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1.
Biol Pharm Bull ; 40(11): 1929-1933, 2017.
Article in English | MEDLINE | ID: mdl-29093340

ABSTRACT

Small interfering RNAs (siRNAs) are expected to offer a means of treating rheumatoid arthritis (RA) because they allow the specific silencing of genes related to RA pathogenesis. In our previous study, we reported that the siRNA targeted against RelA (anti-RelA siRNA), an important nuclear factor-kappaB (NF-κB) subdomain, was an effective therapeutic in atopic dermatitis and RA model animals. In this study, to develop an intra-articular injectable gel formulation against RA, we prepared a hydrogel that contains anti-RelA siRNA, and determined the in vitro release profile (%) and in vivo intra-articular retention of fluorescence-labeled model siRNA, and the anti-arthritic effects of the anti-RelA siRelA containing hydrogel in RA model mice. We selected the silk protein, sericin (SC), as an aqueous gel base, as it is a biocompatible and useful for forming hydrogels without a cross-linker. We showed that fluorescence-labeled model siRNA was continuously released from SC hydrogel in vitro, and retained in the knee joint of rats after injection of siRNA hydrogel. In addition, the knee joint thickness, clinical severity and incidence (%) in collagen-induced arthritis (CIA) mice as RA model treated with anti-RelA siRNA containing hydrogel were more improved than untreated, anti-RelA siRNA solution and negative control siRNA containing hydrogel group. Therefore, the intra-articular injectable sericin hydrogel formulation containing of anti-RelA siRNA could be a great potential therapeutic in rheumatoid arthritis.


Subject(s)
Arthritis, Experimental/therapy , Arthritis, Rheumatoid/therapy , Genetic Therapy/methods , RNA, Small Interfering/therapeutic use , Transcription Factor RelA/genetics , Animals , Arthritis, Experimental/pathology , Arthritis, Rheumatoid/pathology , Drug Liberation , Humans , Hydrogels/administration & dosage , Hydrogels/chemistry , Injections, Intra-Articular , Joints/drug effects , Male , Mice , Mice, Inbred DBA , RNA, Small Interfering/pharmacology , Rats , Rats, Sprague-Dawley , Sericins/administration & dosage , Sericins/chemistry , Transcription Factor RelA/metabolism , Treatment Outcome
2.
Int J Pharm ; 489(1-2): 261-7, 2015 Jul 15.
Article in English | MEDLINE | ID: mdl-25956048

ABSTRACT

Small interfering RNAs (siRNAs) are a potential treatment of atopic dermatitis (AD) because they can specifically silence the gene expression of AD-related factors. However, siRNA alone cannot exert a sufficiently strong therapeutic effect due to low delivery efficiency to the target tissues and cells; simply increasing the amount used is not possible due to the possibility of off-target effects. We previously reported a novel class of therapeutic RNA interference (RNAi) agents called nkRNA(®) and PnkRNA(®), which have been shown to be effective in several disease models, have greater resistance to nuclease degradation than canonical siRNAs, and do not induce any immunotoxicity. In the present study, we describe a non-invasive and effective transdermal RNAi therapeutic system for atopic dermatitis that uses the functional cell-penetrating stearoyl-oligopeptide OK-102 as a cytoplasm-responsive nanocarrier for nkRNA(®) and PnkRNA(®). The two RNAi agents were targeted against RelA, a subclass of NF-κB (nuclear factor kappa B), and, as part of OK-102 complexes, they strongly silenced RelA mRNA in macrophage cells and demonstrated a significant therapeutic effect in a mouse model of AD. It was shown that OK-102-complexed RNAi agents were an efficient therapeutic system for AD and caused no adverse reactions.


Subject(s)
Cell-Penetrating Peptides/administration & dosage , Dermatitis, Atopic/therapy , Oligopeptides/administration & dosage , RNA/administration & dosage , Transcription Factor RelA/genetics , Administration, Topical , Animals , Cell Line , Cell-Penetrating Peptides/chemistry , Dermatitis, Atopic/immunology , Dinitrofluorobenzene , Interleukin-6/immunology , Mice , Oligopeptides/chemistry , Peptides , RNA/chemistry , RNA Interference , Tumor Necrosis Factor-alpha/immunology
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