MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
Condition: Severe Combined Immunodeficiency
MeSH terms: Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      The proposed study population is affected with adenosine deaminase-deficient severe combined
      immune deficiency (ADA-SCID), an autosomal recessive congenital immune deficiency. The basis
      of the proposed study (and product) is retroviral-mediated transduction of autologous, bone
      marrow derived CD34+ hematopoietic progenitor cells with the MND-ADA retroviral vector in a 5
      day cell processing period. Transduction is followed by infusion of the washed cells into
      subjects not receiving enzyme replacement therapy with Polyethylene-conjugated ADA (PEG-ADA,
      ADAGEN7) who have had their PEG-ADA injections discontinued, and have undergone bone marrow
      cytoreductive therapy with a single non-ablative treatment course of Busulfan. The dose of
      cells infused will be determined by the patient-to-patient variation of the number of
      progenitors available from individual patients. Statistical analyses post-infusion will help
      determine the dose-response of the number of cells infused to the level of engraftment and
      resulting level of immune reconstitution. Following cellular infusion, a primary clinical
      end-point will be the absolute numbers of T and B lymphocytes containing the transduced ADA
      gene by quantitative, real-time PCR analyses. Measurement of blood mononuclear cell ADA
      enzyme levels will be analyzed. Based on the degree of marking of lymphocytes and of
      granulocytes, the selective advantage of lymphocytes may be gauged. Subjects will be
      monitored for the development of clonal proliferation, under the 15 year plan required by the
      FDA. One major aim of the study will be to see if subjects can remain off PEG-ADA and
      maintain protective immunity from the population of transduced lymphocytes arising from
      transduced progenitors. If sufficient gene-modified cells result, and PEG-ADA enzyme
      replacement therapy can be permanently discontinued, the advantage of this therapeutic
      approach may change the standard of care for these patients.
    

Intervention name(s): ADA gene transfer
Intervention type(s): Biological
Intervention description(s): Autologous CD34+ cells transduced with the retroviral vector MND-ADA, carrying the human ADA gene.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Severe Combined Immune Deficiency; Adenosine Deaminase Deficiency; Gene Therapy; Hematopoietic Stem Cells; Retroviral Vector; ADA-deficient SCID