Evaluation of therapeutic efficacy and safety of novel small RNA target delivery platform in vivo.

Oncoimmune, Inc., Rockville MD

Investigators

Abstract

Project Summary/Abstract The recent rapid expansion of genomic data greatly contributes to the understanding of disease development and progression. To translate these genetic discoveries into clinical applications, we need to develop therapeutic platforms that can specifically modulate the expression of disease-related genes in vivo. Small RNAs, such as microRNAs and siRNAs function in messenger RNA silencing and post-transcriptional regulation of gene expression. Given the challenge of targeting delivery of these small RNAs to specific cells and tissues in vivo, we developed a small RNA targeting delivery platform, comprising a miRNA/siRNA sequence and a cell surface receptor-targeting DNA aptamer (a ?chemical antibody?). In addition, as unmodified RNA oligonucleotides usually have a very short half-life in circulation in vivo, we incorporated cholesterol conjugation and base modifications into the components. This newly designed delivery platform combines all the desired attributes of a small RNA targeting molecule by enabling the specific delivery of miRNA/siRNA into the desired cells by the targeting aptamers and increasing half-life by limiting nuclease degradation and renal excretion. Furthermore, these three components are assembled together by complementary base pairing of the RNA sequences, thus creating a highly versatile platform in which the therapeutic or targeting moieties can be changed to suit the intended purpose or target indication. Using this platform, we recently developed a miR-26a delivery therapeutic that targets cells expressing the receptor tyrosine kinase, c-Kit, which we called ?miR-26a chimera?. The miR-26a chimera significantly attenuated the myelosuppressive adverse effect of chemotherapy by silencing a miR-26a target gene Bak1 (pro-apoptotic gene) in c-Kit+ hematopoietic progenitor cells in vivo. Furthermore, the miR-26a chimera remarkably inhibited tumor growth of c-Kit+ breast cancer by silencing a miR-26a target gene Ezh2 (oncogene) in xenograft models. Using this model, we will further establish the therapeutic potential of this targeting delivery platform through two specific aims: 1) we will design optimal treatment regimen for myeloprotection and evaluate the safety of miR-26a chimera using chemotherapy-treated mice, and 2) we will determine the anti-tumor effects of miR-26a chimera using chemotherapy-treated tumor xenograft mouse models, which will drive the decision regarding further development. Our proposed studies not only provide the proof of concept data to support formal preclinical development of a novel small RNA targeting delivery platform for patients with advanced breast cancer, but also support the potential of our platform in the development of novel therapeutics and research tools for a broad range of diseases.