Direct Lentiviral Injection Gene Therapy for MLD

Direct Lentiviral TYF-ARSA Injection Gene Therapy for Metachromatic Leukodystrophy (MLD)

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.

Study Overview

• Status: Recruiting
• Conditions: Metachromatic Leukodystrophy (MLD)
• Intervention / Treatment: Genetic: Intrathecal and intravenous LV gene therapy

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Lung-Ji Chang, Ph.D; Phone Number: +86 0755-86573763; Email: c@szgimi.org

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China, 518000
      • Recruiting
      • Lung-Ji Chang
      • Contact: Lung-Ji Chang, Ph.D; Phone Number: +86 0755-86573763; Email: c@szgimi.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lentivirus-mediated delivery of ARSA to the CNS and the body; Intrathecal and intravenous injections with lentiviral TYF-ARSA vector carrying the functional gene	Genetic: Intrathecal and intravenous LV gene therapy; Direct IT and IV LV gene therapy to deliver high levels of LVs at 1-2×10^9 transduction units/ml which carry a normal ARSA gene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of IT and IV injections of lentiviral TYF-ARSA	Safety of IT and IV injections 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 the study drug(s). The grade of AEs will be summarized if related to the treatment.	up to 1 year follow up
Altered disease progression	Altered disease progression based on biochemical analysis.	up to 3 year follow up after treatment
Altered disease progression	Altered disease progression based on MRI brain imaging analysis	up to 3 year follow up after treatment

Collaborators and Investigators

• Sponsor: Shenzhen Geno-Immune Medical Institute
• Investigators: Principal Investigator: Lung-Ji Chang, Ph.D, Shenzhen Geno-immune Medical Institute

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2025
• Primary Completion (Actual): May 31, 2025
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: September 25, 2018
• First Submitted That Met QC Criteria: October 29, 2018
• First Posted (Actual): October 31, 2018

Study Record Updates

• Last Update Posted (Actual): June 26, 2025
• Last Update Submitted That Met QC Criteria: June 23, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: lentiviral vector; Metachromatic leukodystrophy (MLD); Intrathecal injection; Intravenous injection
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Demyelinating Diseases; Lipid Metabolism Disorders; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Sulfatidosis; Leukodystrophy, Metachromatic
• Other Study ID Numbers: GIMI-IRB-18005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No