Autologous Transplant of EFS-ADA Modified Bone Marrow Cells for ADA-Deficient Severe Combined Immunodeficiency (SCID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01852071
Recruitment Status : Active, not recruiting
First Posted : May 13, 2013
Last Update Posted : August 24, 2018
National Institute of Allergy and Infectious Diseases (NIAID)
National Human Genome Research Institute (NHGRI)
National Heart, Lung, and Blood Institute (NHLBI)
University of California, Los Angeles
Information provided by (Responsible Party):
Orchard Therapeutics Limited

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.

Condition or disease Intervention/treatment Phase
ADA-SCID Genetic: EFS-ADA transduced CD34+ cells from the bone marrow Phase 1 Phase 2

Detailed Description:
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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (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)
Study Start Date : May 2013
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : September 2018

Arm Intervention/treatment
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.

Primary Outcome Measures :
  1. Assess safety by recording clinical toxicities. [ Time Frame: 2 years ]
    Safety will be assessed by recording clinical adverse events.

  2. 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.

  3. 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

  4. Overall survival [ Time Frame: 2 years ]
    Overall survival will be assessed

  5. 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.

Secondary Outcome Measures :
  1. 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.

  2. Quantify clonal diversity of vector integrants [ Time Frame: 2 Years ]
    The clonal diversity of vector integration sites will be determined using nrLAM-PCR

  3. 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.

  4. Quantify total adenine nucleotides in erythrocytes [ Time Frame: 2 years ]
    The levels of adenine nucleotides in erythrocytes will be measured by HPLC.

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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 from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   1 Month and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

-Children ≥ 1.0 months of age with a diagnosis of ADA-deficient SCID based on A. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-deficient SCID as determined by reference laboratory or confirmed ADA gene mutation(s) known to cause disease , AND

B. Evidence of severe combined immunodeficiency based on either:

  1. Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, OR
  2. Evidence of severe immunologic deficiency in subject prior to institution of immune restorative therapy, based on

    1. lymphopenia (absolute lymphocyte count <400 cells/mcL) OR absence or low number of T cells (absolute CD3+ count <300 cells/mcL) OR
    2. severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, <10% of the response of the normal control of the day, or stimulation index <10)

      • Ineligible for matched sibling allogeneic bone marrow transplantation: absence of a medically eligible HLA-identical sibling, with normal immune function, who may serve as an allogeneic bone marrow donor
      • Signed written informed consent according to guidelines of the IRB (UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) Institutional Review Board

Exclusion Criteria:

  1. Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 8 weeks of entering this trial.
  2. Hematologic

    1. Anemia (hemoglobin < 10.5 g/dl at < 2 years of age, or < 11.5 g/dl at > 2 years of age).
    2. Neutropenia (absolute granulocyte count <500/mm3.
    3. Thrombocytopenia (platelet count < 150,000/mm3, at any age).
    4. INR or PT > 2X the upper limits of normal or PTT > 2.33X the upper limit of normal (patients with a correctable deficiency controlled on medication will not be excluded).
    5. Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
    6. Prior allogeneic HSCT with cytoreductive conditioning
  3. Infectious

    a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, Hepatitis C, or parvovirus B 19 by DNA PCR within 30-90 days prior to bone marrow harvest. If other infection is present, it must be under control (e.g. stable or decreasing viral load) at the time of screening

  4. Pulmonary

    1. Resting O2 saturation by pulse oximetry < 95% on room air.
    2. Chest x-ray indicating active or progressive pulmonary disease.
  5. Cardiac

    1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.
    2. Uncorrected congenital cardiac malformation with clinical symptomatology.
    3. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
    4. Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram.
  6. Neurologic

    1. Significant neurologic abnormality by examination.
    2. Uncontrolled seizure disorder.
  7. Renal

    1. Renal insufficiency: serum creatinine >= 1.2 mg/dl, 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 the upper limit of normal (ULN).
    2. Serum bilirubin > 2X ULN.
    3. Serum glucose > 1.5x ULN.
    4. Intractable severe diarrhea.
  9. Oncologic

    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. Ineligible for autologous HSCT by the criteria at the clinical site.
    5. Other conditions which in the opinion of the principal investigator and/or co-investigators, contra-indicate the bone marrow harvest, the administration of busulfan, infusion of transduced cells or indicate the patient or patient's parents/primary caregivers inability to follow protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01852071

United States, California
Mattel Children's Hospital, UCLA
Los Angeles, California, United States, 90095
United States, Maryland
Mark O. Hatfield Clinical Research Center, NIH
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Orchard Therapeutics Limited
National Institute of Allergy and Infectious Diseases (NIAID)
National Human Genome Research Institute (NHGRI)
National Heart, Lung, and Blood Institute (NHLBI)
University of California, Los Angeles
Principal Investigator: Donald B Kohn, MD University of California, Los Angeles

Responsible Party: Orchard Therapeutics Limited Identifier: NCT01852071     History of Changes
Other Study ID Numbers: IND 15440
U01AI100801 ( U.S. NIH Grant/Contract )
2P01HL073104 ( U.S. NIH Grant/Contract )
0910-1006 ( Other Identifier: OBA-RAC )
First Posted: May 13, 2013    Key Record Dates
Last Update Posted: August 24, 2018
Last Verified: August 2018

Keywords provided by Orchard Therapeutics Limited:
gene therapy, hematopoietic stem cell, SCID, lentivirus

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Severe Combined Immunodeficiency
Immune System Diseases
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases