Autologous Transplant of EFS-ADA Modified Bone Marrow Cells for ADA-Deficient Severe Combined Immunodeficiency (SCID)
In this current study, the investigators will determine whether using a lentiviral vector (based on HIV-1) will be more effective and safer at gene transfer to hematopoietic stem cells compared to previous gene transfer vectors based on murine (mouse) retroviruses for ADA-deficient SCID. The level of gene transfer in blood cells and immune function will be measured as endpoints.
Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency
Genetic: EFS-ADA transduced CD34+ cells from the bone marrow
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Autologous Transplantation of Bone Marrow CD34+ Stem/Progenitor Cells After Addition of a Normal Human ADA cDNA by the EFS-ADA Lentiviral Vector for Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID)|
- Assess safety by recording clinical toxicities. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]Safety will be assessed by recording clinical adverse events.
- Assess safety by determining absence or presence of exposure to replication-competent lentivirus (RCL) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]Replication-competent lentivirus exposure will be assessed by Western blot analysis for antibodies to VSV-G protein.
- Assess safety by evaluating the absence or development of monoclonal expansion or leukoproliferative complications from vector insertional effects [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]Monoclonal expansion of blood cells by vector-mediated activity will be assessed by nrLAM-PCR
- Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]Overall survival will be assessed
- Event-free survival [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]Event-free survival will be assessed by determining the numbers of subjects who remain alive with adequate immune reconstitution and do not need an allogeneic hematopoietic stem cell transplant or re-institution of enzyme replacement therapy.
- Determine the frequency of gene marking in peripheral blood cells [ Time Frame: 2 years ] [ Designated as safety issue: No ]The frequency of peripheral blood cells containing the EFS-ADA transferred human ADA cDNA will be determined by qPCR as an index of gene transduction and engraftment of hematopoietic stem cells.
- Quantify clonal diversity of vector integrants [ Time Frame: 2 Years ] [ Designated as safety issue: No ]The clonal diversity of vector integration sites will be determined using nrLAM-PCR
- Quantify ADA enzyme activity in peripheral blood mononuclear cells [ Time Frame: 2 years ] [ Designated as safety issue: No ]The ADA enzymatic activity in peripheral blood mononuclear cells will be measured by biochemical assay.
- Quantify total adenine nucleotides in erythrocytes [ Time Frame: 2 years ] [ Designated as safety issue: No ]The levels of adenine nucleotides in erythrocytes will be measured by HPLC.
- Determine absolute lymphocytes on complete blood count [ Time Frame: 2 years ] [ Designated as safety issue: No ]The absolute lymphocyte counts (ALC) on complete blood count will be measured as an index of immune reconstitution.
- Quantify the absolute numbers T, B, and NK lymphocytes [ Time Frame: 2 years ] [ Designated as safety issue: No ]The absolute numbers of T, B and NK lymphocytes will be determined using flow cytometry as an index of immune reconstitution
- Assess lymphocyte mitogenic proliferation [ Time Frame: 2 years ] [ Designated as safety issue: No ]The proliferative responses of lymphocyte to mitogen stimulation will be quantified as an index of immune reconstitution.
- Measure quantitative immunoglobulins by class [ Time Frame: 2 years ] [ Designated as safety issue: No ]The levels of immunoglobulin classes (IgG, IgM, IgA) will be quantified as an index of immune reconstitution
- Quantify specific antibody responses [ Time Frame: 2 years ] [ Designated as safety issue: No ]The development of specific antibody responses to vaccine antigens will be quantified as an index of immune reconstitution
- Assess T lymphocyte reconstitution [ Time Frame: 2 years ] [ Designated as safety issue: No ]T lymphocyte reconstitution will be assessed by TCR Vbeta family usage enumeration by flow cytometry and TREC assay
|Study Start Date:||May 2013|
|Estimated Study Completion Date:||May 2018|
|Estimated Primary Completion Date:||May 2016 (Final data collection date for primary outcome measure)|
Experimental: Autologous transplant of ADA gene corrected bone marrow
Autologous transplantation of EFS-ADA transduced bone marrow CD34+ cells
Genetic: EFS-ADA transduced CD34+ cells from the bone marrow
Eligible subjects will undergo bone marrow harvest under general anesthesia. The marrow will be processed to isolate CD34+ cells and transduced with the EFS-ADA lentiviral vector. If sufficient cells are obtained, the subjects will undergo marrow cytoreduction with busulfan (4 mg/kg). If the transduced CD34+ final cell product meets all release criteria, the cells will be infused intravenously. PEG-ADA enzyme replacement therapy will be discontinued at day +30. After discharge from the hospital, the subject will be seen for interval history and examination by either their home physician, the principal investigator or a clinical investigator and have blood drawn at months 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 21, and 24.
The study will be open to fifteen (15) infants and children diagnosed with ADA-deficient SCID who do not have a medically eligible, HLA-identical sibling donor for bone marrow transplantation. The EFS-ADA lentiviral vector with the human ADA cDNA will be used to transduce autologous CD34+ cells from the bone marrow of these subjects. The subjects will receive 4 mg/kg busulfan prior to re-infusion of their gene-modified cells. Safety is the primary endpoint. During the follow-up phase, the investigators will determine whether the cells can engraft and produce mature cells that contain and express the corrected ADA gene in the absence of PEG-ADA enzyme replacement therapy (ERT), which will be withheld at Day +30 following transplant. Efficacy studies to evaluate level of immune reconstitution will begin in the first year and will continue in the second year. This Phase I/II clinical trial will be performed at Mattel Children's Hospital, UCLA and at the Mark O. Hatfield Clinical Research Center, NIH.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01852071
|Contact: Donald B Kohn, MD||(310) firstname.lastname@example.org|
|Contact: Kit L Shaw, PhD||(310) email@example.com|
|United States, California|
|Mattel Children's Hospital, UCLA||Recruiting|
|Los Angeles, California, United States, 90095|
|Contact: Donald B Kohn, MD 310-794-1964 firstname.lastname@example.org|
|Contact: Kit L Shaw, PhD (310) 267-0584 email@example.com|
|Principal Investigator: Satiro de Oliveira, MD|
|Sub-Investigator: Ami Shah, MD|
|Sub-Investigator: Gay M Crooks, MD|
|Sub-Investigator: Theodore Moore, MD|
|United States, Maryland|
|Mark O. Hatfield Clinical Research Center, NIH||Active, not recruiting|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Donald B Kohn, MD||University of California, Los Angeles|