Bone marrow-targeted extracellular vesicles as a novel non-viral gene editor delivery platform

骨髓靶向细胞外囊泡作为新型非病毒基因编辑器传递平台

基本信息

批准号：
10656545
负责人：
JONATHAN N THON
金额：
$ 104.73万
依托单位：
STRM.BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10656545
关键词：
Acceleration Award Biodistribution Blood Chemical Analysis Bone Marrow Bone Marrow Cells Bone Marrow Stem Cell Bone Marrow Transplantation Bypass CD34 gene Carrying Capacities Cell Culture Techniques Cells Clinic Clinical Coagulation Process Cyclic GMP Data Development Diameter Disease Dose Electroporation Enzymes Fanconi Anemia Complementation Group A Protein Fanconi&apos s Anemia Funding Gene Delivery Genes Genetic Genome Goals Hematological Disease Hematopoietic stem cells Hereditary Disease Home Human Human Genetics In Vitro Inherited Intravenous Liver Marketing Mediating Medical Megakaryocytes Messenger RNA Methodology Methods Modality Molecular Mus Mutation Nucleic Acids Organ Patients Pattern Phase Phenotype Positioning Attribute Procedures Proteins Protocols documentation Reporter Reproducibility Ribonucleoproteins Risk Safety Small Business Innovation Research Grant Specificity Surface System Systems Development Techniques Technology Temperature Testing Therapeutic Tissues Translating Translations Tropism Work cell type clinical application clinically significant cost cytokine delivery vehicle extracellular vesicles gene therapy genomic locus human model immunogenicity in vivo intravenous injection manufacture mouse model novel peripheral blood phenotypic biomarker plasmid DNA pre-Investigational New Drug meeting pre-clinical preclinical study prevent stem cells success symptom treatment targeted delivery transplantation therapy

项目摘要

Despite advances in gene therapy techniques, novel methods that facilitate tight targeting of gene therapy products to specific tissues and cell types are necessary to achieve widespread clinical applicability. Inherited hematologic diseases represent an ideal target for novel genetic therapies, as gene therapy approaches can bypass the significant limitations associated with bone marrow transplantation and symptomatic treatment. Extracellular vesicles (EVs) capable of targeting hematopoietic stem cells (HSCs) are a promising option for the targeted delivery of gene editor machinery to treat genetic hematologic diseases. Successful system development represents a billion-dollar market opportunity that will be defined by the ability to show: (1) targeting specificity, (2) a favorable safety profile, and (3) efficient in vivo delivery of gene editor machinery. We have developed a proprietary EV-based system for in vivo nucleic acid and protein delivery that specifically targets HSCs in bone marrow, is amenable to large scale/commercial manufacture, and presents with low immunogenicity which confers unique potential for repeat dosing. Our hypothesis is that the STRM.BIO EV-based system can be efficiently loaded with gene editor cargo, safely home to the bone marrow following intravenous delivery, and effectively edit targeted genes in HSCs. With funds provided by this Phase II award, we will (1) establish SOPs for loading STRM.BIO EVs with cargo, (2) characterize the biodistribution and delivery pattern of cargo-loaded EVs, and (3) verify feasibility of STRM.BIO EVs for in vivo cargo delivery in a mouse model of human genetic hematologic disease. The current proposal aims to establish pre-clinical proof-of-concept support for the use of our proprietary system as a non-viral, in vivo genome editor delivery system for the treatment of inherited hematologic diseases.

尽管基因治疗技术取得了进步，但促进基因紧密靶向的新方法针对特定组织和细胞类型的治疗产品是实现广泛临床应用所必需的适用性。遗传性血液疾病是新型基因疗法的理想靶标，因为基因治疗方法可以绕过与骨髓相关的重大限制移植和对症治疗。能够靶向的细胞外囊泡 (EV) 造血干细胞（HSC）是基因编辑器靶向递送的一个有前途的选择治疗遗传性血液病的机器。成功的系统开发代表着价值数十亿美元的市场机会将由以下能力来定义：(1) 目标特异性， (2) 良好的安全性，以及 (3) 基因编辑器的有效体内递送。我们有开发了一种基于 EV 的专有系统，用于体内核酸和蛋白质输送专门针对骨髓中的 HSC，适合大规模/商业生产，并且具有低免疫原性，这赋予了重复给药的独特潜力。我们的假设基于 STRM.BIO EV 的系统可以有效地加载基因编辑器货物，在静脉注射后安全地回到骨髓，并有效地编辑 HSC 中的靶基因。利用第二阶段资助提供的资金，我们将 (1) 建立 SOP 为了给 STRM.BIO EV 装载货物，(2) 描述货物的生物分布和输送模式载有货物的电动汽车，以及 (3) 验证 STRM.BIO EV 在小鼠体内货物输送的可行性人类遗传性血液病模型。目前的提案旨在建立临床前使用我们的专有系统作为非病毒体内基因组的概念验证支持用于治疗遗传性血液病的编辑器递送系统。