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

• 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
• 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' 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

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展，但促进基因紧密靶向的新方法仍然存在。 治疗产品的特定组织和细胞类型是必要的，以实现广泛的临床 适用性遗传性血液病代表了新型遗传疗法的理想靶点， 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有希望的选择。 治疗遗传性血液病的机器。成功的系统开发代表着 10亿美元的市场机会，将由以下能力定义：（1）目标特异性， (2)有利的安全性特征，和（3）基因编辑器机制的有效体内递送。我们有 开发了一种专有的基于EV的系统，用于体内核酸和蛋白质递送， 特异性靶向骨髓中的HSC，适于大规模/商业化生产， 并且具有低免疫原性，这赋予了重复给药的独特潜力。我们 一个假设是，基于STRM.BIO EV的系统可以有效地加载基因编辑器 货物，安全地回家骨髓后，静脉输送，并有效地编辑 HSC中的靶基因。利用第二阶段奖励提供的资金，我们将（1）建立SOP 用于装载STRM.BIO EV与货物，（2）表征生物分布和交付模式 装载货物的EV，以及（3）验证STRM.BIO EV用于小鼠体内货物递送的可行性 人类遗传性血液病模型。目前的建议旨在建立临床前 概念验证支持将我们的专有系统用作非病毒体内基因组 用于治疗遗传性血液病的编辑器递送系统。