Induction of Donor Tolerance in Renal Transplants

肾移植中诱导供体耐受

基本信息

批准号：
8333414
负责人：
SUZANNE T ILDSTAD
金额：
$ 173.34万
依托单位：
REGENEREX, LLC
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-03 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8333414
关键词：
Address Aplastic Anemia Autoimmunity Biological Assay Biomedical Engineering Biopsy Blood Bone Marrow Bone Marrow Cells Businesses CD8B1 gene Cell Transplants Cells Childhood Chimerism Chronic Chronic Granulomatous Disease Collection Creatinine Cyclophosphamide Data Diabetes Mellitus Disease Dose Engineering Engraftment Enrollment FDA approved Face Generations Goals Grant Hand Health Heart Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemoglobinopathies Immune Immune Tolerance Immune system Immunologic Monitoring Immunosuppression Immunosuppressive Agents Inherited Islets of Langerhans Kidney Kidney Failure Kidney Transplantation Laboratories Lead Legal patent Life Liver Living Donors Lupus Macular degeneration Malignant Neoplasms Metabolic Diseases Modeling Morbidity - disease rate Mucopolysaccharidosis II Multiple Sclerosis Myocardial Infarction Natural regeneration Opportunistic Infections Organ Organ Transplantation Organ failure Patients Pharmaceutical Preparations Phase Population Preparation Procedures Process Prograf Property Protocols documentation Psoriasis Regimen Regulatory T-Lymphocyte Renal function Reproducibility Rheumatoid Arthritis Safety Serum Shipping Ships Sickle Cell Anemia Solid Stem cell transplant Stem cells T-Lymphocyte Technology Testing Thalassemia Therapeutic Therapeutic immunosuppression Tissues Toxic effect Transplant Recipients Transplantation Universities Weaning base commercialization conditioning cost experience fludarabine follow-up graft vs host disease in vitro Assay in vivo islet kidney allograft large bowel Crohn&apos s disease leukemia leukodystrophy meetings mortality mouse model nephrotoxicity novel prevent quality assurance regenerative repaired stem

项目摘要

DESCRIPTION: Renal transplantation is the preferred therapeutic approach for end organ failure. However, the chronic use of immunosuppressive agents is critical to prevent rejection. The drugs are costly ($15,000-25,000/year) and have significant toxicities including opportunistic infection, an increased rate of malignancy, nephrotoxicity, and other end organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism induces tolerance to transplanted organs. However, the toxicity and complications associated with conventional hematopoietic stem cell transplants (HSCT), primarily graft-versus-host disease (GVHD) and the need for a matched donor, has limited the therapeutic application of HSCT to tolerance induction. We have identified and patented a novel tolerogenic bone marrow cell population of CD8+/TCR- facilitating cells (FC) that enhances engraftment of stem cells in mismatched recipients without causing GVHD. The discovery of FC opens the door to employing HSCT as a viable cell-based approach for tolerance induction. The product, FCRx, addresses the major challenges preventing the widespread use of HSCT for tolerance induction. FCRx is a bioengineered bone marrow product that includes hematopoietic stem cells (HSC) and FC, but avoids GVHD in mismatched recipients. In phase I of this proposal, we achieved our proposed milestones, demonstrating that we could reliably produce and transport FCRx and safely infuse it into nonmyeloablatively conditioned renal transplant recipients. We demonstrated that the proprietary FCRx procedure can routinely produce a graft with defined 12-TCR+ T cell composition and enriched for HSC and engraftment-enhancing FC. The ultimate goal is the induction of immune tolerance and the elimination of or reduction in the need for expensive and harmful immunosuppressive drugs. We have developed a nonmyeloablative conditioning regimen with 200 cGy TBI/fludarabine/cyclophosphamide/MMF/prograf to avoid the toxicity of conditioning. Since completing Phase I, we have addressed a major concern expressed by the reviewers regarding our ability to enroll subjects and have now successfully transplanted 6 living donor kidney patients, all of whom demonstrated donor chimerism at one month post-transplant. The approaches for collection, shipping, and FCRx preparation have also been approved by the FDA. Three patients show laboratory evidence of donor-specific tolerance, and immunosuppression is being weaned. The remaining subjects are early in follow-up. The reproducibility and quality assurance of the FCRx process will lead to its successful commercial launch. In phase II we will increase the pace of transplants and demonstrate that FCRx consistently achieves engraftment of HLA mismatched HSC in nonmyeloablatively conditioned kidney transplant recipients, induces donor-specific tolerance without causing significant GVHD, and reduces or eliminates the need for long-term immunosuppression. A recent meeting with FDA classified our product as Phase II, another milestone that will enhance commercialization.

描述：肾移植是最终器官衰竭的首选治疗方法。但是，长期使用免疫抑制剂对于防止排斥至关重要。这些药物的昂贵（每年为15,000-25,000美元），并且具有重大毒性，包括机会性感染，恶性肿瘤，肾毒性和其他最终器官损害。捐助者特异性公差的诱导将解决这些局限性。骨髓嵌合体诱导对移植器官的耐受性。然而，与常规造血干细胞移植（HSCT），主要是移植物与宿主疾病（GVHD）相关的毒性和并发症以及对匹配供体的需求限制了HSCT对耐受性诱导的治疗应用。我们已经确定并为CD8+/TCR-促进细胞（FC）的新型耐受性骨髓细胞群（FC）确定并获得了专利，该细胞（FC）增强了不匹配受体中干细胞的植入而不会引起GVHD。 FC的发现为采用HSCT作为一种可行的基于细胞的耐受性诱导方法打开了大门。该产品FCRX解决了阻止HSCT广泛使用耐受性诱导的主要挑战。 FCRX是一种生物工程的骨髓产物，包括造血干细胞（HSC）和FC，但避免了不匹配的受体中GVHD。在该提案的第一阶段中，我们实现了我们提出的里程碑，表明我们可以可靠地生产和运输FCRX，并将其安全地注入非甲状腺素的肾移植受者中。我们证明，专有的FCRX程序可以常规地产生具有定义的12-TCR+ T细胞组成的移植物，并富含HSC和植入增强的FC。最终目标是诱导免疫耐受性以及消除或减少对昂贵和有害的免疫抑制药物的需求。我们已经开发了一种非乳化性调理方案，该方案具有200 CGY TBI/Fludarabine/Cyctophamide/MMF/Prograf，以避免调节的毒性。自完成第一阶段以来，我们已经解决了审稿人对我们注册受试者的能力并现在成功移植6名活着的供体肾脏肾脏患者的主要关注点，所有这些患者都在移植后一个月证明了供体嵌合。 FDA也批准了收集，运输和FCRX准备的方法。三名患者显示了实验室特异性耐受性的实验室证据，并断奶了免疫抑制。其余的受试者在随访的早期。 FCRX流程的可重复性和质量保证将导致其成功的商业发布。在第二阶段，我们将提高移植的速度，并证明FCRX始终达到非甲状腺素不足的HSC植入非甲状腺素的肾脏移植受者中，会导致供体特异性耐受性，而诱导了显着的GVHD，并且会导致显着的GVHD，并减少或消除长期免疫抑制的需求。最近与FDA的一次会议将我们的产品归类为II期，这是另一个将增强商业化的里程碑。