Clinical Trial: Autologous Transplant of EFS-ADA Modified Bone Marrow Cells for ADA-Deficient Severe Combined Immunodeficiency (SCID)
Study Status: Active, not recruiting
Recruit Status: Active, not recruiting
Study Type: Interventional
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
Brief Summary: 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.
Detailed Summary: The study will be open to twenty (20) 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.
Sponsor: Donald B. Kohn, M.D.
Current Primary Outcome:
- Assess safety by recording clinical toxicities. [ Time Frame: 2 years ]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 ]Replication-competent lentivirus exposure will be assessed by polymerase chain reaction (PCR) 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 ]Monoclonal expansion of blood cells by vector-mediated activity will be assessed by nrLAM-PCR
- Overall survival [ Time Frame: 2 years ]Overall survival will be assessed
- Event-free survival [ Time Frame: 2 years ]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.
Original Primary Outcome:
- Assess safety by recording clinical toxicites. [ Time Frame: 2 years ]Safety will be assessed by recording clinical adverse events.
- Assess safety by determing absence or presence of exposure to replication-competent lentivirus (RCL) [ Time Frame: 2 years ]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 ]Monoclonal expansion of blood cells by vector-mediated activity will be assessed by nrLAM-PCR
- Overall survival [ Time Frame: 2 years ]Overall survival will be assessed
- Event-free survival [ Time Frame: 2 years ]Event-free survival will be assessed by determing 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 enyzme replacement therapy.
Current Secondary Outcome:
- Determine the frequency of gene marking in peripheral blood cells [ Time Frame: 2 years ]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 ]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 ]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 ]The levels of adenine nucleotides in erythrocytes will be measured by HPLC.
- Determine absolute lymphocytes on complete blood count [ Time Frame: 2 years ]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 ]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 ]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 ]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 ]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 ]T lymphocyte reconstitution will be assessed by TCR Vbeta family usage enumeration by flow cytometry and TREC assay
Original Secondary Outcome:
- Determine the frequency of gene marking in peripheral blood cells [ Time Frame: 2 years ]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 ]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 ]The ADA eznymatic activity in peripheral blood mononuclear cells will be measured by biochemical assay.
- Quantify total adenine nucleotides in erythrocytes [ Time Frame: 2 years ]The levels of adenine nucleotides in erythrocytes will be measured by HPLC.
- Determine absolute lymphocytes on complete blood count [ Time Frame: 2 years ]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 ]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 ]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 ]The levels of immunglobulin classes (IgG, IgM, IgA) will be quantified as an index of immune reconstitution
- Quantify specific antibody responses [ Time Frame: 2 years ]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 ]T lymphocyte reconstitution will be assessed by TCR Vbeta family usage enumeration by flow cytometry and TREC assay
Information By: University of California, Los Angeles
Dates:
Date Received: May 7, 2013
Date Started: May 2013
Date Completion: September 2018
Last Updated: August 1, 2016
Last Verified: August 2016
