A Gene Transfer Study Inducing Fetal Hemoglobin in Sickle Cell Disease (GRASP, BMT CTN 2001)

A promising approach for the treatment of genetic diseases is called gene therapy. Gene therapy is a relatively new field of medicine in which genetic material (mostly DNA) in the patient is changed to treat his or her own disease. In gene therapy, we 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 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. To introduce new genetic material into the patient's own blood stem cells we 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.

Fetal hemoglobin (HbF) is a healthy, non-sickling kind of hemoglobin. The investigators have discovered a gene that is very important in controlling the amount of HbF. Decreasing 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, specifically the amount in red blood cells where sickle hemoglobin causes damage to the cell, and therefore potentially cure or significantly improve the condition. The gene we are targeting for change in this study that controls the level of fetal hemoglobin is called BCL11A.

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 certain strong medicines often required to prevent and treat GVHD and rejection. Our lab studies with normal mice, mice that have a form of SCD, and with cells from the bone marrow of SCD patients who have donated bone marrow for research purposes show this approach is very effective in reducing the amount of sickle hemoglobin in red cells. Our pilot trial testing this approach in 10 patients with SCD has shown that the treatment has not caused any unexpected safety problems, and that it increases HbF within the red blood cells. Our goal is to continue to test whether this approach is safe, and whether using gene therapy to change the expression of BCL11A will lead to decreased episodes of vaso-occlusive crisis pain in people with SCD.

This is an open-label, non-randomized, multi-center, phase 2 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. 25 patients ages 13 to 40 will be enrolled at sites across the US.

The main goal of this study is to determine whether the treatment will lead to a complete absence of severe vaso-occlusive events (VOEs) in patients with severe SCD.

After meeting eligibility criteria for the study, patients will receive blood transfusions for a period of at least 3 months prior to hematopoietic stem cell collection, with a goal of achieving a HbS level ≤ 30% by the time of mobilization. Patients will then 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 transduction with the lentiviral vector, 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. Transduction will be carried out on the selected CD34+ cells and transduced cells will be cryopreserved.

Patients will undergo standard work-up for autologous bone marrow transplantation prior to proceeding with conditioning and infusion of gene-modified cells. Patients will receive myeloablative conditioning with busulfan administered on days -5 to -2, prior to infusion of transduced cells. The transduced cells will be infused intravenously over 30-45 minutes after standard pre-hydration and premedication according to institutional guidelines.

Patients will be followed for 24 months post-infusion of gene modified cells.