Application of RNA interference (RNAi) in the clinic has improved with the development of novel delivery reagents (e.g., lipidoids).
Although RNAi promises a therapeutic approach at silencing gene expression, practical methods for enhancing gene production still remain a challenge. Previously, we reported that double-stranded RNA (dsRNA) can activate gene expression by targeting promoter sequence in a phenomenon termed RNA activation (RNAa). In the present study, we investigate the therapeutic potential of RNAa in prostate cancer xenografts by using lipidoid-based formulation to facilitate in vivo delivery. We identify a strong activator of gene expression by screening several dsRNAs targeting the promoter of tumor suppressor p21(WAF1/ Cip1) (p21). Chemical modification is subsequently implemented to improve the medicinal properties of the candidate duplex. Lipidoid-encapsulated nanoparticle (LNP) formulation is validated as a delivery vehicle to mediate p21 induction and inhibit growth of prostate tumor xenografts grown in nude mice following intratumoral injection. We provide insight into the stepwise creation and analysis of a putative RNAa-based therapeutic with antitumor activity. Our results provide proof-of-principle that RNAa in conjunction with lipidioids may represent a novel approach for stimulating gene expression in vivo to treat disease.
Written by:
Place RF, Wang J, Noonan EJ, Meyers R, Manoharan M, Charisse K, Duncan R, Huang V, Wang X, Li LC. Are you the author?
Department of Urology and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California, USA, RNA Therapeutics, Inc., San Francisco, California, USA
Reference: Mol Ther Nucleic Acids. 2012 Mar 27;1:e15
doi: 10.1038/mtna.2012.5
PubMed Abstract
PMID: 23343884
