Stem Cell Graft Engineering to Treat Sickle Cell Disease

干细胞移植工程治疗镰状细胞病

基本信息

批准号：
7537905
负责人：
SUZANNE T ILDSTAD
金额：
$ 71.14万
依托单位：
REGENEREX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-23 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7537905
关键词：
Abnormal Red Blood Cell Absenteeism Accreditation Address Affect African American Age Animal Model Autoimmune Diseases B-Lymphocytes Bone Marrow Bone Marrow Stem Cell Bone Marrow Transplantation Businesses Canis familiaris Cell physiology Cells Central Nervous System Diseases Child Childhood Chimerism Chronic Class Complication Condition Data Disease Disease Progression Donor person Dose End Point Engineering Engraftment Enrollment Erythrocytes Family Foundations Genes Goals Guanosine Monophosphate Health Personnel Healthcare Industry Hematological Disease Hematopoietic stem cells Hemoglobinopathies Hereditary Disease Hospitalization Hospitals Immune Immunosuppression Individual Inherited Institutes Insurance International Joints Kidney Failure Legal patent MabCampath Malignant - descriptor Marketing Marrow Methods Modeling Molecular Abnormality Morbidity - disease rate Mus Organ Orphan Disease Pain Parents Patients Peripheral Blood Stem Cell Personal Satisfaction Pharmaceutical Preparations Phase Phase I Clinical Trials Phase III Clinical Trials Positioning Attribute Process Production Protocols documentation Public Health Quality Control Quality of life Range Research Risk Role Safety Siblings Sickle Cell Sickle Cell Anemia Small Business Technology Transfer Research Solid Stem cell transplant Stem cells Stroke Structure Symptoms System Systemic disease Technology Thalassemia Therapeutic Therapeutic immunosuppression Toxic effect Transfusion Transplantation Treatment Protocols United States United States Food and Drug Administration Universities Weaning Work acute chest syndrome base conditioning experience graft failure graft vs host disease improved islet leukemia mortality mycophenolate mofetil prevent progenitor success

Abnormal Red Blood Cell Absenteeism Accreditation Address Affect African American Age Animal Model Autoimmune Diseases B-Lymphocytes Bone Marrow Bone Marrow Stem Cell Bone Marrow Transplantation Businesses Canis familiaris Cell physiology Cells Central Nervous System Diseases Child Childhood Chimerism Chronic Class Complication Condition Data Disease Disease Progression Donor person Dose End Point Engineering Engraftment Enrollment Erythrocytes Family Foundations Genes Goals Guanosine Monophosphate Health Personnel Healthcare Industry Hematological Disease Hematopoietic stem cells Hemoglobinopathies Hereditary Disease Hospitalization Hospitals Immune Immunosuppression Individual Inherited Institutes Insurance International Joints Kidney Failure Legal patent MabCampath Malignant - descriptor Marketing Marrow Methods Modeling Molecular Abnormality Morbidity - disease rate Mus Organ Orphan Disease Pain Parents Patients Peripheral Blood Stem Cell Personal Satisfaction Pharmaceutical Preparations Phase Phase I Clinical Trials Phase III Clinical Trials Positioning Attribute Process Production Protocols documentation Public Health Quality Control Quality of life Range Research Risk Role Safety Siblings Sickle Cell Sickle Cell Anemia Small Business Technology Transfer Research Solid Stem cell transplant Stem cells Stroke Structure Symptoms System Systemic disease Technology Thalassemia Therapeutic Therapeutic immunosuppression Toxic effect Transfusion Transplantation Treatment Protocols United States United States Food and Drug Administration Universities Weaning Work acute chest syndrome base conditioning experience graft failure graft vs host disease improved islet leukemia mortality mycophenolate mofetil prevent progenitor success

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项目摘要

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.

描述（由申请人提供）：镰状细胞疾病（SCD）是红细胞（RBC）的遗传异常（RBC），影响了美国70,000多人，每500名非裔美国人中约有1人。使用当前的疗法，到40岁时，美国的死亡率为50％。SCD是一种慢性，使人衰弱的疾病，与频繁的疼痛危机，急性胸部综合征，中风和肾衰竭相关。结果，患者需要频繁的住院和工作经历。迄今为止，SCD的唯一治愈方法是造血干细胞移植（HSCT）。但是，目前与消融HSCT相关的发病率和死亡率限制了这种方法的广泛应用。此外，对匹配捐赠者的要求将HSCT限于仅17％的候选人。我们已经开发了一种方法来设计一种骨髓移植物，以避免HSCT的主要并发症：移植物抗抗性反应性（GVHD）；移植失败；以及需要完美匹配的需求。我们的方法优于当前疗法，因为它涉及专有过程，该过程丰富了专利的促进细胞（FC）和干细胞，但可以去除产生GVHD的细胞。在此提案中，我们将利用FCRX产品，已经证明可以有效治疗白血病患者，以治疗SCD患者。在第一阶段，我们成功地开发了一种降低的强度非甲状腺素调节方法，该方法在两名具有匹配的兄弟姐妹供体的小儿镰状细胞患者中建立了E20％的供体嵌合。我们通过正常的RBC产生了植入的定义终点，从而在功能上可以治愈该疾病。两名患者都很好地耐受调理，并在移植后529和644中保持嵌合和无症状。患者＃1脱离了所有免疫抑制，患者＃2处于低剂量单一疗法中，并将在2007年12月完成该药物的逐渐减少。我们将开发和销售由FDA批准的质量控制/质量保证的FDA批准的骨髓产品（SCD FCRX），以使用SCD治疗个体。我们的平台技术将提供给全球医院系统。这种治疗方法可以扩展到其他血液疾病，包括Thalassya，这是世界上最常见的遗传疾病。公司和大学的互补结构和专业知识很好地借助了这一共同努力。该公司将继续制定和执行一项制定和销售产品的战略，而大学将在其事实认可的细胞处理设施中进行早期临床试验和处理骨髓。公共卫生相关性：骨髓移植是镰状细胞疾病（SCD）和地中海贫血的唯一治疗方法。但是，这种方法的广泛应用受到了需要完美的HLA匹配和不可接受的条件毒性的限制。该II期STTR项目将应用我们的专有促进细胞/干细胞加工方法来制备称为FCRX的产品，对于大约80％的SCD患者中，他们没有适当匹配的同胞供体。我们成功地证明了我们在该项目的I阶段在功能上治愈SCD的方法。