MND-ADA Transduction of CD34+ Cells From Children With ADA-SCID
Condition: Severe Combined Immunodeficiency
MeSH terms: Severe Combined Immunodeficiency; Immunologic Deficiency Syndromes
Intervention: ADA gene transfer
Intervention description: Autologous CD34+ cells transduced with the retroviral vector MND-ADA, carrying the human ADA gene.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 10.0
Sex: All
Minimum age: 1 Month
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Severe Combined Immune Deficiency; Adenosine Deaminase Deficiency; Gene Therapy; Hematopoietic Stem Cells; Retroviral Vector; ADA-deficient SCID

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          2. 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.

          3. 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:

          1. Age less than 1 month

          2. 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.

          3. 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.

          4. Pulmonary

               1. Resting O2 saturation by pulse oximetry <95%.

               2. Chest x-ray indicating active or progressive pulmonary disease.

          5. Cardiac

               1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.

               2. Uncorrected congenital cardiac malformation.

               3. Active cardiac disease, including clinical evidence of congestive heart
                  failure,cyanosis, hypotension.

          6. Neurologic

               1. Significant neurologic abnormality by examination.

               2. Uncontrolled seizure disorder.

          7. Renal

               1. Renal insufficiency: serum creatinine > or = 1.2 mg/dl, or > or = 3+ proteinuria.

               2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or
                  IV by Division of AIDS Toxicity Scale.

          8. Hepatic/GI:

               1. Serum transaminases > 5X normal.

               2. Serum bilirubin > 3.0 mg/dl.

               3. Serum glucose > 250mg/dl.

               4. Intractable severe diarrhea.

          9. Oncologic (see below*)

               1. Evidence of active malignant disease other than dermatofibrosarcoma protuberans
                  (DFSP)

               2. Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years
                  following the infusion of genetically corrected cells

               3. Evidence of DFSP expected to be life limiting within the 5 years following the
                  infusion of genetically corrected cells

         10. Known sensitivity to Busulfan

         11. General

               1. Expected survival <6 months.

               2. Pregnant.

               3. Major congenital anomaly.

               4. Medically eligible HLA-matched sibling.

               5. 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.