Targeted non-genotoxic hematopoietic stem cell transplant conditioning approach

靶向非基因毒性造血干细胞移植调理方法

基本信息

批准号：
10475199
负责人：
Shanmuganathan Chandrakasan
金额：
$ 16.31万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475199
关键词：
Acute Address Adjuvant Affect Aging Alkylating Agents Animal Model Animals Antibodies Antibody Therapy Autologous Award Bioinformatics Bone Marrow Busulfan CD34 gene Cell Compartmentation Cell Cycle Cell Death Cell Surface Receptors Cell Therapy Cell-Mediated Cytolysis Cells Cellular biology Clinical Clinical Trials Coculture Techniques Complication Data Development Disease Disease Management Donor person Dose Engraftment Enhancers FANCD2 protein Fanconi Anemia Complementation Group A Protein Fluorescent Dyes Funding Goals Grant Hematological Disease Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hemophilia A Human Immune Immune System Diseases Immunocompetent Immunotoxins Infertility Inherited Knowledge Leadership MPL gene Malignant - descriptor Mediating Mentors Mentorship Methods Modeling Molecular Morbidity - disease rate Mus Mutagens Neuraxis Non-Malignant Organ PTPRC gene Persons Pharmaceutical Preparations Pharmacology Phase Physicians Pre-Clinical Model Predisposition Proto-Oncogene Protein c-kit Publications Regimen Research Research Methodology Research Personnel Research Technics Residual state Ribosomes Risk Role Scientist Second Primary Cancers Sickle Cell Signal Transduction Structure Testing Therapeutic Thrombopoietin Time Tissues Toxic effect Toxin Training Translational Research Transplantation Transplantation Conditioning Transplantation Immunology Universities Whole-Body Irradiation Work Xenograft procedure analytical method antibody-dependent cell cytotoxicity base career career development cellular imaging chemotherapy chimeric antigen receptor T cells conditioning cytotoxicity efficacy evaluation experimental study gene therapy genotoxicity in vivo insight irradiation minimal risk mortality mouse model novel pre-clinical receptor skills stem cell biology stem cell engraftment targeted agent therapeutic development transcriptome transplantation therapy

项目摘要

Project Summary Hematopoietic stem cell transplant (HSCT) and gene therapy are increasingly utilized for definitive management of disorders affecting the lymphohematopoietic compartment. Conditioning regimens are one of the critical components HSCT. The majority of conditioning regimens used today are either based on alkylating chemotherapy, such as busulfan, or involve varying doses of total body irradiation (TBI). These agents are genotoxic and affect organs other than the hematopoietic compartment, leading to myriad acute and long-term HSCT associated complications. Our overarching goal is to develop a non-genotoxic conditioning regimen targeting hematopoietic stem and progenitor cells (HSPCs). Preliminary data from our lab indicates MPL (thrombopoietin receptor), a critical survival signal in hematopoietic stem cells (HSCs), could be an ideal candidate for development of HSPC-targeted HSCT conditioning approaches. Restricted expression profiles within the hematopoietic compartment, with a higher expression in HSC when compared to the hematopoietic progenitor compartment, make MPL a very attractive target. We have developed two strategies to target the MPL expressing HSPC compartment. First, an immunotoxin approach, generated by conjugating MPL antibody to a ribosomal toxin, saporin (MPL-ab-SAP), and the second, a MPL receptor engaging thrombopoietin based CAR-T cell (TPO-CAR-T cells). We hypothesize that a conditioning agent targeting the MPL receptor will result in selective HSPC depletion thereby creating adequate niche space to allow donor engraftment and will have minimal risk of cytotoxicity outside the hematopoietic compartment. We will determine the mechanism, and critical determinants of MPL-ab-SAP-mediated cytotoxicity in the HSC compartment. Then, we will determine whether HSPC depletion by MPL-ab-SAP could be utilized as an effective conditioning strategy for HSCT and autologous HSC-based gene therapy. The role of TPO-CAR-T cells as an HSCT conditioning will also be studied. The K08 Award will be used to protect my time for research, help broaden my research skills and knowledge, and provide an outstanding basis for a career in basic and translational HSCT and gene therapy. This mentored phase of training will allow me to further integrate and build on my research skills as a physician-scientist. Over the next five years, I will (1) gain expertise in molecular methods needed for development of therapeutic antibodies, and gene therapy based therapeutics, (2) gain further exposure in HSC biology, transplant immunology, and murine HSCT, (3) acquire skills in cell imaging and bioinformatics, (4) acquire skills in translational research methodology, grantsmanship and leadership, and (5) build on my publication record and develop research ideas for independent investigator grants. To accomplish these goals, I have developed a well-structured training plan, and I have assembled a highly-qualified mentorship team of Dr. Spencer (expertise in cell and gene therapy), Dr. Bunting (HSC biology), Dr. Waller (HSPC biology and clinical transplantation), and Dr. Larsen (transplant immunology) at Emory University.

项目概要造血干细胞移植 (HSCT) 和基因治疗越来越多地用于明确的治疗影响淋巴造血室的疾病。调理方案是关键之一成分 HSCT。当今使用的大多数调理方案都是基于烷基化化疗，例如白消安，或涉及不同剂量的全身照射（TBI）。这些代理是遗传毒性并影响造血室以外的器官，导致无数急性和长期的 HSCT 相关并发症。我们的首要目标是开发一种非基因毒性调理方案靶向造血干细胞和祖细胞 (HSPC)。我们实验室的初步数据表明 MPL （血小板生成素受体）是造血干细胞 (HSC) 的关键生存信号，可能是一种理想的开发针对 HSPC 的 HSCT 调理方法的候选者。限制表达谱在造血室中，与造血室相比，HSC 中的表达更高祖室，使 MPL 成为一个非常有吸引力的目标。我们制定了两项战略来瞄准 MPL 表达 HSPC 区室。首先，通过缀合 MPL 抗体产生免疫毒素方法一种是核糖体毒素皂草素 (MPL-ab-SAP)，第二种是一种基于血小板生成素的 MPL 受体 CAR-T细胞（TPO-CAR-T细胞）。我们假设靶向 MPL 受体的调节剂会产生选择性 HSPC 耗竭，从而创造足够的利基空间以允许供体植入，并且将具有造血室外细胞毒性的风险最小。我们将确定机制，并且 MPL-ab-SAP 介导的 HSC 细胞毒性的关键决定因素。然后，我们将确定 MPL-ab-SAP 消耗 HSPC 是否可以作为 HSCT 的有效调理策略基于自体 HSC 的基因治疗。 TPO-CAR-T细胞作为HSCT调理的作用也将被研究。 K08 奖将用于保护我的研究时间，帮助拓宽我的研究技能和知识，并为基础和转化 HSCT 和基因治疗的职业生涯提供良好的基础。此次辅导的培训阶段将使我能够进一步整合和发展我作为一名医师科学家的研究技能。超过未来五年，我将 (1) 获得开发治疗药物所需的分子方法方面的专业知识抗体和基于基因治疗的疗法，(2) 进一步接触 HSC 生物学、移植免疫学和小鼠 HSCT，(3) 获得细胞成像和生物信息学技能，(4) 获得以下方面的技能：转化研究方法、资助能力和领导力，以及（5）以我的出版记录为基础，为独立研究者资助制定研究想法。为了实现这些目标，我开发了一个结构完善的培训计划，并组建了一支高素质的Spencer博士导师团队（专业知识细胞和基因治疗）、Bunting 博士（HSC 生物学）、Waller 博士（HSPC 生物学和临床移植）和埃默里大学拉森博士（移植免疫学）。