Modulation of scratching behavior by silencing an endogenous cyclooxygenase‐1 gene in the skin through the administration of siRNA

Sugimoto, Masako; Sakurai, Takanobu; Saito, Rie; Futaki, Nobuko; Hashimoto, Yuki; Honma, Yusuke; Arai, Iwao; Nakaike, Shiro

doi:10.1002/jgm.1091

Cited by 42 publications

(23 citation statements)

References 32 publications

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“…38,39 Such data have led to a proposed clinical trial using siRNA directed against keratin genes in patients with dominant-negative keratin disorders. 40 Other groups have reported effects of siRNAs delivered to skin by electroporation 41,42 or by cream-emulsified preparations of siRNA 43 as well as in human organotypic skin models, 44 supporting potential future use of synthetic siRNAs in skin. However, recent striking reports exploring gene-regulatory efficacy of synthetic siRNAs directed against vascular endothelial growth factor in the eye have demonstrated that therapeutic effects of sequencespecific RNA agents administered as ex vivo synthesized RNAs are not necessarily triggered by sequence-specific degradation of mRNA.…”

Section: Discussionmentioning

confidence: 98%

Amelioration of Psoriasis by Anti-TNF-α RNAi in the Xenograft Transplantation Model

et al. 2009

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Tumor necrosis factor-alpha (TNF-alpha) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-alpha-encoding mRNA, however, is not increased in psoriatic skin, and it remains unclear whether intervention strategies based on RNA interference (RNAi) are therapeutically relevant. To test this hypothesis the present study describes first the in vitro functional screening of a panel of short hairpin RNAs (shRNAs) targeting human TNF-alpha mRNA and, next, the transfer of the most potent TNF-alpha shRNA variant, as assessed in vitro, to human skin in the psoriasis xenograft transplantation model by the use of lentiviral vectors. TNF-alpha shRNA treatment leads to amelioration of the psoriasis phentotype in the model, as documented by reduced epidermal thickness, normalization of the skin morphology, and reduced levels of TNF-alpha mRNA as detected in skin biopsies 3 weeks after a single vector injection of lentiviral vectors encoding TNF-alpha shRNA. Our data show efficient lentiviral gene delivery to psoriatic skin and therapeutic applicability of anti-TNF-alpha shRNAs in human skin. These findings validate TNF-alpha mRNA as a target molecule for a potential persistent RNA-based treatment of psoriasis and establish the use of small RNA effectors as a novel platform for target validation in psoriasis and other skin disorders.

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Section: Discussionmentioning

confidence: 98%

Amelioration of Psoriasis by Anti-TNF-α RNAi in the Xenograft Transplantation Model

et al. 2009

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“…Further supporting its anti-pruritic actions, both pharmacological inhibition and in vivo silencing of cyclooxygenase COX1 resulted in (among else) decreased PGD2 levels and enhanced the scratching behavior in NC/Nga mice, a murine model of AD [123,124].…”

Section: Inflammatory Mediators As Peripheral Itch Sensitizersmentioning

confidence: 80%

TRP Channels and Pruritus

Tóth¹,

Bı́ró²

2013

TOPAINJ

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Itch (pruritus) is one of the most often seen sensory phenomena in clinical practice. Recent neurophysiological findings proposed the existence of a novel pruriceptive system which includes a multitude of pruritogenic (itch-inducing) peripheral mediators, itch-selective pruriceptors, sensory afferent networks, spinal cord neurons, and certain central nervous system regions. In this review, we first introduce major features of the pruriceptive system. We then focus on defining the roles of transient receptor potential (TRP) ion channels in skin-coupled itch and provide compelling evidence that certain thermosensitive TRP channels (especially TRPV1, TRPV3, TRPV4, and TRPA1) are indeed key players in pruritus pathogenesis. Finally, we propose TRP-centered future experimental directions towards the therapeutic targeting of TRP channels in the clinical management of itch.

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“…Topical introduction of siRNA into the skin by intradermal injection (Wang et al, 2007a,b) or electroporation (Inoue et al, 2007) had been performed at a dosage of 20 g or 12.5 g, respectively. Moreover, topical application of antisense oligonucleotides against IL-10 has been done at 120 g (Sakamoto et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

“…However, it is difficult to deliver siRNA into the skin by conventional methods based on passive diffusion (simple swabbing or application of a patch) because siRNA is a hydrophilic macromolecule. Recently, it was reported that intradermal injection or electroporation could be used to deliver siRNA directly into the skin (Wang et al, 2007a,b;Inoue et al, 2007). However, these methods are invasive or require special devices.…”

Section: Introductionmentioning

confidence: 98%

Noninvasive delivery of siRNA into the epidermis by iontophoresis using an atopic dermatitis-like model rat

Kigasawa

Kajimoto

Hama

et al. 2010

International Journal of Pharmaceutics

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Modulation of scratching behavior by silencing an endogenous cyclooxygenase‐1 gene in the skin through the administration of siRNA

Abstract: We have demonstrated the successful silencing of endogenous gene expression in the skin using the intradermal transfection of unmodified siRNA via electroporation. Using this method, we revealed that COX- 1-mediated prostaglandins may act as endogenous inhibitors of scratching behavior.

Cited by 42 publications

References 32 publications

Amelioration of Psoriasis by Anti-TNF-α RNAi in the Xenograft Transplantation Model

Amelioration of Psoriasis by Anti-TNF-α RNAi in the Xenograft Transplantation Model

TRP Channels and Pruritus

Noninvasive delivery of siRNA into the epidermis by iontophoresis using an atopic dermatitis-like model rat

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