MND-ADA Transduction of CD34+ Cells From Children With Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID)
Severe combined immune deficiency (SCID) may result from inherited deficiency of the enzyme adenosine deaminase (ADA). Children with ADA-deficient SCID often die from infections in infancy, unless treated with either a bone marrow transplant or with ongoing injections of PEG-ADA (Adagen) enzyme replacement therapy. Successful BMT requires the availability of a matched sibling donor for greatest success, and treatment using bone marrow from a less-well matched donor may have a higher rate of complications. PEG-ADA may restore and sustain immunity for many years, but is very expensive and requires injections 1-2 times per week on an ongoing basis. This clinical trial is evaluating the efficacy and safety of an alternative approach, by adding a normal copy of the human ADA gene into stem cells from the bone marrow of patients with ADA-deficient SCID. Eligible patients with ADA-deficient SCID, lacking a matched sibling donor, will be eligible if they meet entry criteria for adequate organ function and absence of active infections and following the informed consent process. Bone marrow will be collected from the back of the pelvis from the patients and processed in the laboratory to isolate the stem cells and add the human ADA gene using a retroviral vector. The patients will receive a moderate dosage of busulfan, a chemotherapy agent that eliminates some of the bone marrow stem cells in the patient, to "make space" for the gene-corrected stem cells to grow once they are given back by IV. Patients will be followed for two years to assess the potentially beneficial effects of the procedure on the function of their immune system and to assess possible side-effects. This gene transfer approach may provide a better and safer alternative for treatment of patients with ADA-deficient SCID.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||MND-ADA Transduction Of CD34+ Cells From The Umbilical Cord Blood Of Infants Or The Bone Marrow Of Children With Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID)|
- Assess the efficacy of stem cell transduction/engraftment by serial examination of peripheral blood lymphocytes and hematopoietic cells to quantitate the percentages of cells containing the ADA cDNA by semi-quantitative DNA-PCR. [ Time Frame: Monthly x 1 year, then every 2-3 months x 1 year ] [ Designated as safety issue: No ]
- Assess vector expression by ADA enzymatic activity, and possibly RT-linked PCR, of peripheral blood leukocytes. [ Time Frame: Monthly x 1 year, then every 2-3 months x 1 year ] [ Designated as safety issue: No ]
- Examine the safety of undergoing the procedure: marrow harvest, PEG-ADA withdrawal, busulfan administration, cell reinfusion. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
|Study Start Date:||November 2008|
|Estimated Study Completion Date:||December 2014|
|Estimated Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Retroviral-mediated ADA gene transfer
Transfer of the human ADA gene to isolated CD34+ cells from the bone marrow.
Biological: ADA gene transfer
Autologous CD34+ cells transduced with the retroviral vector MND-ADA, carrying the human ADA gene.
The proposed study population is affected with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID), an autosomal recessive congenital immune deficiency. The basis of the proposed study (and product) is retroviral-mediated transduction of autologous, bone marrow derived CD34+ hematopoietic progenitor cells with the MND-ADA retroviral vector in a 5 day cell processing period. Transduction is followed by infusion of the washed cells into subjects not receiving enzyme replacement therapy with Polyethylene-conjugated ADA (PEG-ADA, ADAGEN7) who have had their PEG-ADA injections discontinued, and have undergone bone marrow cytoreductive therapy with a single non-ablative treatment course of Busulfan. The dose of cells infused will be determined by the patient-to-patient variation of the number of progenitors available from individual patients. Statistical analyses post-infusion will help determine the dose-response of the number of cells infused to the level of engraftment and resulting level of immune reconstitution. Following cellular infusion, a primary clinical end-point will be the absolute numbers of T and B lymphocytes containing the transduced ADA gene by quantitative, real-time PCR analyses. Measurement of blood mononuclear cell ADA enzyme levels will be analyzed. Based on the degree of marking of lymphocytes and of granulocytes, the selective advantage of lymphocytes may be gauged. Subjects will be monitored for the development of clonal proliferation, under the 15 year plan required by the FDA. One major aim of the study will be to see if subjects can remain off PEG-ADA and maintain protective immunity from the population of transduced lymphocytes arising from transduced progenitors. If sufficient gene-modified cells result, and PEG-ADA enzyme replacement therapy can be permanently discontinued, the advantage of this therapeutic approach may change the standard of care for these patients.
|United States, California|
|University of California, Los Angeles|
|Los Angeles, California, United States, 90095|
|Principal Investigator:||Donald B. Kohn, M.D.||University of California, Los Angeles|