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 a diseased 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 Graft-Versus-Host Disease (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 fix or replace a diseased gene is called gene editing. A person's own cells are edited using a specialized biological medicine that has been formulated for use in human beings.
Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. Investigators have recently discovered a gene called BCL11A 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.
Diagnosis of either a) sickle cell disease with genotype HbSS, HbS/B0 thalassemia, HbSD, or HbSO, or b) transfusion-dependent β-thalassemia
Age 13-40 years.
Clinically severe disease, defined as: For sickle cell disease, the presence of one or more of the following clinical complications: i) Minimum of two episodes of acute chest syndrome (ACS) in the 2 years before study entry. ii) 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. For β-thalassemia patients: i) At least 100 mL/kg/year or 10 units/year of blood transfusions, on an annualized basis for the two years preceding enrollment.
White blood cell (WBC) count within the range of 2.5 - 25.0 x 109 /L
Uncontrolled infection, such as current febrile illness, infection requiring parenteral antibiotics, or systemic fungal infection.
Active malignancy.
Active complication of underlying hemoglobinopathy that would place the patient at unacceptable risk for participation, in the judgment of the Investigators.
Major surgery in the past 30 days.
Single group
autologous bone marrow derived CD34+ HSPCs electroporated with BCL11A enhancer targeting Cas9 ribonucleoprotein
Biological/Vaccineautologous bone marrow derived CD34+ HSPCs electroporated with BCL11A enhancer targeting Cas9 ribonucleoprotein
Sequencing Assay for Variant rs114518452
DeviceDevice used to carry out the diagnostic testing for exclusion criteria number 12
Primary engraftment
Successful hematopoietic reconstitution after conditioning (defined by absolute neutrophil count (ANC) greater than or equal to 0.5 x 10\^9 /L for three consecutive days without growth factor support), achieved by day 42 after day 0 of stem cell infusion (i.e., "primary engraftment").
Hemoglobin
Total hemoglobin (in g/dL), hemoglobin fractions (A, F, and S in g/dL), percent HbF, and percent F cells
Platelet Engraftment
Platelet engraftment (defined as platelet count ≥20,000/L without transfusion for 7 days by day +42 after stem cell infusion)
Severe vaso-occlusive crises (for sickle cell disease (SCD) patients)
Change from baseline in incidence of severe vaso-occlusive crises (requiring emergency department visit or hospital admission)
Acute chest syndrome (for sickle cell disease (SCD) patients)
Change from baseline in incidence of acute chest syndrome
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Daniel Bauer
Lead sponsor
Boston Children's Hospital
Sponsor institution
