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

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Brief Title

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

Official Title

MND-ADA Transduction of CD34+ Cells From the Bone Marrow Of Children With Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID): Effect of Discontinuation of PEG-ADA and Marrow Cytoreduction With Busulfan

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.

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.

Study Phase

Phase 2

Study Type


Primary Outcome

Number of Participants With Adverse Events

Secondary Outcome

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


Severe Combined Immunodeficiency


ADA gene transfer

Study Arms / Comparison Groups

 Retroviral-mediated ADA gene transfer
Description:  Transfer of the human ADA gene to isolated CD34+ cells from the bone marrow.


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

November 2008

Completion Date

January 2015

Primary Completion Date

December 2014

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.


               -  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.

          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

               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.




1 Month - 18 Years

Accepts Healthy Volunteers



Donald B. Kohn, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID

ADA Gene Therapy

Secondary IDs


Responsible Party


Study Sponsor

Donald B. Kohn, M.D.


 FDA Office of Orphan Products Development

Study Sponsor

Donald B. Kohn, M.D., Principal Investigator, University of California, Los Angeles

Verification Date

April 2021