Gene Transfer for Sickle Cell Disease

Plain-language summary

This Phase 1 study tests a single infusion of the patient's own bone marrow-derived CD34+ stem cells transduced with a lentiviral vector containing a short-hairpin RNA targeting BCL11a in sickle cell disease (SCD). The procedure is similar to a bone marrow transplant, but the patient's own blood stem cells are returned after the new genetic material is introduced, which eliminates the risk of graft-versus-host disease and reduces the risk of graft rejection. Eligibility requires a diagnosis of SCD with genotype HbSS, HbS/0 thalassemia, HbSD or HbSO, and severe symptomatic disease defined by complications such as at least two episodes of acute chest syndrome in the 2 years before study entry.

The summary above is a plain-language rendering of the official record. The original English title is shown for reference.

Trial details

Phase

Phase 1

Status

Active, not recruiting

Sponsor

David Williams

Intervention

single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a

Start date

2/13/2018

Estimated completion

11/13/2026

Countries

United States

Related genes

Locations

• Los Angeles, United States
• Boston, United States

Eligibility criteria

Criteria are reproduced from the ClinicalTrials.gov record in the original English. Only the trial team can determine eligibility.

Inclusion Criteria:

* Diagnosis of SCD with genotype HbSS, HbS/0 thalassemia, HbSD, or HbSO
* 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 entry.
  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 40 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 trial.
* 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 years)
  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 enrollment.
* 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