Year 4

CIRM DR1-01452 – Stem Cell Gene Therapy for Sickle Cell Disease
Scientific Progress in Year 4
The clinical complications of sickle cell disease are due to the inherited abnormality of the oxygen-carrying hemoglobin protein in red blood cells (RBC). The RBC are made from stem cells in the bone marrow and transplantation of stem cells from the bone marrow of a healthy donor to someone with sickle cell disease (SCD) can lead to significant improvements in their health. However, most people do not have a matched sibling donor, and transplants from unrelated donors have higher risks for complications, mainly due to immune reactions between the donor and the recipient.
The goal of this project is to develop a clinical trial to treat patients with SCD by transplanting them with their own bone marrow stem cells that have been modified in the laboratory by adding the gene for a version of human beta-globin that will act to inhibit sickling of the patient’s RBC (“anti-sickling” gene). This approach may provide a way to improve the health of people with SCD, with advantages over clinical treatments using transplantation of bone marrow stem cells from another person.
In the first 2 years of this project, we demonstrated the feasibility of this approach, i.e. that the clinical cell product, the subject’s bone marrow stem cells modified with the anti-sickling gene, can be produced suitably for clinical transplantation and that enough of the anti-sickling hemoglobin is made to reverse sickling of RBC made from the gene-modified stem cells. The Clinical/Regulatory component of our Disease Team established the proposed network of California clinical hematology sites to obtain bone marrow samples from volunteer donors with SCD for laboratory research studies on cell product development (UCLA, CHLA and CHRCO). We put into place the necessary IRB-approved protocols to collect bone marrow samples at these sites to use for the laboratory research at UCLA and USC. This network obtained its first BM sample from a SCD donor on 3/18/2010 and a total of 56 over 4 years. These patient-derived samples have been truly essential to the advancement of the laboratory work because bone marrow from SCD patients is needed for studies to measure expression of the anti-sickling gene and improvement in RBC sickling. The Clinical Regulatory component has also produced the clinical trial protocol, which defines which specific people with SCD would be eligible for participation in this study, and the exact approach of the clinical study, including how the patients will be evaluated before the procedure, the details of the bone marrow harvest, stem cell processing and transplant processes, and how the effects of the procedure will be assessed. This protocol was conceived with input from the Team of physicians and scientists with expertise in clinical and experimental hematology, bone marrow transplantation, transfusion medicine, gene therapy and cell processing laboratory methods, regulatory affairs, and biostatistics. It has now been approved by the UCLA Institutional Review Board and the Institutional Scientific Protocol review Committee, as well as the NIH Recombinant DNA Advisory Committee.
During the last 2 years the Clinical Gene Therapy Laboratory component of the Team has demonstrated the feasibility of the stem cell processing procedure. Mimicking the future clinical scenario, the Lab was able to isolate stem cells from a large scale bone marrow harvest, insert the anti-sickling gene in adequate amount and recover the needed amount of stem cells that would be transplanted into the patient. The Clinical/Regulatory component of our Disease Team validated all the assays that will be used during the clinical trial i.e. to characterize the final cell product and also the end-point assays to analyze the efficacy of this approach in patients. Another major focus during the third and fourth year has been safety and toxicology studies in a murine model of bone marrow transplant; these successful results allow advancement to support an IND application in the second quarter of 2014, with a goal of opening the trial in the third quarter of the year.