Practical methods for enhancing protein production in vivo remain a challenge.
RNA activation (RNAa) is emerging as one potential solution by using double-stranded RNA (dsRNA) to increase endogenous gene expression. This approach, although related to RNA interference (RNAi), facilitates a response opposite to gene silencing. Duplex dsP21-322 and its chemically modified variants are examples of RNAa-based drugs that inhibit cancer cell growth by inducing expression of tumor suppressor p21WAF1/CIP1 (p21). In this study, we investigate the therapeutic potential of dsP21-322 in an orthotopic model of bladder cancer by formulating a 2'-fluoro-modified derivative (dsP21-322-2'F) into lipid nanoparticles (LNP) for intravesical delivery. LNP composition is based upon clinically relevant formulations used in RNAi-based therapies consisting of PEG-stabilized unilamellar liposomes built with lipid DLin-KC2-DMA. We confirm p21 induction, cell-cycle arrest, and apoptosis in vitro following treatment with LNP-formulated dsP21-322-2'F (LNP-dsP21-322-2'F) or one of its nonformulated variants. Both 2'-fluoro modification and LNP formulation also improve duplex stability in urine. Intravesical delivery of LNP-dsP21-322-2'F into mouse bladder results in urothelium uptake and extends survival of mice with established orthotopic human bladder cancer. LNP-dsP21-322-2'F treatment also facilitates p21 activation in vivo leading to regression/disappearance of tumors in 40% of the treated mice. Our results provide preclinical proof-of-concept for a novel method to treat bladder cancer by intravesical administration of LNP-formulated RNA duplexes.
Written by:
Kang MR, Yang G, Place RF, Charisse K, Epstein-Barash H, Manoharan M, Li LC. Are you the author?
Department of Urology and Helen Diller Comprehensive Cancer Center, University of California; RNA Therapeutics Inc., San Francisco, California; and Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts.
Reference: Cancer Res. 2012 Oct 1;72(19):5069-79.
doi: 10.1158/0008-5472.CAN-12-1871
PubMed Abstract
PMID: 22869584
UroToday.com Investigative Urology Section
