Publications (10) View all
-
Article: MicroRNAs as new player in rheumatoid arthritis.
[show abstract] [hide abstract]
ABSTRACT: MicroRNAs (miRNAs) are small noncoding RNA molecules that negatively regulate gene expression at the post-transcriptional level. Currently, there are 939 mature human miRNA sequences listed in the Sanger updated miRNA registry. There are approximately 1500 predicted miRNAs in the human genome that may regulate the expression of one third of our genes. By controlling the accumulation of the target protein(s) in cells, these regulatory RNA molecules participate in key functions in many physiological networks and their deregulation has been implicated in the pathogenesis of serious human disorders, such as cancer and infection. The implication of miRNAs in immune-mediated disorders such as rheumatoid arthritis (RA) has recently emerged suggesting that miRNA-based therapeutic approaches may have a promising potential in these diseases. Here, we provide an overview of the state-of-the-art on miRNAs in RA, focusing on both systemic and local features of the pathology.Joint, bone, spine: revue du rhumatisme 01/2011; 78(1):17-22. · 2.25 Impact Factor -
Article: In vivo RNAi-mediated silencing of TAK1 decreases inflammatory Th1 and Th17 cells through targeting of myeloid cells.
[show abstract] [hide abstract]
ABSTRACT: Cells from the mononuclear phagocyte system (MPS) act as systemic and local amplifiers that contribute to the progression of chronic inflammatory disorders. Transforming growth factor-β-activated kinase 1 (TAK1) is a pivotal upstream mitogen-activated protein kinase-kinase-kinase acting as a mediator of cytokine expression. It remains critical to determine in vivo the implication of TAK1 in controlling the innate immune system. Here, we describe a vehicle tailored to selectively deliver siRNAs into MPS cells after intravenous administration, and validate in vivo the potential of the RNAi-mediated TAK1 knock down for immunomodulation. In a mouse model of immune-mediated inflammatory disorder, we show that anti-TAK1 siRNA lipoplexes efficiently alleviate inflammation, severely impair the downstream c-Jun N-terminal kinase and nuclear factor-κB signaling pathways, and decrease the expression of proinflammatory mediators. Importantly, the systemic TAK1 gene silencing decreases the frequency of Th1 and Th17 cells, both mediating autoimmunity in experimental arthritis, demonstrating the immunomodulatory potential of TAK1. Finally, in vitro inhibition of TAK1 in myeloid cells decreases interferon-γ-producing T cells, suggesting that a delivery system able to target MPS cells and to silence TAK1 impacts on pathogenic T effector cells in autoimmunity.Blood 11/2010; 116(18):3505-16. · 9.90 Impact Factor -
Article: Cationic liposome formulations for RNAi-based validation of therapeutic targets in rheumatoid arthritis.
[show abstract] [hide abstract]
ABSTRACT: Several molecules have been identified as critical mediators of chronic inflammation in immune system-mediated disorders such as rheumatoid arthritis (RA), and biological therapies targeting these molecules have been developed during the past two decades. Compared with conventional therapies, anti-TNF biotherapies have greatly improved the treatment of patients with RA, and several biological agents with distinct mechanisms of action are under development. Despite significant advances in this field, unmet medical needs remain. RA is the prototype disease for the evaluation of targeted therapies, and various novel genes have been described as being critically involved in disease pathogenesis. Thus, a novel area of research has recently emerged in the field of RA therapy, involving the genetic screening and validation of novel candidates in vivo using RNAi. Among the vehicles for the efficient targeting of macrophages, which play a critical role in disease chronicity, cationic liposomes represent the most promising option for the safe and specific use of RNAi in vivo. This review discusses the role of cationic liposomes as a mechanism for the systemic administration of siRNAs in the validation of RA therapeutic targets.Current opinion in molecular therapeutics 06/2010; 12(3):325-30. · 3.68 Impact Factor -
Article: Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces disease severity in collagen-induced arthritis.
