Interferência por RNA: uma nova alternativa para terapia nas doenças reumáticas

Abstract

RNA interference (RNAi) is a post-transcriptional gene silencing mechanism preserved during evolution. This mechanism, recently described, is mediated by small double-stranded RNAs (dsRNAs) that can specifically recognize a target mRNA sequence and mediate its cleavage or translational repression. The use of RNAi as a tool for gene therapy has been extensively studied, especially in viral infections, cancer, inherited genetic disorders, cardiovascular and rheumatic diseases. Together with data from human genome, the knowledge of gene silencing mediated by RNAi could allow a functional determination of virtually any cell expressed gene and its involvement in cellular functioning and homeostasis. Several in vitro and in vivo therapeutic studies with autoimmune disease animal models have been carried out with promising results. The pathways of tolerance breakage and inflammation are potential targets for RNAi therapy in inflammatory autoimmune diseases. This review will present the basic principles of RNAi and discuss several aspects of RNAi-based therapeutic approaches, from in vitro tool design and target identification to in vivo pre-clinical drug delivery, and tests of autoimmune diseases in human cells and animal models. Finally, this review will present some recent clinical experience with RNAi-based therapy.

Silencing of P2X7R by RNA interference in the hippocampus can attenuate morphological and behavioral impact of pilocarpine-induced epilepsy

“…RNA interference (RNAi) is a method that reduces the expression of the receptor of interest, allowing studying the direct impact in behavioral or morphological parameters besides excluding pharmacological effects [47].…”

Post-transcriptional silencing of the SGE1 gene induced by a dsRNA hairpin in Fusarium oxysporum f. sp cubense, the causal agent of Panama disease

“…Additionally, RNAi efficiency is not affected by the presence of dikaryotic nuclei or multicopy genes (Fire et al, 1998;França et al, 2010). As such, RNAi is a cellular defense mechanism used by fungi and various other organisms (Napoli et al, 1990;Romano and Macino, 1992;Fire et al, 1998;Ketting et al, 1999).…”

Avaliação in vitro e in vivo de nanodispersões líquido cristalinas para veiculação de siRNA-TRP-1 para o tratamento tópico do vitiligo

“…Fire e Craig C. Mello (1998), descobriram que a molécula de RNA de dupla fita poderia silenciar a expressão de genes, ao trabalharem com o nematóide Carnorhabditis elegans (MENCK, 2010). Esses pesquisadores observaram que o silenciamento da expressão do gene de interesse era mais efetivo quando injetaram uma molécula de RNA de dupla fita de sequência similar em relação às fitas de RNA simples sense e antisense administradas separadamente (SIFUENTES-ROMERO et al, 2011 FRANÇA et al, 2010;WHITEHEAD;LANGER;ANDERSON, 2009;GELEY;MÜLLER, 2004).…”

“…Essas estruturas são transportadas para o citoplasma formando miRNAs maduros com 22 pares de base por meio clivagem pela enzima Dicer, regulando a transcrição de genes ao se ligar à extremidade 3' UTR do RNAm alvo bloqueando a translação ou por facilitar a sua degradação (RESHI et al, 2014). Os short hairpin RNAs (shRNAs) são moléculas de RNA de dupla fita contendo uma alça de fita simples denominadas hairpin, com estruturas semelhantes ao miRNA, podendo ser sintéticos ou transcritos dentro das células por meio de vetores que codificam o shRNA, sendo processados pela enzima Dicer, da mesma maneira que ocorre com siRNAs e miRNAs (FRANÇA et al, 2010;GELEY;MÜLLER, 2004). Recentemente, a função de muitos genes foi elucidada pela análise funcional de RNAi (MIYAGISHI & TAIRA, 2003).…”