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Intratumor RNA interference of cell cycle genes slows down tumor progression

Gene Therapy volume 18, pages 727–733 (2011)Cite this article

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Abstract

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.

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Author notes

  1. S Dharmapuri

    Present address: Current address: PharManagement Ltd, London, UK.,

  2. D Peruzzi

    Present address: Current address: Department of Medicina Interna, University of Rome ‘La Sapienza’, Italy.,

  3. E Marra & L Aurisicchio

    Present address: Current address: BIOGEM,scarl, via Camporeale, Ariano Irpino (Av), Italy.,

  4. F Palombo

    Present address: Current address: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.,

  5. G Ciliberto

    Present address: Current address: University of Catanzaro, Department of Experimental and Clinical Medicine ‘G Salvatore’, Campus Germaneto, Catanzaro, Italy.,

  6. N La Monica

    Present address: Current address: Idera Pharmaceuticals, 167 Sidney Street, Cambridge, MA, USA.,

  7. S Dharmapuri and D Peruzzi: These authors contributed equally to this work.

Authors and Affiliations

  1. Merck Research Laboratories, IRBM ‘P Angeletti’, Pomezia (Rome), Italy

    S Dharmapuri, D Peruzzi, E Marra, F Palombo, G Ciliberto, N La Monica & L Aurisicchio

  2. Merck Research Laboratories, West Point, PA, USA

    A J Bett & C A Buser

  3. Merck Research Laboratories, Sirna, San Francisco, CA, USA

    S R Bartz & M Yong

  4. Merck Research Laboratories, Boston, MA, USA

    C Toniatti

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  1. S Dharmapuri
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Correspondence to L Aurisicchio.

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Dharmapuri, S., Peruzzi, D., Marra, E. et al. Intratumor RNA interference of cell cycle genes slows down tumor progression. Gene Ther 18, 727–733 (2011). https://doi.org/10.1038/gt.2011.27

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  • DOI: https://doi.org/10.1038/gt.2011.27

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