MicroRNAs have a powerful and well described role in the control of biological processes, both in healthy andpathologic tissue. Yet, their success in gene therapy applications, particularly for cancer, has been very limitedto date. This shortcoming is mainly due to the fact that single microRNA strategies have been implemented. Onthe contrary, the promise of microRNAs as a valid therapeutic tool relies on their unique property to function inclusters, whereby groups of closely associated microRNAs regulate intertwined, and often redundant, cellularpathways. This oncogenic redundancy is at the base for the failure of many targeted therapies, as it mediatesrescue phenomena responsible for resistance.Ternalys Therapeutics, Inc., is a startup company based on intellectual property which allows the design andproduction of chimeric artificial RNA genes that can simultaneously modulate multiple microRNAs of choice, thusre-establishing expression of desired microRNA clusters, and achieve precision multitargeting. We havedemonstrated the validity of this approach in glioblastoma, the most lethal and common of brain cancers in theadult population. This cancer relies on a complex of undruggable chromatin-modifying enzymes to enactresistance against genotoxic stress and sustain stemness. This complex, and the crucial biologic responsesthat it mediates, can be successfully targeted with a combination of multiple microRNAs encoded by recombinantRNA transgenes of our design.In this proposal we seek to fine tune the potency and applicability of our product, by pursuing two independentand correlated specific aims. In Aim 1, three transgenic RNAs with progressively higher microRNA-modulatingcapability will be compared for their ability to interfere with the glioblastoma epigenetic landscape, and tosynergize with genotoxic stress provided by standard of care chemoradiation. In Aim 2 we will select a suitabledelivery 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
Public Health Relevance Statement: NARRATIVE
Glioblastoma is a rapidly fatal brain cancer which has no cure. Ternalys Therapeutics leverages previously
untapped biological features of microRNA biology to provide a novel therapeutic tool against this tumor, based
on concepts of precision multitargeting and epigenetic interference. The proposed work will select a RNA
transgene with maximal antitumor properties, and define its optimal delivery strategy.
Project Terms: <21+ years old> | | 