Formulation of Small Activating RNA Into Lipidoid Nanoparticles Inhibits Xenograft Prostate Tumor Growth by Inducing p21 Expression

Molecular Therapy: Nucleic Acids

Klaus Charisse¹  Muthiah Manoharan¹  Rachel Meyers¹  Rick Duncan¹  Emily J Noonan²  Xiaoling Wang³  Robert F Place³  Ji Wang³  Long-Cheng Li³  Vera Huang³ 

[1] Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts, USA;Center for Molecular Biology in Medicine, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA;Department of Urology and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, California, USA;

关键词: CDKN1A;    delivery;    gene activation;    gene therapy;    lipid nanoparticles;    prostate cancer;    saRNA;    siRNA;   

DOI  :  10.1038/mtna.2012.5

来源: DOAJ

【 摘 要 】

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 p21WAF1/ 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.

【 授权许可】

Unknown