Mcl-1 inhibition for induction of hematopoietic chimerism without nonselective myeloablative treatments in nonhuman primates

Mcl-1 抑制在非人灵长类动物中诱导造血嵌合，无需非选择性清髓治疗

基本信息

批准号：
10288014
负责人：
TATSUO KAWAI
金额：
$ 24.58万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-20 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10288014
关键词：
Allogenic Allograft Tolerance Animals Apoptosis Apoptotic Autoimmune Diseases BCL-2 Protein BCL2 gene Benign Bone Marrow Bone Marrow Transplantation Cessation of life Chimerism Clinical Clinical Trials Cyclophosphamide Dependence Development Dose Gene-Modified Genetically Engineered Mouse Hematological Disease Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Infection Infertility MCL1 gene Malignant - descriptor Mature Lymphocyte Medical Modality Modeling Mus Observational Study Organ Transplantation Pancytopenia Pathway interactions Primates Protein Family Proteins Protocols documentation Regimen Reporting Research Proposals Role Sampling Testing Therapeutic Toxic effect Transplantation Tolerance Whole-Body Irradiation base cell type clinical application conditioning fludarabine gene induction genotoxicity inhibitor/antagonist kidney allograft mouse model nonhuman primate novel patient population response side effect standard of care stem cell engraftment stem cell survival

项目摘要

PROJECT SUMMARY / ABSTRACT Hematopoietic stem cell transplantation (HSCT) is potentially applicable to various medical settings beyond current standard of care (SOC), such as therapy for autoimmune disease, gene modification or induction of transplant tolerance. However, its wider clinical application is currently hampered by the myeloablative and genotoxic conditioning required for successful HSC engraftment. Such conditioning generally includes non- selective myeloablative treatments, such as total body irradiation (TBI), cyclophosphamide, or fludarabine that are associated with serious systemic side-effects including pancytopenia, infections, infertility, and, not infrequently, death. To develop a safer conditioning regimen without such myeloablative and genotoxic consequences, a therapeutic modality that selectively depletes host hematopoietic stem cells (HSCs) and opens a physical space in bone marrow (BM) niches needs to be identified. Based on murine studies, we hypothesized that selective inhibition of antiapoptotic B cell lymphoma 2 (Bcl-2) may effectively induce apoptosis of HSCs, thereby promoting HSC engraftment without need for non-selective myeloablative treatments. Indeed, a selective Bcl-2 inhibitor, Venetoclax, appeared significantly promotes hematopoietic chimerism by depleting HSCs in BM niches in non- human primates (NHPs). Although this was achieved without severe pancytopenia, some TBI was still required to induce chimerism as depletion of HSCs was limited with Venetoclax alone. Since Mcl-1, another anti-apoptotic protein, has recently been reported to be more critical for survival of HSCs, we further hypothesize that inhibition of Mcl-1 alone or in combination with Bcl-2 will more effectively deplete host HSCs, thereby creating sufficient space in BM niches and allowing optimal allogeneic HSC engraftment without any myeloablative treatment. The results of preliminary study have been encouraging, where successful induction of hematopoietic chimerism was achieved without TBI by combining low dose Mcl-1 inhibitor and Venetoclax. The main objective of this R21 project is to test whether Mcl-1 inhibition alone or with Bcl-2 co-inhibition can consistently and safely induce hematopoietic chimerism without TBI in MHC mismatched NHP HSCT. Chimerism induced by this approach will then be tested for induction of renal allograft tolerance. Since there is only limited information available on the role of different anti-apoptotic Bcl-2 proteins in primates, we will also characterize the intrinsic apoptotic pathways of HSCs in NHPs in this study.

项目概要/摘要造血干细胞移植（HSCT）可能适用于各种医疗环境超出当前护理标准 (SOC)，例如自身免疫性疾病治疗、基因修饰或诱导移植耐受性。然而，其更广泛的临床应用目前受到清髓性和清髓性的阻碍。 HSC 成功植入所需的基因毒性调节。这种调节通常包括非选择性清髓治疗，例如全身照射 (TBI)、环磷酰胺或氟达拉滨与严重的全身副作用相关，包括全血细胞减少症、感染、不孕症，并且不很少发生，死亡。为了开发一种更安全的预处理方案，而不会造成清髓和基因毒性后果，选择性消耗宿主造血干细胞 (HSC) 并打开物理空间的治疗方式需要确定骨髓（BM）中的生态位。基于小鼠研究，我们假设选择性抑制抗凋亡 B 细胞淋巴瘤 2 (Bcl-2) 可有效诱导 HSC 凋亡，从而促进 HSC 植入无需非选择性清髓治疗。事实上，一种选择性 Bcl-2 抑制剂， Venetoclax 似乎通过消耗非骨髓中的 BM 生态位中的 HSC 来显着促进造血嵌合。人类灵长类动物（NHP）。尽管这是在没有严重全血细胞减少症的情况下实现的，但仍然需要一些 TBI 诱导嵌合现象，因为单独使用 Venetoclax 时 HSC 的消耗受到限制。继Mcl-1之后，另一种抗凋亡药物最近有报道称蛋白质对 HSC 的存活更为关键，我们进一步假设抑制单独使用 Mcl-1 或与 Bcl-2 联合使用将更有效地消耗宿主 HSC，从而产生足够的 BM 生态位中的空间，允许最佳的同种异体 HSC 植入，无需任何清髓治疗。这初步研究结果令人鼓舞，成功诱导造血嵌合状态通过组合低剂量 Mcl-1 抑制剂和 Venetoclax，无需 TBI 即可实现。 R21的主要目标该项目旨在测试单独抑制 Mcl-1 或与 Bcl-2 共同抑制是否能够一致且安全地诱导 MHC 不匹配的 NHP HSCT 中无 TBI 的造血嵌合状态。这种方法诱导的嵌合现象将然后测试肾同种异体移植耐受的诱导。由于有关信息有限为了了解不同抗凋亡 Bcl-2 蛋白在灵长类动物中的作用，我们还将表征内在的凋亡途径本研究中 NHP 中 HSC 的分布。