Intratumor RNA interference of cell cycle genes slows down tumor progression

• Published in: Gene therapy Vol. 18; no. 7; pp. 727 - 733
• Main Authors: DHARMAPURI, S, PERUZZI, D, TONIATTI, C, AURISICCHIO, L, MARRA, E, PALOMBO, F, BETT, A. J, BARTZ, S. R, YONG, M, CILIBERTO, G, LA MONICA, N, BUSER, C. A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.07.2011
• Subjects: Adenoviridae - genetics; Animals; Bioavailability; Biological and medical sciences; Biotechnology; Cell cycle; Cell cycle, cell proliferation; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cholesterol - administration & dosage; Cholesterol - analogs & derivatives; Development and progression; Disease Progression; Expression vectors; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Silencing; Gene Targeting; Gene therapy; Genes, cdc; Genetic aspects; Genetic Vectors; Health aspects; Health. Pharmaceutical industry; Humans; Industrial applications and implications. Economical aspects; Kinases; Kinesin; Liposomes; Male; Mice; Mice, Nude; Molecular and cellular biology; Nanoparticles; Neoplasms - genetics; Neoplasms - therapy; Polo-like kinase; Polo-like kinase 1; Polyethylene Glycols - administration & dosage; Ribonucleic acid; RNA; RNA Interference; RNA-mediated interference; siRNA; Therapeutic targets; Transduction, Genetic; Tumors; United States; Gene silencing; liponanoparticle; RNA interference; Gene; Cell cycle; Tumor progression; PLK1; KSP; siRNA; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2011.27

Small interfering RNAs (siRNAs) are emerging as promising therapeutic tools. However, the widespread clinical application of such molecules as modulators of gene expression is still dependent on several aspects that limit their bioavailability. One of the most promising strategies to overcome the barriers faced by gene silencing molecules involves the use of lipid-based nanoparticles (LNPs) and viral vectors, such as adenoviruses (Ads). The primary obstacle for translating gene silencing technology from an effective research tool into a feasible therapeutic strategy remains its efficient delivery to the targeted cell type in vivo. In this study, we tested the capability of LNPs and Ad to transduce and treat locally tumors in vivo. Efficient knockdown of a surrogate reporter (luciferase) and therapeutic target genes such as the kinesin spindle protein (KIF11) and polo-like kinase 1 were observed. Most importantly, this activity led to a cell cycle block as a consequence and slowed down tumor progression in tumor-bearing animals. Our data indicate that it is possible to achieve tumor transduction with si/short hairpin RNAs and further improve the delivery strategy that likely in the future will lead to the ideal non-viral particle for targeted cancer gene silencing.