Study of Gene Therapy Using a Lentiviral Vector to Treat X-linked Chronic Granulomatous Disease

Status: Recruiting
Phase: Phase 1/Phase 2
DFCI Protocol ID:

Chronic Granulomatous Disease (CGD) is an inherited immunodeficiency disorder which results from defects that prevent white blood cells from effectively killing bacteria, fungi and other microorganisms. Chronic granulomatous inflammation may compromise vital organs and account for additional morbidity. CGD is thought to affect approximately 1 in 200,000 persons, although the real incidence might be higher due to under-diagnosis of milder phenotypes. The first gene therapy approaches in X-CGD have shown that effective gene therapy requires bone-marrow (BM) conditioning with chemotherapy to make space for the gene-modified cells to engraft. These studies demonstrated that transplantation of gene modified stem cells led to production of white blood cells that could clear existing infections. However, some trails using mouse-derived retroviral vectors were complicated by the development of myelodysplasia and leukemia-like growth of blood cells. This trial will evaluate a new lentiviral vector that may be able to correct the defect, but have much lower risk for the complication. This study is a prospective non-controlled, non-randomized Phase I/II clinical trial to assess the safety, feasibility and efficacy of cellular gene therapy in patients with chronic granulomatous disease using transplantation of autologous bone marrow CD34+ cells transduced ex vivo by the G1XCGD lentiviral vector containing the human CGD gene. Primary objectives include evaluation of safety and evaluation of efficacy by biochemical and functional reconstitution in progeny of engrafted cells and stability at 12 months. Secondary objectives include evaluation of clinical efficacy, longitudinal evaluation of clinical effect in terms of augmented immunity against bacterial and fungal infection, transduction of CD34+ hematopoietic cells from X-CGD patients by ex vivo lentivirus-mediated gene transfer, and evaluation of engraftment kinetics and stability. Approximately 3-5 patients will be treated per site with a goal of 10 total patients to be treated with G1XCGD lentiviral vector.

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

David Williams, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:


Children's Hospital Boston: Colleen Dansereau,

Eligibility Criteria

Inclusion Criteria:

  -  Male X-CGD patients > 23 months of age

  -  Molecular diagnosis confirmed by DNA sequencing and supported by laboratory evidence
     for absent or reduction > 95% of the biochemical activity of the NADPH-oxidase

  -  At least one prior, ongoing or refractory severe infection and/or inflammatory
     complications requiring hospitalization despite conventional therapy

  -  No 10/10 HLA-matched donor available after searching of NMDP registries

  -  No co-infection with Human Immunodeficiency Virus (HIV) or hepatitis B virus (HBsAg
     positive) or hepatitis C virus (HCV RNA positive), CMV, adenovirus, parvovirus B 19
     or toxoplasmosis

  -  Written informed consent for adult patient, and assent for pediatric subjects seven
     years or older.

  -  Parental/guardian and, where appropriate, child's signed consent/assent

Exclusion Criteria:

  -  Age < 23 months

  -  10/10 HLA identical (A,B,C,DR,DQ) family or unrelated or cord blood donor unless
     there is deemed to be an unacceptable risk associated with an allogeneic procedure

  -  Contraindication for leukapheresis or bone marrow harvest (anemia Hb <8g/dl,
     cardiovascular instability, severe coagulopathy)

  -  Appropriate organ function as outlined below must be observed within 8 weeks of
     entering this trial.

       1. Hematologic

    1. Anemia (hemoglobin < 8 g/dl).

    2. Neutropenia (absolute granulocyte count <1,000/mm3)

    3. Thrombocytopenia (platelet count < 150,000/mm3).

    4. PT or PTT > 2X the upper limits of normal (patients with a correctable
       deficiency controlled on medication will not be excluded).

    5. Cytogenetic abnormalities known to be associated with hematopoietic defect
       on peripheral blood or bone marrow.

       2. Infectious

  a. Evidence of active infection with HIV-1, hepatitis B, Hepatitis C, CMV,
  adenovirus, parvovirus B19 or toxoplasmosis by DNA PCR within 8 weeks prior to
  mobilization/pheresis or bone marrow harvest.

       3. Pulmonary

  a. Resting O2 saturation by pulse oximetry < 90% on room air.

       4. 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

       5. Neurologic

    1. Significant neurologic abnormality by examination.

    2. Uncontrolled seizure disorder.

       6. Renal

    1. Renal insufficiency: serum creatinine ≥ 1.5 mg/dl, or ≥ 3+ proteinuria.

    2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade
       III or IV by the Common Terminology Criteria for Adverse Events (CTCAE)
       version 4.0.

       7. Hepatic/GI:

    1. Serum transaminases > 5X the upper limit of normal (ULN).

    2. Serum bilirubin > 2X ULN.

    3. Serum glucose > 1.5x ULN.

       8. Oncologic

  a. Evidence of active malignant disease

       9. General

    1. Expected survival < 6 months

    2. Major congenital anomaly

    3. Ineligible for autologous HSCT by the criteria at the clinical site.

    4. Contraindication for administration of conditioning medication. (Known
       sensitivity to Busulfan)

    5. Administration of gamma-interferon within 30 days before the infusion of
       transduced, autologous CD34+ cells.

    6. Participation in another experimental therapeutic protocol within 6 months
       prior to baseline and during the study period.

    7. Any other condition that, in the opinion of the Investigator, may
       compromise the safety or compliance of the patient or would preclude the
       patient from successful study completion.

    8. Patient/Parent/Guardian unable or unwilling to comply with the protocol

Know Your Options

Not sure which clinical trials might be right for your child? Email our clinical trials team at
We can help you navigate your options.

Get Clinical Trial Updates


Stay informed about Dana-Farber/Boston Children's research efforts, including information on new and current clinical trials. Sign up to receive our email newsletter Advances in Pediatric Hematology/Oncology.