MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
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|ClinicalTrials.gov Identifier: NCT00794508|
Recruitment Status : Completed
First Posted : November 20, 2008
Results First Posted : May 30, 2016
Last Update Posted : April 23, 2021
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|Condition or disease||Intervention/treatment||Phase|
|Severe Combined Immunodeficiency||Biological: ADA gene transfer||Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||MND-ADA Transduction of CD34+ Cells From the Bone Marrow Of Children With Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID): Effect of Discontinuation of PEG-ADA and Marrow Cytoreduction With Busulfan|
|Study Start Date :||November 2008|
|Actual Primary Completion Date :||December 2014|
|Actual Study Completion Date :||January 2015|
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.
- Number of Participants With Adverse Events [ Time Frame: 2 years ]Examine the safety of the procedure: harvesting bone marrow, isolating CD34+ hematopoietic stem/progenitor cells, performing ex vivo gene transduction with the MND-ADA gamma-retroviral vector, giving 90 mg/m2 busulfan to "make space" in the bone marrow to aid engraftment, and re-infusing the autologous gene-modified cells.
- Number of Participants With Greater Than 1% of Gene-Modified Cells in the Peripheral Blood [ Time Frame: 2 years ]As measured by quantitative polymerase chain reaction in peripheral blood cells separated into mononuclear and granulocyte fractions.
- Number of Participants Reaching the Normal Range of ADA Enzyme Activity [ Time Frame: 2 years ]As measured by ADA enzyme activity in peripheral blood mononuclear cells
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|Ages Eligible for Study:||1 Month to 18 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
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.
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.
- Written informed consent according to guidelines of the Institutional Review Board (IRB) at the University of California Los Angeles (UCLA).
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.
- Age less than 1 month
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.
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.
- Resting O2 saturation by pulse oximetry <95%.
- Chest x-ray indicating active or progressive pulmonary disease.
- Abnormal electrocardiogram (EKG) indicating cardiac pathology.
- Uncorrected congenital cardiac malformation.
- Active cardiac disease, including clinical evidence of congestive heart failure,cyanosis, hypotension.
- Significant neurologic abnormality by examination.
- Uncontrolled seizure disorder.
- Renal insufficiency: serum creatinine > or = 1.2 mg/dl, or > or = 3+ proteinuria.
- Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale.
- Serum transaminases > 5X normal.
- Serum bilirubin > 3.0 mg/dl.
- Serum glucose > 250mg/dl.
- Intractable severe diarrhea.
Oncologic (see below*)
- Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP)
- Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells
- Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells
- Known sensitivity to Busulfan
- Expected survival <6 months.
- Major congenital anomaly.
- Medically eligible HLA-matched sibling.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00794508
|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|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||Donald B. Kohn, M.D., Professor, University of California, Los Angeles|
|Other Study ID Numbers:||
ADA Gene Therapy
1R01FD003005-01 ( U.S. FDA Grant/Contract )
9908-337 ( Other Identifier: OBA-RAC )
|First Posted:||November 20, 2008 Key Record Dates|
|Results First Posted:||May 30, 2016|
|Last Update Posted:||April 23, 2021|
|Last Verified:||April 2021|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||No|
Severe Combined Immune Deficiency
Adenosine Deaminase Deficiency
Hematopoietic Stem Cells
Severe Combined Immunodeficiency
Immunologic Deficiency Syndromes
Immune System Diseases
Primary Immunodeficiency Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders