Gene Transfer for Sickle Cell Disease

Status: Recruiting
DFCI Protocol ID:

A promising approach for the treatment of genetic diseases is called gene therapy. Gene therapy is a relatively new field of medicine that uses genetic material (mostly DNA) from the patient to treat his or her own disease. In gene therapy, the investigators introduce new genetic material in order to fix or replace the patient's disease gene, with the goal of curing the disease. The procedure is similar to a bone marrow transplant, in that the patient's malfunctioning blood stem cells are reduced or eliminated using chemotherapy, but it is different because instead of using a different person's (donor) blood stem cells for the transplant, the patient's own blood stem cells are given back after the new genetic material has been introduced into those cells. This approach has the advantage of eliminating any risk of GVHD, reducing the risk of graft rejection, and may also allow less chemotherapy to be utilized for the conditioning portion of the transplant procedure. The method used to introduce the gene into the patient's own blood stem cells is to engineer and use a modified version of a virus (called a 'vector') that efficiently inserts the "correcting" genetic material into the cells. The vector is a specialized biological medicine that has been formulated for use in human beings. The investigators have recently discovered a gene that is very important in the control of fetal hemoglobin expression. Increasing the expression of this gene in sickle cell patients could increase the amount of fetal hemoglobin while simultaneously reducing the amount of sickle hemoglobin in their blood, and therefore potentially cure the condition. In summary, the advantages of a gene therapy approach include: 1) it can be used even if the patient does not have a matched donor available; 2) it may allow a reduction in the amount of chemotherapy required to prepare the patient for the transplant; and 3) it will avoid the strong medicines often required to prevent and treat GVHD and rejection. The goal is to test whether this approach is safe, and whether using gene therapy to change the expression of this particular gene will lead to increased fetal hemoglobin production in people with sickle cell disease.

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

David Williams, MD, Dana-Farber Cancer Institute

Site-responsible Investigators:

Erika Esrick, MD, Boston Children's Hospital


Children's Hospital Boston: Gene Therapy Program,

Eligibility Criteria

Inclusion Criteria:

  -  Diagnosis of SCD with genotype HbSS, HbS/0 thalassemia, HbSD, or HbSO, and HbF <10% by

  -  Severe symptomatic SCD, defined by the presence of one or more of the following
     clinical complications:

       1. Minimum of two episodes of acute chest syndrome (ACS) in the 2 years before study

       2. History of three or more episodes of severe pain events requiring a visit to a
  medical facility and treatment with parenteral opioids in the 2 years before
  study entry.

       3. Recurrent priapism (> 2 episodes) in the 2 years before study entry.

       4. Red-cell alloimmunization (>2 antibodies) during long-term transfusion therapy.

       5. Receiving, or indicated to receive (based on prior stroke or elevated
  transcranial Doppler (TCD) results), chronic transfusions for primary or
  secondary stroke prophylaxis.

  -  Age 3 years to 35 years .

  -  Failure of hydroxyurea therapy due to lack of clinical improvement or inability to
     tolerate due to side effects (e.g., myelosuppression, gastrointestinal symptoms, or
     hepatic enzyme elevations). Clinical criteria must be met despite taking hydroxyurea
     for greater than or equal to 6 months, unless contraindicated or not tolerated.
     Patients taking hydroxyurea who still meet all inclusion criteria are eligible for the

  -  No HLA-genotypically identical related bone marrow donor available

  -  Parental/guardian/patient signed informed consent

  -  Willingness to return for follow-up for 15 years

  -  White blood cell (WBC) count within the range of 3.0 - 20.0 x 109 /L Hemoglobin within
     the range of 5 - 11 g/dL Platelet count within the range of 100 - 600 x 109 /L PT and
     PTT within normal limits, unless prolonged due to anticoagulation requirement.

  -  Adequate organ function and performance status:

       1. Performance status ≥70% (Lansky play for age <16 years, Karnofsky for age ≥16

       2. Left ventricular ejection fraction >40% or shortening fraction >25%

       3. Direct bilirubin ≤ 2.0 mg/dL

       4. Serum creatinine </= 1.5 times the upper limit of normal for age, and creatinine
  clearance or GFR >/= 70 mL/min/1.73 m2.

       5. For ages > 7 years, DLCO (corrected for hemoglobin), FEV1, FVC >50% of predicted;
  if age < 7 years, then oxygen saturation >92% on room air.

Exclusion Criteria:

  -  Contraindication to bone marrow harvest, or to administration of conditioning
     medication (busulfan).

  -  Subjects who have undergone allogeneic transplant previously.

  -  Known positive HIV serology or HIV nucleic acid testing, or positive serology for HCV,
     HBV, or HTLV.

  -  Uncontrolled infection.

  -  Active malignancy.

  -  Known myelodysplasia of the bone marrow or abnormal bone marrow cytogenetics.

  -  Receipt of an investigational study drug or procedure within 90 days of study

  -  Pregnancy, or breastfeeding in a postpartum female, or absence of adequate
     contraception for fertile subjects. Females of child-bearing potential must agree to
     use a medically acceptable method of birth control such as oral contraceptive,
     intrauterine device, barrier and spermicide, or contraceptive implant/injection from
     Screening through at least 6 months after drug product infusion. Male subjects must
     agree to use effective contraception (including condoms) from Screening through at
     least 6 months after drug product infusion.

  -  Acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on
     prior biopsy.

  -  An assessment by the Investigators that the subject will not comply with the study
     procedures outlined in the study protocol

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