- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00794508
MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
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 Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
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California
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Los Angeles, California, United States, 90095
- University of California, Los Angeles
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
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.
AND
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,
OR
- 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.
OR
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.
Exclusion Criteria:
- Age less than 1 month
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.
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.
Pulmonary
- Resting O2 saturation by pulse oximetry <95%.
- Chest x-ray indicating active or progressive pulmonary disease.
Cardiac
- Abnormal electrocardiogram (EKG) indicating cardiac pathology.
- Uncorrected congenital cardiac malformation.
- Active cardiac disease, including clinical evidence of congestive heart failure,cyanosis, hypotension.
Neurologic
- Significant neurologic abnormality by examination.
- Uncontrolled seizure disorder.
Renal
- 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.
Hepatic/GI:
- 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
General
- Expected survival <6 months.
- Pregnant.
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Retroviral-mediated ADA gene transfer
Transfer of the human ADA gene to isolated CD34+ cells from the bone marrow.
|
Autologous CD34+ cells transduced with the retroviral vector MND-ADA, carrying the human ADA gene.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
2 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
2 years
|
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
|
2 years
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Donald B. Kohn, M.D., University of California, Los Angeles
Publications and helpful links
General Publications
- Candotti F, Shaw KL, Muul L, Carbonaro D, Sokolic R, Choi C, Schurman SH, Garabedian E, Kesserwan C, Jagadeesh GJ, Fu PY, Gschweng E, Cooper A, Tisdale JF, Weinberg KI, Crooks GM, Kapoor N, Shah A, Abdel-Azim H, Yu XJ, Smogorzewska M, Wayne AS, Rosenblatt HM, Davis CM, Hanson C, Rishi RG, Wang X, Gjertson D, Yang OO, Balamurugan A, Bauer G, Ireland JA, Engel BC, Podsakoff GM, Hershfield MS, Blaese RM, Parkman R, Kohn DB. Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans. Blood. 2012 Nov 1;120(18):3635-46. doi: 10.1182/blood-2012-02-400937. Epub 2012 Sep 11.
- White SL, Lee TD, Toy T, Carroll JE, Polsky L, Campo Fernandez B, Davila A, Kohn DB, Chang VY. Evaluation of clonal hematopoiesis in pediatric ADA-SCID gene therapy participants. Blood Adv. 2022 Nov 8;6(21):5732-5736. doi: 10.1182/bloodadvances.2022007803.
- Reinhardt B, Habib O, Shaw KL, Garabedian E, Carbonaro-Sarracino DA, Terrazas D, Fernandez BC, De Oliveira S, Moore TB, Ikeda AK, Engel BC, Podsakoff GM, Hollis RP, Fernandes A, Jackson C, Shupien S, Mishra S, Davila A, Mottahedeh J, Vitomirov A, Meng W, Rosenfeld AM, Roche AM, Hokama P, Reddy S, Everett J, Wang X, Luning Prak ET, Cornetta K, Hershfield MS, Sokolic R, De Ravin SS, Malech HL, Bushman FD, Candotti F, Kohn DB. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency. Blood. 2021 Oct 14;138(15):1304-1316. doi: 10.1182/blood.2020010260.
- Shaw KL, Garabedian E, Mishra S, Barman P, Davila A, Carbonaro D, Shupien S, Silvin C, Geiger S, Nowicki B, Smogorzewska EM, Brown B, Wang X, de Oliveira S, Choi Y, Ikeda A, Terrazas D, Fu PY, Yu A, Fernandez BC, Cooper AR, Engel B, Podsakoff G, Balamurugan A, Anderson S, Muul L, Jagadeesh GJ, Kapoor N, Tse J, Moore TB, Purdy K, Rishi R, Mohan K, Skoda-Smith S, Buchbinder D, Abraham RS, Scharenberg A, Yang OO, Cornetta K, Gjertson D, Hershfield M, Sokolic R, Candotti F, Kohn DB. Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. J Clin Invest. 2017 May 1;127(5):1689-1699. doi: 10.1172/JCI90367. Epub 2017 Mar 27.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- ADA Gene Therapy
- 1R01FD003005-01 (U.S. FDA Grant/Contract)
- 9908-337 (Other Identifier: OBA-RAC)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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