title: Efficient suppression of murine arthritis by combined anticytokine small interfering RNA lipoplexes.
abstract: OBJECTIVE
  Blocking tumor necrosis factor (TNF) effectively inhibits inflammation and joint damage in rheumatoid arthritis (RA), but 40% of RA patients respond only transiently or not at all to the current anti-TNF biotherapies. The purpose of this study was to develop an alternative targeted therapy for this subgroup of RA patients. As proof of concept, we tested the efficiency of an RNA interference (RNAi)-based intervention that targets proinflammatory cytokines in suppressing murine collagen-induced arthritis (CIA).
  
  
  METHODS
  Two synthetic short interfering RNA (siRNA) sequences were designed for each of the proinflammatory cytokines interleukin-1 (IL-1), IL-6, and IL-18. Their silencing specificity was assessed according to lipopolysaccharide-induced messenger RNA expression in J774.1 mouse macrophages as compared with control siRNA. For in vivo administration, siRNA were formulated as lipoplexes with the RPR209120/DOPE liposome and a carrier DNA and were injected intravenously (0.5 mg/kg) into DBA/1 mice with CIA.
  
  
  RESULTS
  Weekly injections of anti-IL-1, anti-IL-6, or anti-IL-18 siRNA-based lipoplexes significantly reduced the incidence and severity of arthritis, abrogating joint swelling and destruction of cartilage and bone, both in the preventative and the curative settings. The most striking therapeutic effect was observed when the 3 siRNA were delivered in combination. The siRNA lipoplex cocktail reduced all pathologic features of RA, including inflammation, joint destruction, and the Th1 response, and overall parameters of RA were improved as compared with anti-TNF siRNA lipoplex-based treatment.
  
  
  CONCLUSIONS
  Our results present a novel option for in vivo RNAi-based antiinflammatory immunotherapy. Our findings indicate that intravenous administration of a lipoplex cocktail containing several anticytokine siRNA is a promising novel antiinflammatory therapy for RA, as well as a useful and simple tool for understanding the pathophysiology of RA and for evaluating new therapeutic candidates.
authors.affiliation: INSERM, U 844, INM, Hôpital St Eloi, and Université Montpellier 1, UFR de Médecine, Montpellier, France.
authors.forename: Maroun
authors.initials: M
authors.lastname: Khoury
authors.forename: Virginie
authors.initials: V
authors.lastname: Escriou
authors.forename: Gabriel
authors.initials: G
authors.lastname: Courties
authors.forename: Anne
authors.initials: A
authors.lastname: Galy
authors.forename: Roseline
authors.initials: R
authors.lastname: Yao
authors.forename: Céline
authors.initials: C
authors.lastname: Largeau
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherman
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.forename: Florence
authors.initials: F
authors.lastname: Apparailly
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D002460:Cell Line; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D020868:Gene Silencing; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D008081:Liposomes; D051379:Mice; D008811:Mice, Inbred DBA; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D000093242:Interleukin-6 Inhibitors
chemical_list: D007375:Interleukin-1; D020382:Interleukin-18; D008081:Liposomes; D034741:RNA, Small Interfering; D000093242:Interleukin-6 Inhibitors