Optimizing Composition and Delivery of a Novel RNA Therapy for Glioblastoma

优化胶质母细胞瘤新型 RNA 疗法的成分和递送

基本信息

批准号：
10603203
负责人：
KENNETH MOCH
金额：
$ 27.58万
依托单位：
TERNALYS THERAPEUTICS, 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：
2022-09-07 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10603203
关键词：
Adult Affect Alkylating Agents BMI1 gene Base Sequence Biological Biological Process Biology Biotechnology Cells Cellular biology Chairperson Chromatin Clinical Trials Cognition Complement Complex Coupled DNA DNA Damage Data Disease EZH2 gene Engineering Enzymes Epigenetic Process Failure Generations Genes Genetic Engineering Genetic Transcription Genotoxic Stress Glioblastoma Glioma Goals Healthcare Hospitals Human In Vitro Individual Injections Intellectual Property KDM1A gene Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Methods MicroRNAs Nature Oncogenes Oncogenic Pathologic Pathway interactions Patients Pharmaceutical Preparations Phase Physiological Play Population Process Production Property Publications RNA RNA Sequences Radiation Recurrence Resistance Role Serotyping Stress Therapeutic TimeLine Tissues Toxic effect Transgenes Transgenic Organisms Tumor Subtype Untranslated RNA Woman Work adeno-associated viral vector base cancer cell cancer therapy candidate selection chemoradiation chromatin modification clinical practice design effective therapy follow-up gene therapy in vivo innovation medical schools mouse model neoplastic cell neurosurgery novel novel therapeutics overtreatment pre-clinical preclinical study prevent professor protein complex recombinant RNA response standard of care stem-like cell stemness success targeted treatment therapeutic miRNA therapy design tool transgene delivery tumor

项目摘要

ABSTRACT MicroRNAs have a powerful and well described role in the control of biological processes, both in healthy and pathologic tissue. Yet, their success in gene therapy applications, particularly for cancer, has been very limited to date. This shortcoming is mainly due to the fact that single microRNA strategies have been implemented. On the contrary, the promise of microRNAs as a valid therapeutic tool relies on their unique property to function in clusters, whereby groups of closely associated microRNAs regulate intertwined, and often redundant, cellular pathways. This oncogenic redundancy is at the base for the failure of many targeted therapies, as it mediates rescue phenomena responsible for resistance. Ternalys Therapeutics, Inc., is a startup company based on intellectual property which allows the design and production of chimeric artificial RNA genes that can simultaneously modulate multiple microRNAs of choice, thus re-establishing expression of desired microRNA clusters, and achieve precision multitargeting. We have demonstrated the validity of this approach in glioblastoma, the most lethal and common of brain cancers in the adult population. This cancer relies on a complex of undruggable chromatin-modifying enzymes to enact resistance against genotoxic stress and sustain stemness. This complex, and the crucial biologic responses that it mediates, can be successfully targeted with a combination of multiple microRNAs encoded by recombinant RNA transgenes of our design. In this proposal we seek to fine tune the potency and applicability of our product, by pursuing two independent and correlated specific aims. In Aim 1, three transgenic RNAs with progressively higher microRNA-modulating capability will be compared for their ability to interfere with the glioblastoma epigenetic landscape, and to synergize with genotoxic stress provided by standard of care chemoradiation. In Aim 2 we will select a suitable delivery strategy for the candidate transgene, comparing delivery efficiency between Lentiviral and Adeno- Associated Virus vectors in a preclinical mouse model of intracranial glioblastoma. EXPECTED OUTCOME: By the end of Phase I, we will have sufficient data to select the best performing product, which will then undergo IND-enabling studies in a follow-up Phase II application

抽象的 MicroRNA 在控制健康和生物过程的生物过程中具有强大且详细的作用。病理组织。然而，他们在基因治疗应用（特别是癌症）方面的成功非常有限迄今为止。这一缺点主要是由于实施了单一的microRNA策略。在相反，microRNA 作为有效治疗工具的前景依赖于其独特的功能簇，密切相关的 microRNA 组通过这些簇调节相互缠绕且通常是冗余的细胞途径。这种致癌冗余是许多靶向治疗失败的基础，因为它介导救援现象对抵抗负有责任。 Ternalys Therapeutics, Inc. 是一家基于知识产权的初创公司，允许设计和产生可以同时调节多个所选 microRNA 的嵌合人工 RNA 基因，从而重新建立所需 microRNA 簇的表达，并实现精确的多靶点。我们有证明了这种方法在胶质母细胞瘤中的有效性，胶质母细胞瘤是世界上最致命和最常见的脑癌成年人口。这种癌症依赖于一种不可成药的染色质修饰酶复合物来发挥作用抵抗遗传毒性应激并维持干性。这种复杂且关键的生物反应它介导的，可以通过重组编码的多种 microRNA 的组合成功靶向我们设计的RNA转基因。在本提案中，我们寻求通过追求两个独立的产品来微调我们产品的效力和适用性以及相关的具体目标。在目标 1 中，三种转基因 RNA 具有逐渐增强的 microRNA 调节作用将比较它们干扰胶质母细胞瘤表观遗传景观的能力，并与标准放化疗提供的基因毒性应激产生协同作用。在目标 2 中，我们将选择一个合适的候选转基因的递送策略，比较慢病毒和腺病毒之间的递送效率颅内胶质母细胞瘤临床前小鼠模型中的相关病毒载体。预期结果：到第一阶段结束时，我们将有足够的数据来选择性能最佳的产品，然后将在后续 II 期申请中进行 IND 支持研究