Stem Cell Graft Engineering to Treat Sickle Cell Disease

DESCRIPTION (provided by applicant): Sickle Cell Disease (SCD) is a genetic abnormality of red blood cells (RBC) that affects over 70,000 people in the United States, or approximately 1 in every 500 African-Americans. With current therapies, the mortality in the United States is 50% by age 40. SCD is a chronic, debilitating disease associated with frequent painful crises, acute chest syndrome, stroke, and renal failure. As a result, patients require frequent hospitalizations and experience absenteeism from work. The only cure for SCD to date is hematopoietic stem cell transplant (HSCT). However, at present the morbidity and mortality associated with ablative HSCT has limited the widespread application of this approach. Moreover, the requirement for a matched donor has limited HSCT to only 17% of candidates. We have developed an approach to engineer a bone marrow graft to avoid the major complications of HSCT: graft-versus-host reactivity (GVHD); graft failure; and the need for perfect matching. Our approach i s superior to current therapies because it involves a proprietary process that enriches for patented facilitating cells (FC) and stem cells but removes GVHD-producing cells. In this proposal we will utilize the FCRx product, already demonstrated to be effe ctive for treatment of leukemic patients, for treatment of patients with SCD. In phase I, we successfully developed a reduced-intensity nonmyeloablative conditioning approach that established e20% donor chimerism in two pediatric sickle cell patients with matched sibling donors. We met our defined end point of engraftment with production of normal RBC, functionally curing the disease. Both patients tolerated the conditioning very well and remain chimeric and asymptomatic at 529 and 644 post-transplant. Pati ent #1 is off all immunosuppression and Patient #2 is on low dose monotherapy and will complete tapering of the drug in December 2007. We will develop and market a quality controlled/quality assured FDA-approved bone marrow product (SCD FCRx) to treat indi viduals with SCD. Our platform technology will be provided to hospital systems worldwide. Such a treatment approach could be expanded to other blood disorders, including thalassemia, the most commonly inherited genetic disease in the world. The complementa ry structure and expertise of the company and the University lends itself nicely to this joint effort. The company will continue to develop and execute a strategy to produce and market the product while the University will conduct the early stage clinical trial and process the marrow in its FACT-accredited cell processing facility. PUBLIC HEALTH RELEVANCE: Bone marrow transplantation is the only curative treatment for sickle cell disease (SCD) and thalassemia. However, the widespread application of this app roach has been limited by a need for perfect HLA matching and the unacceptable toxicity of conditioning. This Phase II STTR project will apply our proprietary facilitating cell/stem cell processing approach to prepare a product, called FCRx, for the approx imately 80% of SCD patients who do not have a suitably matched sibling donor. We successfully demonstrated our approach to functionally cure SCD in Phase I of this project.