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Alternative for Anti-TNF Antibodies for Arthritis Treatment

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Presentation on theme: "Alternative for Anti-TNF Antibodies for Arthritis Treatment"— Presentation transcript:

1 Alternative for Anti-TNF Antibodies for Arthritis Treatment
Joseph Paquet, Christel Henrionnet, Astrid Pinzano, Jean-Baptiste Vincourt, Pierre Gillet, Patrick Netter, Isabelle Chary-Valckenaere, Damien Loeuille, Jacques Pourel, Laurent Grossin  Molecular Therapy  Volume 19, Issue 10, Pages (October 2011) DOI: /mt Copyright © 2011 The American Society of Gene & Cell Therapy Terms and Conditions

2 Figure 1 In vitro evaluation of triplex-forming oligonucleotide (TFO) and small interfering RNA (siRNA) specifically designed to target rat tumor necrosis factor-α (TNF-α). Inhibition of TNF-α mRNA was assessed by real-time quantitative reverse transcription-PCR analysis of transfected (with TFO or siRNA) rat P3 synoviocytes 4 hours after challenge with (a) interleukin-1β (10 ng/ml) or (b) lipopolysaccharide (LPS). (c) TNF-α and nitric oxide (NO) released in supernatants were assessed 18 hours after inflammation induction using ELISA and GRIESS method, respectively. (d) Biological effects of TNF-α inhibition by oligonucleotides (TFO and siRNA) on proinflammatory cytokines mRNA expression levels (IL-1β, IL-6, iNos, and cox-2). Levels were assessed by real-time quantitative reverse transcription-PCR analysis of transfected (with TFO or siRNA) rat P3 synoviocytes 4 hours after challenge with interleukin-1β (10 ng/ml). Nontargeting siRNA and TFO were used as control and RT-qPCR results presented for anti-TNF-α TFO and siRNA are normalized to these controls. Results are representative of three independent experiments and are expressed as the mean ± s.e.m. of nine samples. Molecular Therapy  , DOI: ( /mt ) Copyright © 2011 The American Society of Gene & Cell Therapy Terms and Conditions

3 Figure 2 Triplex-forming oligonucleotide (TFO) tissue distribution and time course of acute arthritis-related changes in rats. (a) Confocal microscopy images of cartilage and synovial membrane from rats intra-articularly injected with 10 µg of Cy 3′ TFO labeled (×10). (b) Time course of arthritis-related changes in rat with Mycobacterium tuberculosis walls-induced arthritis preventively treated or no with 10 µg of anti-TNF-α oligonucleotides [TFO or small interfering RNA (siRNA)] or control oligonucleotide (sham = naive rats, control oligo. = arthritic rats preventively injected with 10 µg of control oligonucleotide, TFO treated = arthritic rats preventively injected with 10 µg of anti-TNF-α TFO, siRNA treated = arthritic rats preventively treated with 10 µg of anti-TNF-α siRNA). Joint circumference of rat knees was estimated from joint width. (c) Tumor necrosis factor-α (TNF-α), (d) IL-1β, iNos, vEGF, and MMP13 mRNA expression level in synovial membrane from arthritic rats preventively treated with 10 µg of TFO or siRNA (24 hours after arthritis induction). Levels were assessed by real-time quantitative reverse transcription-PCR analysis; results are expressed as mean ± s.e.m. of 24 samples (experiment was made three times with eight rats per group in each one). (e) Assessment of TNF-α and NO secretion in synovial fluid from rats. Levels were measured 2 days after arthritis induction by ELISA and GRIESS method for TNF-α and NO, respectively. (f) Assessment of matrix synthesis in patellar chondrocytes from rats (treated or not with TFO or siRNA), 2 days after arthritis induction. Proteoglycan synthesis was measured by Na235SO4 incorporation in patellar cartilage. oligo., oligonucleotide. Molecular Therapy  , DOI: ( /mt ) Copyright © 2011 The American Society of Gene & Cell Therapy Terms and Conditions

4 Figure 3 Histological evaluation of anti-TNF-α triplex-forming oligonucleotide (TFO) and small interfering RNA (siRNA) (10 µg) efficiency in an acute arthritis model. (a) Histological sections of joints from Mycobacterium tuberculosis walls-induced arthritic rats preventively injected or not with anti-TNF-α TFO or siRNA or with control oligonucleotide (sham = naive rats, control oligo. = arthritic rats preventively injected with 10 µg of control oligonucleotide, TFO treated = arthritic rats preventively injected with 10 µg of anti-TNF-α TFO, siRNA treated = arthritic rats preventively treated with 10 µg of anti-TNF-α siRNA). Knees were taken 3 days after arthritis induction. Formalin fixed, decalcified, paraffin-embedded, hematoxylin and eosin and safranin-O stained 5 µm sections were assessed for cartilage and bone erosion. Synovial membranes were taken 24 hours after arthritis induction and hematoxylin/eosin stained. Representative images of the different groups are shown. (b) Histological grading of knee synovium, cartilage, and bone lesions in rats developing Mycobacterium walls-induced arthritis and preventively treated or not with anti-TNF-α oligonucleotides (TFO and siRNA). Values are expressed as the mean ± s.e.m. of 18 rats per time and group. *P < 0.05 in comparison with control, #P < 0.05 in comparison with arthritic rats. oligo., oligonucleotide; TNF-α, tumor necrosis factor-α. Molecular Therapy  , DOI: ( /mt ) Copyright © 2011 The American Society of Gene & Cell Therapy Terms and Conditions

5 Figure 4 Time course of arthritis-related changes in rat with antigen-induced (chronic) arthritis preventively treated or not with anti-TNF-α triplex-forming oligonucleotide (TFO) (sham = naive rats, control oligo. = arthritic rats preventively injected with 10 µg of control oligonucleotide, TFO treated = arthritic rats preventively injected with 10 µg of anti-TNF-α TFO). (a) Joint circumference of rat knees was estimated from joint width. (b) Hindpaw weight-distribution of chronic arthritic and preventively treated rats compared to healthy controls. Data are expressed as percentage of weight distribution onto the sensitized hindlimb. (c) Histological sections of joints from arthritic rats preventively injected or no with anti-TNF-α TFO. Knees were taken 3 days after arthritis induction. Formalin fixed, decalcified, paraffin-embedded, hematoxylin and eosin and safranin-O stained 5 µm sections were assessed for cartilage and bone erosion. Synovial membranes were taken 24 hours after arthritis induction and hematoxylin/eosin stained. Representative images of the different groups are shown. (d) Histological grading of knee synovium, cartilage, and bone in rats developing antigen-induced arthritis (AIA) and preventively treated or no with anti-TNF-α TFO. Rats were immunized with 0.5 g of methylated bovine serum albumin (mBSA) emulsified with complete Freund's adjuvant 21 and 14 days before articular injection (D0) of 0.5 mg of mBSA (sensitized) or saline (contralateral) into the knees. Values are expressed as the mean ± s.e.m. of eight rats per time. *P < 0.05 in comparison with control, #P < 0.05 in comparison with arthritic rats. oligo., oligonucleotide; TNF-α, tumor necrosis factor-α. