector carrying the functional gene

Treatment:

Genetic: Intrathecal and intravenous LV gene therapy