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

Project Summary AbstractThe recent rapid expansion of genomic data greatly contributes to the understanding of disease development and progressionTo translate these genetic discoveries into clinical applicationswe need to develop therapeutic platforms that can specifically modulate the expression of disease related genes in vivoSmall RNAssuch as microRNAs and siRNAs function in messenger RNA silencing and post transcriptional regulation of gene expressionGiven the challenge of targeting delivery of these small RNAs to specific cells and tissues in vivowe developed a small RNA targeting delivery platformcomprising a miRNA siRNA sequence and a cell surface receptor targeting DNA aptamerachemical antibodyIn additionas unmodified RNA oligonucleotides usually have a very short half life in circulation in vivowe incorporated cholesterol conjugation and base modifications into the componentsThis 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 excretionFurthermorethese three components are assembled together by complementary base pairing of the RNA sequencesthus creating a highly versatile platform in which the therapeutic or targeting moieties can be changed to suit the intended purpose or target indicationUsing this platformwe recently developed a miRa delivery therapeutic that targets cells expressing the receptor tyrosine kinasec Kitwhich we calledmiRa chimeraThe miRa chimera significantly attenuated the myelosuppressive adverse effect of chemotherapy by silencing a miRa target gene Bakpro apoptotic genein c Kithematopoietic progenitor cells in vivoFurthermorethe miRa chimera remarkably inhibited tumor growth of c Kitbreast cancer by silencing a miRa target gene Ezhoncogenein xenograft modelsUsing this modelwe will further establish the therapeutic potential of this targeting delivery platform through two specific aimswe will design optimal treatment regimen for myeloprotection and evaluate the safety of miRa chimera using chemotherapy treated miceandwe will determine the anti tumor effects of miRa chimera using chemotherapy treated tumor xenograft mouse modelswhich will drive the decision regarding further developmentOur 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 cancerbut also support the potential of our platform in the development of novel therapeutics and research tools for a broad range of diseases Project narrative We will evaluate the therapeutic potential and safety of a novel small RNA targeting delivery platform using a breast cancer model in vivoThis platform addresses the limitations observed with current approachesspecifically delivering active oligonucleotides for RNA interference to desired cells tissues with high efficiencyand combines all the requirements for therapeutic application into a single versatile modular platformOur proposed studies not only provide the preclinical proof of concept data for therapeutic development of this platform for advanced breast cancerbut will also contribute to the development of novel therapeutics and research tools for a broad range of diseases