Inhibition of IkK to treat lethal Graft-vs.-Host Disease

异基因干细胞移植(allo-sct)是治疗急性髓系白血病的一种潜在的治疗方法。 患有白血病、淋巴瘤和多发性骨髓瘤的患者。然而， 与移植物抗宿主病(GVHD)相关的问题极大地限制了它的使用 人类白细胞抗原相合的家庭成员或无血缘关系的供者的异基因干细胞移植 很多移植中心。因此，新疗法的开发 对于需要异体移植的患者来说，预防或治疗GVHD将是一个重大的进步- SCT。 目前，预防移植物抗宿主病最常见的方法是 甲氨蝶呤、甲氨蝶呤等S期活性化疗药物联合应用 使用以下抗体的体内T细胞耗竭的方法或钙化抑制 CamPath-1H。虽然这些方法可以诱导T细胞耐受，但它们不会影响 促炎症细胞因子和趋化因子的产生 条件疗法对移植物抗宿主病的发展至关重要。因为大多数新疗法 用于治疗或预防移植物抗宿主病的研究源于对固体器官的研究 移植，不涉及炎症诱导的条件性治疗，我们 相信有一种新的方法专门关注allo-SCT和 需要进行调理治疗才能开发出新的药剂。 核因子-βB是一种由Rel蛋白组成的二聚体，在T细胞的诱导中起关键作用 耐受性和参与炎症的200多种蛋白质的产生。我们的团队 之前发现，针对核因子-βB的难溶药物的影响不大 关于GVHD在动物模型中的发生，这在很大程度上受到生物利用度的限制 在院子里。 在这份提案中，我们发起了与生物技术公司的合作， 理论，以评估TLX1001在预防中的使用情况 或GVHD的治疗。该药是IKK？催化域的抑制剂。和 通过干扰I？B的磷酸化来阻断核因子-βB的激活。 TheraLogics的创始人Al Baldwin博士和首席科学官Sankar Ghosh 博士是国际公认的核因子-B生物学专家？这项建议 汇集了两位在GVHD生物学方面非常有经验的研究人员，在DRS Serody和Blazar，以及Theralogics的科学家，他们都是核因子生物学的专家- ？鲍德温和戈什博士和两名靶向药理学的外部专家 威廉·赞博尼博士和理查德·纳什博士的GVHD狗模型的治疗。三 为研究TLX1001在治疗移植物抗宿主病中的应用提出了具体的目标 在供者脾细胞输注模型中用于预防GVHD 非清髓性骨髓移植。建议进行实验以评估 TLX1001与钙调神经磷酸酶抑制剂他克莫司联合应用。最后，研究是 建议研究该化合物的药代动力学和药效学。 在移植后的狗身上。如果第二阶段赠款成功，将为以下项目铺平道路 北卡罗来纳大学教堂山分校对这种疗法进行了临床试验。骨髓或干细胞移植对个人来说是一种挽救生命的程序。 患有某些类型的血癌。在大多数情况下，接受骨骼的人 骨髓或干细胞移植需要与捐赠者完美匹配才是最好的 可能的结果。这是由于捐赠者的白细胞可以对 在受体细胞上发现的蛋白质导致一种称为移植物抗宿主病的疾病 疾病(GVHD)。即使有最好的预防性治疗，移植物抗宿主病也会发生在 大约50%的接受骨髓或干细胞移植的人 完全匹配的供体，可能会导致多种并发症，包括死亡 收件人。因此，需要新的治疗形式来预防或治疗移植物抗宿主病。 更广泛地使用移植作为一种治疗形式。 这项提案研究了一种新的化合物，它可以阻止导致 GVHD和导致GVHD相关症状的蛋白质。实验 在动物模型中被提出用来测试化合物的活性，如果成功， 这项工作的长期目标是将这种化合物用于人体临床试验 移植物抗宿主病的治疗。

Allogeneic stem cell transplantation (allo-SCT) is potentially curative therapy for a patients suffering from leukemia, lymphoma and multiple myeloma. However, the problems associated with graft-versus-host disease (GVHD) have greatly limited the use of allo-SCT to patients with either an HLA-identical family member or unrelated donor in many transplant centers. As a consequence, the development of new therapies that could prevent or treat GVHD would be a significant advance for patients needing an allo- SCT. Currently, the most common approaches to the prevention of GVHD are either a combination of S-phase active chemotherapy drugs such as methotrexate and a calcineuring inhibitor or in vivo methods of T cell depletion using antibodies such as Campath -1H. While these approaches can induce T cell tolerance, they do not impact on the generation of proinflammatory cytokines and chemokines that are induced by conditioning therapy and critical to the development of GVHD. As most new therapies for the treatment or prevention of GVHD have arisen from studies in solid organ transplantation, which does not involve inflammation-inducing conditioning therapy, we believe a new approach that focuses specifically on allo-SCT and the complications of conditioning treatment are needed for new agents to be developed. NF-?B is a dimmer composed of Rel proteins and is critical in the induction of T cell tolerance and the generation of over 200 proteins involved in inflammation. Our group has previously found that poorly soluable drugs that target NF-?B have a modest effect on the occurrence of GVHD in animal models, that is greatly limited by the bioavailability of the compound. In this proposal, we have initiated a collaboration with the biotechnology company, Theralogics, to evaluate the use of TLX1001 licensed by the company in the prevention or treatment of GVHD. This drug is an inhibitor of the catalytic domain of IKK ? and blocks the activation of NF-?B by interfering with the phosphorylation of I?B. The founder of TheraLogics Al Baldwin PhD and the chief scientific officer Sankar Ghosh Ph.D. are internationally recognized experts in the biology of NF-?B. This proposal brings together two extremely experienced investigators in the biology of GVHD, in Drs Serody and Blazar, with scientists at Theralogics who are experts on the biology of NF- ?B in Drs Baldwin and Ghosh and two outside experts in the pharmacology of targeted therapy in Dr. William Zamboni and dog models of GVHD in Dr. Richard Nash. Three specific aims are proposed to investigate the use of TLX1001 in the treatment of GVHD in a donor splenocyte infusion model and for the prevention of GVHD after nonmyeloablative marrow transplantation. Experiments are proposed to evaluate the combination of TLX1001 with the calcineurin inhibitor tacrolimus. Finally, studies are proposed to investigate the pharmacokinetics and pharmacodynamics of the compound in dogs after transplantation. If this phase II grant is successful, it will pave the way for clinical trials of this therapy at the University of North Carolina at Chapel Hill. Bone marrow or stem cell transplantation can be a life-saving procedure for individuals with certain types of blood cancers. In most instances an individual receiving a bone marrow or stem cell transplant needs to be perfectly matched with the donor for the best possible result. This is due to the fact that donor white cells can react against the proteins found on the cells of the recipient causing a disease termed graft-versus-host disease (GVHD). Even with the best possible preventative therapies, GVHD occurs in around 50% of the individuals receiving a bone marrow or stem cell transplant from a perfectly matched donor and can cause multiple complications including death of the recipient. Thus, new forms of therapy to prevent or treat GVHD are needed for the broader use of transplantation as a form of therapy. This proposal investigates a new compound that can block the white cells that cause GVHD and the proteins that cause the symptoms associated with GVHD. Experiments are proposed in animal models to test the activity of the compound and if successful the long-term goal of this work is to take this compound in human clinical trials for the treatment of GVHD.