[show abstract] [hide abstract]
ABSTRACT: Several lines of evidence implicate cytosolic phospholipase A(2)α (cPLA(2)α) as a critical enzyme in inflammatory disorders, including rheumatoid arthritis. Since cells from the myeloid compartment regulate local and systemic disease pathogenesis, the present study was undertaken to examine the effect of cPLA(2)α inhibition in experimental arthritis, using a delivery system tailored to target monocyte functions by RNA interference (RNAi). Mice with collagen-induced arthritis (CIA) were injected intravenously with an anti-cPLA(2)α small interfering RNA (siRNA) sequence (siPLA2) formulated as lipoplexes with the RPR209120/DOPE cationic liposome and a carrier DNA. The clinical course of joint inflammation was assessed, and the immunologic balance was analyzed by measuring T helper cell frequencies and cytokine expression. Biodistribution studies of siRNA were also performed. Weekly systemic injection of siPLA2 lipoplexes significantly reduced the incidence and severity of CIA, in both preventive and curative settings, as compared with findings in control animals. Histologic scores for inflammation and cartilage damage were reduced. The clinical effect was associated with local inhibition of tumor necrosis factor α secretion and lower cPLA(2)α expression and activity. The siPLA2 lipoplexes enabled triggering of in vivo RNAi-mediated gene silencing of cPLA(2)α in CD11b+ cells recovered from the spleen. While the treatment had no effect on anti-type II collagen (anti-CII) antibodies, CII-specific T helper cells producing interferon-γ, but not interleukin-17, in draining lymph node cells were decreased. Our findings indicate that systemic RNAi-mediated cPLA(2)α gene silencing in CD11b+ cells is effective in the treatment of CIA, and Th1 suppression is one of the potential underlying mechanisms, whereas Th17 suppression is not.Arthritis & Rheumatism 03/2011; 63(3):681-90. · 7.87 Impact Factor -
Article: Cytosolic phospholipase A2α gene silencing in the myeloid lineage alters development of Th1 responses and reduces autoimmune arthritis.
[show abstract] [hide abstract]
ABSTRACT: OBJECTIVE:: Several lines of evidence imply cytosolic phospholipase A(2)α (cPLA(2)α) as a critical enzyme in inflammatory disorders including rheumatoid arthritis (RA). Since cells from the myeloid compartment regulate local and systemic disease pathogenesis, the present study aimed at examining the effect of the cPLA(2)α inhibition using a delivery system tailored to target monocyte functions by RNA interference in experimental arthritis. METHODS:: Mice with collagen-induced arthritis (CIA) were injected intravenously with a cPLA(2)α small interfering RNA (siRNA) sequence formulated as lipoplexes with the RPR209120/DOPE cationic liposome and a carrier DNA. Clinical course of the joint inflammation was assessed and the immunological balance analyzed by measuring T helper cell frequencies and cytokine expression. Biodistribution studies of siRNA were performed. RESULTS:: Weekly systemic injections of anti-cPLA(2)α siRNA-lipoplexes significantly reduced incidence and severity of CIA, both in preventive and curative settings, as compared with control animals. Histological scores of inflammation and cartilage damage were lowered. The clinical effect was associated with local inhibition of TNF-α secretion and lower cPLA(2)α expression and activity. The siPLA2 lipoplexes enabled to trigger in vivo RNAi-mediated gene silencing of cPLA(2)α in CD11b(+) cells recovered from the spleen. While the treatment had no effect on anti-collagen II antibodies, CII-specific T helper cells producing IFN-γ- but not IL-17 in draining lymph nodes cells were decreased. CONCLUSION:: Our findings indicate that systemic RNAi-mediated cPLA(2)α gene silencing in CD11b(+) cells results in effective treatment of CIA, and Th1 but not Th17 suppression is one of the potential underlying mechanisms.Arthritis & Rheumatism 12/2010; · 7.87 Impact Factor
