siRNA relieves chronic neuropathic pain

Dorn, Gabriele; Patel, Sadhana; Wotherspoon, Glen; Hemmings‐Mieszczak, Maja; Barclay, J. Elaine; Natt, François; Martin, Pierre; Bevan, Stuart; Fox, Alyson; Ganju, Pam; Wishart, William L.; Hall, Jonathan

doi:10.1093/nar/gnh044

Cited by 358 publications

(239 citation statements)

References 36 publications

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“…The relatively modest (about 50%) knockdown obtained is comparable to that reported after prolonged infusion of siRNA in the central nervous system 24,25 . However, many aspects of this delivery system could be refined to enhance the delivery efficacy.…”

Section: Discussionsupporting

confidence: 76%

Transvascular delivery of small interfering RNA to the central nervous system

Kumar

McBride

et al. 2007

Nature

1,132

895

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A major impediment in the treatment of neurological diseases is the presence of the blood-brain barrier, which precludes the entry of therapeutic molecules from blood to brain. Here we show that a short peptide derived from rabies virus glycoprotein (RVG) enables the transvascular delivery of small interfering RNA (siRNA) to the brain. This 29-amino-acid peptide specifically binds to the acetylcholine receptor expressed by neuronal cells. To enable siRNA binding, a chimaeric peptide was synthesized by adding nonamer arginine residues at the carboxy terminus of RVG. This RVG-9R peptide was able to bind and transduce siRNA to neuronal cells in vitro, resulting in efficient gene silencing. After intravenous injection into mice, RVG-9R delivered siRNA to the neuronal cells, resulting in specific gene silencing within the brain. Furthermore, intravenous treatment with RVG-9R-bound antiviral siRNA afforded robust protection against fatal viral encephalitis in mice. Repeated administration of RVG-9R-bound siRNA did not induce inflammatory cytokines or anti-peptide antibodies. Thus, RVG-9R provides a safe and noninvasive approach for the delivery of siRNA and potentially other therapeutic molecules across the blood-brain barrier.

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Section: Discussionsupporting

confidence: 76%

Transvascular delivery of small interfering RNA to the central nervous system

Kumar

McBride

et al. 2007

Nature

1,132

895

View full text Add to dashboard Cite

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“…25 RNAi could overcome these adverse effects and show greater efficacy because of localized inhibition. 26 This concept has set up the path for therapeutic applications, both locally 27 and systemically. 28 Recently, the demonstration of RNAi in humans from systemically administered siRNA by targeted nanoparticles has been achieved 29 and Alnylam Pharmaceuticals has started clinical trials for the evaluation of a KSP-RNAi therapeutic in a wide variety of cancers.…”

Section: Introductionmentioning

confidence: 99%

Intratumor RNA interference of cell cycle genes slows down tumor progression

et al. 2011

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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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“…Other promising delivery methods for an in vivo approach with potential clinical application include local and direct administration of siRNA to sequestered anatomical sites. 34,35 The ability of viral vectors to efficiently transduce mammalian cells in vitro and in vivo coupled to their effectiveness in expressing transduced genes, make their use a feasible approach in humans. Retrovirus, lentivirus and adenovirus vectors, expressing siRNA, have been described.…”

Section: Discussionmentioning

confidence: 99%

Anticancer activity of an adenoviral vector expressing short hairpin RNA against BK virus T-ag

et al. 2007

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The human polyomavirus BK (BKV) is oncogenic in rodents and induces malignant transformation of rodent cells in vitro. Although its role in human tumorigenesis is still debated, BKV represents an excellent model to evaluate molecularly targeted antineoplastic approaches. Here, we have tested whether stable suppression of the T antigen (T-ag) oncogene expression could inhibit the in vitro and in vivo malignant phenotype of BKV-transformed mouse cells. An adenovirus vector system that expresses small hairpin RNAs (shRNAs), which are converted into active small interfering RNAs (siRNA) molecules against the BKV T-ag, was developed. This vector was able to inhibit the expression of BKV T-ag through a highly efficient in vitro and in vivo delivery of the siRNA molecule. In addition, it allowed a stable expression of siRNA for a period of time sufficient to elicit a biological effect. Inhibition of T-ag expression results in reduction of the in vitro growth rate of BKV-transformed cells, which is, at least in part, caused by restoration of p53 activity and induction of apoptosis. In vivo studies proved that adenovirus vectors expressing anti-T-ag siRNA were able to suppress tumorigenicity of BKV-transformed cells. Moreover, adenovirus vector direct treatment of growing tumors resulted in a significant reduction of tumor growth. This study indicates that siRNAs delivery via a viral vector have a potential usefulness as in vivo anticancer tool against viral and cellular oncogenes.

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siRNA relieves chronic neuropathic pain

Cited by 358 publications

References 36 publications

Transvascular delivery of small interfering RNA to the central nervous system

Transvascular delivery of small interfering RNA to the central nervous system

Intratumor RNA interference of cell cycle genes slows down tumor progression

Anticancer activity of an adenoviral vector expressing short hairpin RNA against BK virus T-ag

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