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

NCT00794508 | Completed Phase 2 Results DMC

• 3 other identifiers: ADA Gene Therapy1R01FD003005-019908-337
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Severe Combined Immunodeficiency

Keywords

Severe Combined Immune Deficiency; Adenosine Deaminase Deficiency; Gene Therapy; Hematopoietic Stem Cells; Retroviral Vector; ADA-deficient SCID

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Adverse Events

  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 Outcomes (2)

• Number of Participants With Greater Than 1% of Gene-Modified Cells in the Peripheral Blood

  2 years

• Number of Participants Reaching the Normal Range of ADA Enzyme Activity

  2 years

Study Arms (1)

Retroviral-mediated ADA gene transfer

EXPERIMENTAL

Transfer of the human ADA gene to isolated CD34+ cells from the bone marrow.

Biological: ADA gene transfer

Interventions

ADA gene transfer BIOLOGICAL

Autologous CD34+ cells transduced with the retroviral vector MND-ADA, carrying the human ADA gene.

Retroviral-mediated ADA gene transfer

Eligibility Criteria

• Age: 1 Month - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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,
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Donald B. Kohn, M.D.: lead
• FDA Office of Orphan Products Development: collaborator
• National Institutes of Health (NIH): collaborator

Study Sites (1)

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Related Publications (4)

• 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.

  PMID: 22968453 BACKGROUND

• 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.

  PMID: 35914227 DERIVED

• 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.

  PMID: 33974038 DERIVED

• 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.

  PMID: 28346229 DERIVED

MeSH Terms

Conditions

Severe Combined Immunodeficiency; Severe combined immunodeficiency due to adenosine deaminase deficiency

Condition Hierarchy (Ancestors)

Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: Dr. Donald B. Kohn
• Organization: University of California Los Angeles

dkohn1@mednet.ucla.edu

310-794-1964

Study Officials

• Donald B. Kohn, M.D.

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: November 19, 2008
• First Posted: November 20, 2008
• Study Start: November 1, 2008
• Primary Completion: December 1, 2014
• Study Completion: January 1, 2015
• Last Updated: April 23, 2021
• Results First Posted: May 30, 2016

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)