Lentiviral Gene Therapy for X-ALD

• ClinicalTrials.gov Identifier: NCT03727555
• Recruitment Status: Unknown
• First Posted: November 1, 2018
• Last Update Posted: September 19, 2019
• Sponsor: Shenzhen Geno-Immune Medical Institute
• Information provided by (Responsible Party): Shenzhen Geno-Immune Medical Institute

Study Description

Brief Summary:

This is a Phase I/II clinical trial of gene therapy for treating X-linked adrenoleukodystrophy using a high-safety, high-efficiency, self-inactivating lentiviral vector TYF-ABCD1 to functionally correct the defective gene. The objectives are to evaluate the safety and efficacy of the gene transfer clinical protocol.

Condition or disease	Intervention/treatment	Phase
X-linked Adrenoleukodystrophy	Genetic: Intracerebral LV gene therapy	Not Applicable

Detailed Description:

X-linked adrenoleukodystrophy (X-ALD) is a devastating neurological disorder caused by mutations in the ABCD1 gene that encodes a peroxisomal ATP-binding cassette transporter (ABCD1). ABCD1 is responsible for transport of CoA-activated very long-chain fatty acids (VLCFA) into the peroxisome for degradation. X-ALD is clinically characterized by two main phenotypes: adrenomyeloneuropathy (AMN) and the inflammatory cerebral ALD. This diease presents most commonly in males. Approximately 50% of heterozygote females show some symptoms later in life. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. The disease is characterized by normal development in early childhood, followed by rapid degeneration to a vegetative state. ALD patients are normally treated with haematopoietic stem cell transplantation (HSCT) from a matched healthy donor. However, HSCT must be performed at a very early stage of the disease, which limits the therapeutic opportunies for juvenile or adult forms of ALD. This trial aims to treat ALD using a safety and efficiency improved self-inactivating lentiviral vector carrying a functional ABCD1 gene to correct the genetic defect. By Intracerebral injection to delivery the lentiviral vector with a normal ALD gene to correct the pathologies associated with this genetic defect.

The primary objectives are to evaluate the safety of the advanced self-inactivating lentiviral vector TYF-ABCD1, 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 patients' disease beheviors.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Lentiviral Gene Therapy for X-linked Adrenoleukodystrophy (X-ALD)
• Actual Study Start Date: October 30, 2018
• Actual Primary Completion Date: October 30, 2018
• Estimated Study Completion Date: October 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Lentivirus-mediated delivery of ABCD1 to the CNS.; Intracerebral injection with lentiviral TYF-ABCD1 vector carrying the functional gene	Genetic: Intracerebral LV gene therapy; Intracerebral LV gene therapy to deliver high levels lenvirus which carry normal ABCD1 gene at 1-2×10^9 multiplicity of infection/ml per site in multiple sites.

Outcome Measures

Primary Outcome Measures :

1. Safety evaluation of intracerebral injection of lentiviral TYF-ABCD1, 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. [ Time Frame: Minimum 1 day, maximum 1 year follow up ]
   Safety of intracerebral injection of lentiviral TYF-ABCD1, 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.
2. Altered disease progression [ Time Frame: Minimum 6 months, maximum 3 year follow up ]
   Altered disease progression based on biochemical analysis.
3. Assess disease progression [ Time Frame: Minimum 6 months, maximum 3 year follow up ]
   Assess disease progression based on MRI brain imaging analysis.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. X-ALD patients ≥0 years of age
2. ALD diagnosis of the brain: evaluation of the VLCFA value in plasma
3. Central imaging of the MRI to examine the damage on the CNS.
4. Neurological function score (NFS) ≥ 1
5. Parent / guardian / patient signing informed consent
6. 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. Stablized condition after statins, Lorenzoas oil, or diet to reduce VLCFA levels
3. Patients who are experiencing severe viral, bacterial or fungal infections, malignant tumors, heart abnormalities, liver dysfunction, or renal insufficiency
4. Cannot perform an MRI
5. Infection or dermatosis at pre-injection site

Contacts and Locations

Contacts

Contact: Lung-Ji Chang, Ph.D; 86-0755-86725195; c@szgimi.org

Locations

China, Guangdong

Shenzhen Geno-immune Medical Institute; Recruiting

Shenzhen, Guangdong, China, 518000

Contact: Lung-Ji Chang, PhD 86-0755-86725195 c@szgimi.org

Sponsors and Collaborators

Shenzhen Geno-Immune Medical Institute

More Information

• Responsible Party: Shenzhen Geno-Immune Medical Institute
• ClinicalTrials.gov Identifier: NCT03727555
• Other Study ID Numbers: GIMI-IRB-18006
• First Posted: November 1, 2018
• Last Update Posted: September 19, 2019
• Last Verified: September 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shenzhen Geno-Immune Medical Institute:

X-linked adrenoleukodystrophy; Lentiviral vector

Additional relevant MeSH terms:

Adrenoleukodystrophy; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Peroxisomal Disorders; Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases