Hematopoietic Stem Cell BCL11A Enhancer Gene Editing for Severe β-Hemoglobinopathies

NCT06647979 | Recruiting Phase 1 FDA Drug FDA Device

• 1 other identifier: BCH-201
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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 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.

Conditions

Sickle Cell Disease; Beta-Thalassemia; Sickle Cell Anemia (HbSS, or HbSβ-thalassemia0); Transfusion Dependent Beta-Thalassaemia

Keywords

gene therapy; stem cell transplant; bone marrow transplant; autologous hematopoietic stem cell transplant; gene editing; hematopoietic stem cell transplant

Outcome Measures

Primary Outcomes (1)

• 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").

  42 days

Secondary Outcomes (14)

• Hemoglobin

  24 months

• Platelet Engraftment

  42 days

• Severe vaso-occlusive crises (for sickle cell disease (SCD) patients)

  24 months

• Acute chest syndrome (for sickle cell disease (SCD) patients)

  24 months

• Stroke (for sickle cell disease (SCD) patients)

  24 months

Study Arms (1)

Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

EXPERIMENTAL

Biological: autologous bone marrow derived CD34+ HSPCs electroporated with BCL11A enhancer targeting Cas9 ribonucleoprotein; Device: Sequencing Assay for Variant rs114518452

Interventions

Sequencing Assay for Variant rs114518452 DEVICE

Device used to carry out the diagnostic testing for exclusion criteria number 12

Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

autologous bone marrow derived CD34+ HSPCs electroporated with BCL11A enhancer targeting Cas9 ribonucleoprotein BIOLOGICAL

autologous bone marrow derived CD34+ HSPCs electroporated with BCL11A enhancer targeting Cas9 ribonucleoprotein

Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

Eligibility Criteria

• Age: 13 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• Adequate hematologic parameters including:
• White blood cell (WBC) count within the range of 2.5 - 25.0 x 109 /L
• Platelet count within the range of 150 - 700 x 109 /L
• Adequate organ function and performance status:
• Karnofsky performance status ≥70%
• Serum creatinine \</=1.5 times the upper limit of normal for age, and calculated creatinine clearance or GFR \</= 60 mL/min/1.73 m2.
• Direct bilirubin ≤ 2.0 mg/dL
• DLCO (corrected for hemoglobin), FEV1, FVC \>50% of predicted
• Left ventricular ejection fraction \>40% or shortening fraction \>25%
• Confirmed sickle cell disease or β-thalassemia diagnosis by molecular genetic testing.
• No HLA genotypically-identical related appropriate bone marrow donor available.
• Parental/guardian/patient signed informed consent.

You may not qualify if:

• Subjects who have concomitant condition or illness including, but not limited to:
• 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.
• Medical/psychiatric illness/social situations that would limit compliance with study requirements as determined by the treating physician.
• Contraindication to administration of conditioning medication (busulfan).
• Subjects who have undergone allogeneic or autologous hematopoietic stem cell transplant previously.
• Either or both of the following findings on screening bone marrow aspirate/biopsy: a) diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) or b) pathogenic mutation in any gene on the Rapid Heme Panel (RHP), a next-generation targeted sequencing clinical assay for hematologic malignancy associated mutations.
• For SCD patients:
• Severe cerebral vasculopathy (defined by occlusion or stenosis in the circle of Willis; or presence of Moyamoya disease)
• Receiving a chronic transfusion regimen for primary or secondary stroke prophylaxis. (Note: patients with a history of abnormal transcranial Doppler (TCD) who have transitioned from transfusions to hydroxyurea for stroke prophylaxis are also not eligible for the study. Most recent TCD must be within one year of screening for patients up to 16 years old.)
• History of overt stroke or any neurologic event lasting \> 24 hours. (Note: patients with imaging evidence of silent stroke but not on a chronic transfusion regimen are not excluded.)
• Known positive HIV serology or HIV nucleic acid testing, or positive serology for HCV, HBV, or HTLV.
• Known acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on prior biopsy.

Sponsors & Collaborators

• Daniel Bauer: lead

Study Sites (1)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

MeSH Terms

Conditions

Anemia, Sickle Cell; beta-Thalassemia

Interventions

Sequence Analysis

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Thalassemia

Intervention Hierarchy (Ancestors)

Genetic Techniques; Investigative Techniques

Central Study Contacts

Emily Morris

CONTACT

617-355-8724; gene.therapy@childrens.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor Pediatrics, Boston Children's Hospital

Study Record Dates

• First Submitted: October 11, 2024
• First Posted: October 18, 2024
• Study Start: December 1, 2025
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2030
• Last Updated: February 3, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)