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

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.

This is a non-randomized, single center, open-label, pilot safety and feasibility study involving a single infusion of autologous bone marrow derived CD34+ hematopoietic stem cells (HSPCs) electroporated with BCL11A enhancer targeting Cas9 ribonucleoprotein. Accrual will be a maximum of 14 evaluable subjects with sickle cell disease (SCD) or β-thalassemia. The study will enroll 7 evaluable subjects within each disease group: SCD and β-thalassemia. The study will have two strata within each diagnosis group. SCD Ages ≥18-40 years: Stratum 1a (n=3-7) Ages ≥13-18 years: Stratum 2a (n=0-4) β-thalassemia Ages ≥18-40 years: Stratum 1b (n=3-7) Ages ≥13-18 years: Stratum 2b (n=0-4) After meeting eligibility criteria, patients will be enrolled. Patients with SCD will receive blood transfusions for a period of 3 months prior to hematopoietic stem cell collection, with a goal of achieving a Hemoglobin S (HbS) level of ≤ 30% by the time of mobilization. All patients will undergo peripheral stem cell mobilization and have their cells collected by apheresis. The collected cells of each subject will be split into 2 portions; one portion for gene editing, and one portion set aside as a back-up product in the event a rescue treatment is needed. Patients may undergo multiple rounds of collection if sufficient numbers of cells are not obtained with the first collection. Patients will undergo a standard work-up for autologous bone marrow transplantation prior to proceeding with conditioning and infusion of their gene-edited cells. Patients will receive myeloablative conditioning with busulfan administered on days -5 to -2, prior to the infusion of edited cells. The edited cells will be infused intravenously. Patients will be followed for 24 months after the infusion of their gene edited cells.