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Gene Transfer for Sickle Cell Disease

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: NCT03282656
Recruitment Status : Active, not recruiting
First Posted : September 14, 2017
Last Update Posted : August 14, 2023
Information provided by (Responsible Party):
David Williams, Boston Children's Hospital

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Sickle Cell Disease Biological: single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a Phase 1

Detailed Description:

This is an open-label, non-randomized, single center, pilot and feasibility, single arm cohort study involving a single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a. Accrual will be a maximum of 7 evaluable patients with SCD. The study will have three strata:

  1. Stratum 1: ages ≥18-40
  2. Stratum 2: ages ≥12-<18
  3. Stratum 3: ages ≥3-<12

To determine the feasibility and safety of administering a lentiviral gene transfer vector encoding a small hairpin (sh) RNA targeting the γ-globin gene repressor, BCL11A, in patients with severe SCD.

Patients will undergo standard work-up for autologous bone marrow transplantation according to institutional guidelines and then undergo two bone marrow harvests at a minimum of 4 weeks apart that will be used for a back-up marrow (minimum of 2 x 106 CD34+ cells/kg) and for a harvest of autologous bone marrow for gene transfer.

Patients will receive blood transfusions for a period of 3 months prior to the planned date of product infusion, with a goal of achieving a HbS level ≤ 30% by the time of gene transfer. If the subject is already on a chronic transfusion regimen as part of baseline disease management, the regimen may be continued. The timing of transfusions will be coordinated to occur within 7 days prior to any procedures requiring anesthesia such as bone marrow harvest.

Hematopoietic cells will be collected from the patient in advance of the treatment, to serve as a salvage procedure ("back-up graft"), should there be no hematopoietic recovery observed following the injection of genetically-manipulated cells, or should manipulated cells fail to meet release criteria. Bone marrow (up to 20 mL/kg) will be harvested from the patient under general anesthesia from the posterior iliac crests on both sides by multiple punctures at a minimum of 4 weeks prior to gene therapy. A portion of the bone marrow containing at least 2 x 106 CD34+ cells/kg will be frozen and stored unmanipulated according to standard clinical procedures for autologous bone marrow collection to constitute the back-up graft. If the number of CD34+ cells that exceeds 2 x 106 cells/kg is greater than or equal to 1 x 106 cells/kg, these excess cells would be processed for transduction, transduced, and then frozen. Transduction will be carried out on the selected CD34+ cells and transduced cells will be cryopreserved. If cells from the first harvest were transduced and frozen, these gene-modified cells will be thawed and prepared for infusion in parallel with the product from the subsequent harvest(s). In this case two separate products would be infused. All cell manipulation procedures and release testing will be performed in the transduction facility in accordance with Good Manufacturing Practice (GMP) following process specific standard operating procedures. Final Drug Product will be accompanied by a Certificate of Analysis, documenting that all release testing is complete and within specification. Subjects will receive myeloablative conditioning with Busulfan administered on days -5 to -2, prior to infusion of transduced cells. Cells will be infused intravenously over 30-45 minutes after standard prehydration and premedication according to Boston Children's Hospital Hematopoietic Stem Cell Transplantation Unit standard guidelines. This standard requires that the patient be on continuous cardiac, respiratory and oxygen saturation monitor throughout the infusion and for 30 minutes afterwards. Vital signs will be measured and recorded pre-transfusion, 15 minutes into transfusion, every hour for duration of infusion, and end of transfusion. The RN will stay with the patient for the first 5 minutes of the transfusion. If two transduction products are administered, the second transduced product will be administered without delay after the first.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, non-randomized, single center, pilot and feasibility, single arm cohort study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot and Feasibility Study of Hematopoietic Stem Cell Gene Transfer for Sickle Cell Disease
Actual Study Start Date : February 13, 2018
Estimated Primary Completion Date : May 13, 2024
Estimated Study Completion Date : November 13, 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Treatment arm
open-label, non-randomized, single center, pilot and feasibility, single arm cohort study of a single infusion of autologous bone marrow derived CD34+ HSC cells transduced with lentiviral vector containing a short-hairpin RNA targeting BC11A.
Biological: single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a
single infusion of autologous bone marrow derived CD34+ HSC cells transduced with the lentiviral vector containing a short-hairpin RNA targeting BCL11a

Primary Outcome Measures :
  1. Rescue of hematopoiesis after conditioning [ Time Frame: within 7 weeks following infusion of gene transfer product ]
    Rescue of hematopoiesis after conditioning (defined by absolute neutrophil count (ANC) greater than or equal to 0.5 x 109 /L for three consecutive days), achieved within 7 weeks following infusion (i.e., "primary engraftment").

Secondary Outcome Measures :
  1. Expression of transgene [ Time Frame: at 6 weeks post gene transfer then every 6 months until 2 years after gene transfer ]
    a. Presence of the transgene (vector copy number) in the following samples: i) Peripheral blood cells [measured in whole blood, mononuclear cells, and the following sorted populations: CD3+, CD15+, CD19+, and CD56+] at 6 weeks, and then every 6 months until 2 years after gene transfer.

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.

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Ages Eligible for Study:   3 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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): NCT03282656

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United States, California
UCLA - Mattel Children's Hospital
Los Angeles, California, United States, 90095
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
David Williams
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Principal Investigator: Erica Esrick, MD Boston Children's Hospital
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: David Williams, Chief Scientific Officer, Boston Children's Hospital Identifier: NCT03282656    
Other Study ID Numbers: P00026188
First Posted: September 14, 2017    Key Record Dates
Last Update Posted: August 14, 2023
Last Verified: August 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David Williams, Boston Children's Hospital:
Gene therapy
lentivirus vector
Fetal Hemoglobin
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hematologic Diseases
Genetic Diseases, Inborn