Lentiviral Gene Therapy for Adenosine Deaminase (ADA) Deficiency
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Purpose
Adenosine Deaminase (ADA) is an enzyme, needed by body to develop lymphocytes of the immune system. Children who are born in mutations with mutations in ADA gene have severe combined immunodeficiency (SCID). Children with ADA-deficient SCID generally die in the first year of life from severe infections because they do not have immune system that can fight against infections. ADA deficient individuals can be cured by bone marrow transplant, but the best results are obtained when there is fully matched family donor is available. In the absence of a matched related donor, transplants from unrelated or mismatched donors have a much worse outcome. There is a form of enzyme therapy (PEG-ADA) for ADA-deficient SCID, in which children receive injections of purified ADA enzyme 1-2 times each week. These injections can allow the immune system to recover to a level that protects children from infections.
However, these injections have to be given weekly and are very expensive (£ 125,000 - 200,000 annually) and the recovery of the immune system is not sustained over time.
Gene therapy for ADA-deficient SCID could be performed by introducing a normal copy of the human ADA gene into the blood forming stem cells of the patient's bone marrow by using a new type of gene delivery system (in this trial called a lentiviral vector). The gene corrected cells are then transplanted back into the patient after small dose of chemotherapy. These gene corrected stem cells can survive into the body and make lymphocytes. In this trial, we will determine whether gene therapy for ADA-deficient SCID using lentiviral vector is safe, feasible and effective
| Condition | Intervention | Phase |
|---|---|---|
|
Adenosine Deaminase Deficiency Severe Combined Immunodeficiencies (SCID) |
Genetic: EF1αS-ADA lentiviral vector transduced patient Cd34+ cells |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase I/II, Non-controlled, Open-label, Non-randomised, Single-centre Trial to Assess the Safety and Efficacy of EF1αS-ADA Lentiviral Vector Mediated Gene Modification of Autologous CD34+ Cells From ADA-deficient Individuals |
- Overall survival following gene therapy [ Time Frame: 3 years follow up ] [ Designated as safety issue: Yes ]
- Reduction in frequency of infections [ Time Frame: evaluated from 1st year after treatment by clinical history, complete physical examinations, haematological and microbiological tests ] [ Designated as safety issue: Yes ]
- Long term immune reconstitution as assessed by sustained improvement in thymic function [ Time Frame: 3 years follow up ] [ Designated as safety issue: No ]
| Estimated Enrollment: | 10 |
| Study Start Date: | November 2011 |
| Estimated Study Completion Date: | November 2021 |
| Estimated Primary Completion Date: | November 2018 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: EF1αS-ADA lentiviral vector transduced patient Cd34+ cells |
Genetic: EF1αS-ADA lentiviral vector transduced patient Cd34+ cells
EF1αS-ADA lentiviral vector transduced patient Cd34+ cells will be infused in a volume of ~10-20 mls/kg intravenously over 30-45 minutes.
|
Eligibility| Ages Eligible for Study: | up to 5 Years |
| Genders Eligible for Study: | Male |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Diagnosis of ADA-SCID confirmed by DNA sequencing or by confirmed absence of <3% of ADA enzymatic activity in peripheral blood (or for neonates) umbilical cord blood erythrocytes and/or leukocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy
- Patients who lack a fully HLA-matched family donor
- Patients < 5 years of age
- Parental/guardian signed informed consent
Exclusion Criteria:
- Patients who have a fully HLA-matched family donor
- Patients > 5 years of age
- Cytogenetic abnormalities on peripheral blood
- Evidence of infection with HIV-1&2, hepatitis B, HCV
- Evidence of active malignant disease
- Known sensitivity to busulfan
Contacts and Locations| Contact: Bobby Gaspar, Professor | +44 (0)207 905 2319 | H.Gaspar@ucl.ac.uk |
| United Kingdom | |
| Great Ormond Street Hospital for Children NHS Trust | Not yet recruiting |
| London, United Kingdom, WC1N 3JH | |
| Contact: Bobby Gaspar, Professor +44 (0)207 905 2319 H.Gaspar@ucl.ac.uk | |
| Principal Investigator: Bobby Gaspar, Professor | |
| Principal Investigator: Adrian Thrasher, Professor | |
| Principal Investigator: | Bobby Gaspar, Professor | Great Ormond Street Hospital for Children NHS Foundation Trust |
More Information
No publications provided
| Responsible Party: | Biren Patel, Great Ormond Street Hospital for Children NHS Trust |
| ClinicalTrials.gov Identifier: | NCT01380990 History of Changes |
| Other Study ID Numbers: | 10-MI-29 |
| Study First Received: | June 23, 2011 |
| Last Updated: | April 2, 2012 |
| Health Authority: | United Kingdom: Medicines and Healthcare Products Regulatory Agency United Kingdom: Research Ethics Committee |
Additional relevant MeSH terms:
|
Immunologic Deficiency Syndromes Severe Combined Immunodeficiency Agammaglobulinemia Immune System Diseases Infant, Newborn, Diseases DNA Repair-Deficiency Disorders |
Metabolic Diseases Blood Protein Disorders Hematologic Diseases Lymphoproliferative Disorders Lymphatic Diseases |
ClinicalTrials.gov processed this record on June 17, 2013