Optimizing Composition and Delivery of a Novel RNA Therapy for Glioblastoma

摘要 微RNA在控制生物过程中具有强大的和充分描述的作用，无论是在健康的还是健康的。 病理组织然而，它们在基因治疗应用中的成功，特别是对于癌症，一直非常有限 迄今这一缺点主要是由于已经实施了单一microRNA策略。对 相反，microRNA作为有效治疗工具的希望依赖于它们独特的特性， 簇，其中密切相关的microRNA组调节相互交织的，往往是多余的，细胞， 途径。这种致癌冗余是许多靶向治疗失败的基础，因为它介导了 拯救抵抗的现象。 Ternalys Therapeutics，Inc.，是一家基于知识产权的初创公司， 产生可以同时调节多种选择的microRNA的嵌合人工RNA基因， 重新建立所需microRNA簇的表达，并实现精确的多靶向。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。 成人人口。这种癌症依赖于一种复杂的不可治疗的染色质修饰酶， 抵抗遗传毒性应激和保持干性。这种复杂的生物反应 它介导的，可以成功地与重组体编码的多种microRNA的组合靶向。 我们设计的RNA转基因。 在这项提案中，我们寻求微调我们的产品的效力和适用性，通过追求两个独立的 和相关的具体目标。在目标1中，三种转基因RNA具有越来越高的微RNA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， 与标准化放疗护理提供遗传毒性应激协同作用。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好的产品， 然后将在后续的第二阶段应用中进行IND使能研究

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