Gene Transfer for Sickle Cell Disease

NCT03282656 | Active Not Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: P00026188
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 2

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.

Conditions

Sickle Cell Disease

Keywords

Gene therapy; lentivirus vector; BCL11A; Fetal Hemoglobin

Outcome Measures

Primary Outcomes (1)

• Rescue of hematopoiesis after conditioning

  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").

  within 7 weeks following infusion of gene transfer product

Secondary Outcomes (1)

• Expression of transgene

  at 6 weeks post gene transfer then every 6 months until 2 years after gene transfer

Study Arms (1)

Treatment arm

EXPERIMENTAL

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

Interventions

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

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

Treatment arm

Eligibility Criteria

• Age: 3 Years - 40 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:
• Minimum of two episodes of acute chest syndrome (ACS) in the 2 years before study entry.
• 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.
• Recurrent priapism (\> 2 episodes) in the 2 years before study entry.
• Red-cell alloimmunization (\>2 antibodies) during long-term transfusion therapy.
• 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 .
• 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:
• Performance status ≥70% (Lansky play for age \<16 years, Karnofsky for age ≥16 years)
• Left ventricular ejection fraction \>40% or shortening fraction \>25%

You may not qualify if:

• 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

Sponsors & Collaborators

• David Williams: lead

Study Sites (2)

UCLA - Mattel Children's Hospital

Los Angeles, California, 90095, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (1)

• Esrick EB, Lehmann LE, Biffi A, Achebe M, Brendel C, Ciuculescu MF, Daley H, MacKinnon B, Morris E, Federico A, Abriss D, Boardman K, Khelladi R, Shaw K, Negre H, Negre O, Nikiforow S, Ritz J, Pai SY, London WB, Dansereau C, Heeney MM, Armant M, Manis JP, Williams DA. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N Engl J Med. 2021 Jan 21;384(3):205-215. doi: 10.1056/NEJMoa2029392. Epub 2020 Dec 5.

  PMID: 33283990 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell; beta-Thalassemia

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

Study Officials

• Erica Esrick, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

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: Chief Scientific Officer

Model Details: Open-label, non-randomized, single center, pilot and feasibility, single arm cohort study

Study Record Dates

• First Submitted: August 22, 2017
• First Posted: September 14, 2017
• Study Start: February 13, 2018
• Primary Completion (Estimated): May 13, 2026
• Study Completion (Estimated): November 13, 2026
• Last Updated: January 9, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)