Gene Transfer for ADA-SCID Using an Improved Lentiviral Vector (TYF-ADA)

Gene Transfer for Adenosine Deaminase-severe Combined Immunodeficiency (ADA-SCID) Using an Improved Self-inactivating Lentiviral Vector (TYF-ADA)

Gene transfer for ADA-SCID using an improved lentiviral vector (TYF-ADA)

Study Overview

• Status: Unknown
• Conditions: Adenosine DeAminase Severe Combined ImmunoDeficiency (ADA-SCID)
• Intervention / Treatment: Genetic: TYF-ADA gene-modified autologous stem cells

Detailed Description

This clinical trial will evaluate a safety and efficiency improved lentiviral vector system for delivering a therapeutic gene to patients with severe combined immunodeficiency (SCID) due to a defective adenosine deaminase (ADA) gene. This gene encodes for the adenosine deaminase enzyme, which is essential for the proper growth and function of infection-fighting white blood cells called T and B lymphocytes. Patients who lack this enzyme are vulnerable to frequent and severe infections.

ADA-SCID patients are normally rescued by a bone marrow transplant (BMT) from a matched healthy donor. However, matched donors are difficult to find and donor BMT is associated with high risk. This trial aims to treat ADA-SCID using a safety and efficiency improved self-inactivating lentiviral vector carrying a functional ADA gene to correct the genetic defect. By collecting an individual's stem cells and modifying them with a lentivirus, the gene-corrected cells can be returned to the patient to help produce normal healthy immune cells.The primary objectives are to evaluate the safety of the improved self-inactivating lentiviral vector TYF-ADA, the ex vivo gene transfer clinical protocol and the efficacy of immune reconstitution in patients overcoming frequent infections present at the time of treatment. We will assess the lentiviral gene integration sites and the long-term effect of this gene transfer procedure.

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

Contacts and Locations

• Study Contact: Name: Lung-Ji Chang, Ph.D; Phone Number: 86-0755-86725195; Email: c@szgimi.org

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China, 518000
      • Recruiting
      • Shenzhen Geno-Immune Medical Institute
      • Contact: Lung-Ji Chang, Ph.D; Phone Number: 86-0755-86725195; Email: c@szgimi.org
      • Principal Investigator: XiaoDong Shi, M.D./P.H.D
      • Principal Investigator: Jie Zheng, M.D./P.H.D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of classical ADA-SCID based on:

  • A proven defective adenosine deaminase (ADA) gene as defined by direct sequencing of patient DNA.
  • T-cell immune deficiency defined as one or more of the following: CD3+ autologous T cells < 300/ul, or less than 50% of normal value for in vitro mitogen stimulation, or absent proliferation in vitro to antigens.
• With severe infections, including but not limited to: pneumonitis; protracted diarrhea requiring total parenteral nutrition; infection with herpes viruses or adenovirus or fungus; disseminated BCG infection.
• No cytogenetic abnormalities (medullary karyotype) and no detection of main rearrangements associated with acute leukemia of children.
• No prior allogeneic stem cell transplantation.
• Life expectancy ≥ 2 months.
• Negative for HIV infection.
• Written, informed consent obtained prior to any study-specific procedures.

Exclusion Criteria:

• None

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: TYF-ADA-modified autologous stem cells; Autologous hematopoietic and/or mesenchymal stem cells transduced with lentiviral vector carrying the ADA gene	Genetic: TYF-ADA gene-modified autologous stem cells; Infusion of TYF-ADA-modified autologous stem cells at 1~10x10^6 gene-modified cells per kg body weight; or more infusions depending on the circumstances

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival up to a year	Patient will be monitored for overall health condition, including immune cell assessments, blood biochemistry and metabolitic activities, metabolic detoxification, gene-modified cell percentage and vector copy number (VCN) in the blood, and continued follow-up for 15 years.	15 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1. Success of immune reconstitution	Immunological and metabolic values including all leukocyte counts (ALC), T, B and NK cell counts (CD3, CD4, CD8, CD19, CD56), T cell TREC levels, T cell repertoire diversity, PHA proliferation rate, immunoglobulins and dATP levels will be measured.	12 month
2. Change of infection status	Immune recovery associated with reduction of infection episodes and frequencies, including viral, fungal and bacterial infections will be documented.	12 month

Collaborators and Investigators

• Sponsor: Shenzhen Geno-Immune Medical Institute

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: July 17, 2018
• First Submitted That Met QC Criteria: August 22, 2018
• First Posted (Actual): August 24, 2018

Study Record Updates

• Last Update Posted (Actual): September 20, 2019
• Last Update Submitted That Met QC Criteria: September 18, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Adenosine deaminase severe combined immunodeficiency lentiviral vector
• Additional Relevant MeSH Terms: Metabolic Diseases; Immune System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Severe Combined Immunodeficiency
• Other Study ID Numbers: GIMI-IRB-18003

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