Stem Cell Graft Engineering to Treat Sickle Cell Disease

描述（由申请人提供）：镰状细胞病（SCD）是一种红细胞（RBC）的遗传异常，在美国影响超过70,000人，或大约每500名非洲裔美国人中有1人。在目前的治疗方法下，美国40岁的死亡率为50%。SCD是一种慢性衰弱性疾病，常伴有疼痛危象、急性胸综合征、中风和肾衰竭。因此，患者需要经常住院治疗，并经常旷工。迄今为止，治疗SCD的唯一方法是造血干细胞移植（HSCT）。然而，目前与消融HSCT相关的发病率和死亡率限制了该方法的广泛应用。此外，对匹配供体的要求限制了HSCT仅占候选人的17%。我们已经开发出一种方法来设计骨髓移植，以避免HSCT的主要并发症：移植物抗宿主反应性（GVHD）；移植失败;以及对完美匹配的需求。我们的方法优于目前的治疗方法，因为它涉及一个专有的过程，丰富专利的促进细胞（FC）和干细胞，但去除产生gvhd的细胞。在本提案中，我们将利用已被证明对白血病患者有效的FCRx产品治疗SCD患者。在I期，我们成功开发了一种低强度非清髓调节方法，在两名儿童镰状细胞患者与匹配的兄弟姐妹供体中建立了e20%的供体嵌合。我们达到了确定的移植终点，产生了正常的红细胞，功能上治愈了疾病。两名患者都能很好地耐受这种条件，在移植后529和644岁时仍保持嵌合和无症状。患者1号停止了所有免疫抑制，患者2号接受低剂量单药治疗，并将于2007年12月完成减量治疗。我们将开发和销售一种质量控制/质量保证的fda批准的骨髓产品（SCD FCRx），用于治疗SCD患者。我们的平台技术将提供给世界各地的医院系统。这种治疗方法可以扩展到其他血液疾病，包括地中海贫血，这是世界上最常见的遗传遗传病。公司和大学的互补结构和专业知识为这一共同努力提供了有利条件。该公司将继续制定和执行生产和销售该产品的战略，而该大学将进行早期临床试验，并在其fact认证的细胞处理设施中处理骨髓。公共卫生相关性：骨髓移植是镰状细胞病（SCD）和地中海贫血的唯一治疗方法。然而，这种方法的广泛应用受到对完美HLA匹配的需要和不可接受的调节毒性的限制。这个二期STTR项目将采用我们专有的促进细胞/干细胞处理方法来制备一种名为FCRx的产品，用于大约80%没有合适的兄弟姐妹供体的SCD患者。在该项目的第一阶段，我们成功地展示了我们对SCD进行功能性修复的方法。

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 is 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 effective 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. Patient #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 individuals 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 complementary 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 approach 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 approximately 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.