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

• 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
• 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

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.

项目摘要/摘要 造血干细胞移植（HSCT）可能适用于各种医疗环境 超出当前标准治疗（SOC），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 HSC成功植入所需的遗传毒性调节。这种调节通常包括非- 选择性清髓性治疗，如全身照射（TBI）、环磷酰胺或氟达拉滨， 与严重的全身性副作用有关，包括全血细胞减少、感染、不育， 偶尔，死亡。 为了开发一种没有清髓性和遗传毒性后果的更安全的预处理方案， 选择性耗尽宿主造血干细胞（HSC）并打开物理空间的治疗方式 骨髓（BM）小生境需要确定。基于对小鼠的研究，我们假设， 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凋亡 HSC植入，无需非选择性清髓性治疗。事实上，选择性Bcl-2抑制剂， 维奈托克通过消耗非造血干细胞的骨髓小生境中的HSC， 人类灵长类动物（NHP）。虽然这是在没有严重全血细胞减少的情况下实现的，但仍然需要一些TBI 诱导嵌合体，因为单独使用维奈托克限制了HSC的消耗。自Mcl-1以来，另一种抗凋亡药物 最近有报道称，这种蛋白对HSC的存活更为关键，我们进一步假设， 单独的Mcl-1或与Bcl-2的组合将更有效地消耗宿主HSC，从而产生足够的 在BM龛中间隔开，并允许最佳的同种异体HSC植入而无需任何清髓性治疗。的 初步研究的结果令人鼓舞，其中成功诱导造血嵌合体， 通过组合低剂量Mcl-1抑制剂和维奈托克实现无TBI。R21的主要目标 项目是测试单独的Mcl-1抑制或与Bcl-2共抑制是否可以一致且安全地诱导 MHC不匹配NHP HSCT中无TBI的造血嵌合体。这种方法诱导的嵌合体将 然后测试肾移植耐受的诱导。由于有关的资料有限， 不同的抗凋亡Bcl-2蛋白在灵长类动物中的作用，我们还将描述内在的凋亡途径 在这项研究中，NHP中的HSC。