MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID

This study is ongoing, but not recruiting participants.
FDA Office of Orphan Products Development
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Donald B. Kohn, M.D., University of California, Los Angeles Identifier:
First received: November 19, 2008
Last updated: March 31, 2015
Last verified: March 2015
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.

Condition Intervention Phase
Severe Combined Immunodeficiency
Biological: ADA gene transfer
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: 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)

Resource links provided by NLM:

Further study details as provided by University of California, Los Angeles:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 10
Study Start Date: November 2008
Estimated Study Completion Date: December 2029
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

Detailed Description:
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.

Ages Eligible for Study:   1 Month to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Children > 1.0 months of age with a diagnosis of ADA-deficient SCID based on:

    • Confirmed absence (<3% of normal levels) of ADA enzymatic activity in peripheral blood or (for neonates) umbilical cord erythrocytes and/or leukocytes, or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of enzyme replacement therapy.


    • Evidence of severe combined immunodeficiency based on either:

      • Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency,


    • Evidence of severe immunologic deficiency in subject based on lymphopenia (absolute lymphocyte count <200) or severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (deltaCPM<5,000), prior to institution of immune restorative therapy.


    • Fulfillment of criterion:

      • A in addition to evidence of genetic mutations affecting the ADA gene as determined by a CLIA certified laboratory and clinical evidence of combined immunodeficiency based on lymphopenia (absolute lymphocyte counts <2SD of age-matched control values) and hypogammaglobulinemia (<2SD of age-matched control values) or lack of specific antibody response to vaccination. In addition, for patients to be eligible under this criterion, they must present with a clinical history indicating life-threatening illness characterized by increased frequency and/or severity of infections resulting in hospitalization and/or the administration of intravenous antibiotics, for bacterial or opportunistic infection.
  2. Ineligible for allogeneic (matched sibling) bone marrow transplantation (BMT):

    • Absence of a medically eligible HLA-identical sibling with normal immune function who may serve as an allogeneic bone marrow donor.
  3. Written informed consent according to guidelines of the Committee on Clinical Investigations (CCI) at Childrens Hospital Los Angeles (CHLA).

This study is also open to delayed/late onset ADA-deficient patients who fulfill the criteria 1, 2.A, and 3 and who are not receiving PEG-ADA treatment after being invited to discuss all alternative treatment options with a physician not connected with the protocol.

Exclusion Criteria:

  1. Age less than 1 month
  2. Hematologic

    a. Anemia (hemoglobin <10.5 mg/dl at <2 years of age, or < 11.5 at >2 years of age,with normal serum iron studies). b. Neutropenia i. absolute granulocyte count <500/mm3 or ii. absolute granulocyte count 500-999/mm3 (1 month - 1 year of age) or 500-1499/mm3 (> 1 year of age)] and bone marrow aspirate and biopsy showing myelodysplasia or other gross abnormality. c. Thrombocytopenia (platelet count 150,000/mm3, at any age). d. PT or PTT >2X normal. e. Cytogenetic abnormalities on peripheral blood, or on cells collected by amniocentesis, if diagnosed in utero.

  3. Infectious

    a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, CMV or parvovirus B 19 by DNA PCR at time of assessment.

  4. Pulmonary

    1. Resting O2 saturation by pulse oximetry <95%.
    2. Chest x-ray indicating active or progressive pulmonary disease.
  5. Cardiac

    1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.
    2. Uncorrected congenital cardiac malformation.
    3. Active cardiac disease, including clinical evidence of congestive heart failure,cyanosis, hypotension.
  6. Neurologic

    1. Significant neurologic abnormality by examination.
    2. Uncontrolled seizure disorder.
  7. Renal

    1. Renal insufficiency: serum creatinine > or = 1.2 mg/dl, or > or = 3+ proteinuria.
    2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale.
  8. Hepatic/GI:

    1. Serum transaminases > 5X normal.
    2. Serum bilirubin > 3.0 mg/dl.
    3. Serum glucose > 250mg/dl.
    4. Intractable severe diarrhea.
  9. Oncologic (see below*)

    1. Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP)
    2. Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells
    3. Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells
  10. Known sensitivity to Busulfan
  11. General

    1. Expected survival <6 months.
    2. Pregnant.
    3. Major congenital anomaly.
    4. Medically eligible HLA-matched sibling.
    5. Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate infusion of transduced cells or indicate patient's inability to follow protocol.
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Please refer to this study by its identifier: NCT00794508

United States, California
University of California, Los Angeles
Los Angeles, California, United States, 90095
Sponsors and Collaborators
Donald B. Kohn, M.D.
FDA Office of Orphan Products Development
National Institutes of Health (NIH)
Principal Investigator: Donald B. Kohn, M.D. University of California, Los Angeles
  More Information

Responsible Party: Donald B. Kohn, M.D., Professor, University of California, Los Angeles Identifier: NCT00794508     History of Changes
Other Study ID Numbers: ADA Gene Therapy  1R01FD003005-01  9908-337 
Study First Received: November 19, 2008
Last Updated: March 31, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, Los Angeles:
Severe Combined Immune Deficiency
Adenosine Deaminase Deficiency
Gene Therapy
Hematopoietic Stem Cells
Retroviral Vector
ADA-deficient SCID

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Severe Combined Immunodeficiency
DNA Repair-Deficiency Disorders
Immune System Diseases
Infant, Newborn, Diseases
Metabolic Diseases processed this record on May 24, 2016