Optimizing Composition and Delivery of a Novel RNA Therapy for Glioblastoma

摘要 MicroRNAs在控制生物过程中具有强大的和已被描述的作用，在健康和 病理组织。然而，它们在基因治疗应用方面的成功，特别是对癌症的应用，一直非常有限。 到目前为止。这一缺陷主要是由于已经实施了单一的microRNA策略。在……上面 相反，microRNAs作为一种有效的治疗工具的前景取决于它们发挥作用的独特性质 簇，借此密切相关的microRNA组调节相互交织的、往往是冗余的细胞 小路。这种致癌基因的冗余是许多靶向治疗失败的基础，因为它介导了 救援现象是造成抵抗的原因。 Ternalys Treateutics，Inc.是一家基于知识产权的初创公司，允许设计和 产生嵌合的人造RNA基因，可以同时调节多个选择的microRNA，因此 重新建立所需的microRNA簇的表达，并实现精确的多靶向。我们有 在胶质母细胞瘤中证明了这种方法的有效性，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无法下药的染色质修饰酶的复合体来实现 能抵抗基因毒性胁迫，并保持茎干。这种复杂的，以及关键的生物反应 它介导的，可以成功地与重组编码的多个microRNAs组合靶向 我们设计的RNA转基因。 在这个建议中，我们寻求微调我们产品的效力和适用性，通过追求两个独立 和相关的具体目标。在目标1中，三个具有逐渐更高的microRNA调节的转基因RNA 将比较它们干扰胶质母细胞瘤表观遗传格局的能力，以及 与标准护理放化疗提供的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 候选转基因的传递策略，比较慢病毒和腺病毒的传递效率。 临床前脑胶质母细胞瘤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表现最好的产品， 然后将在后续的第二阶段应用中接受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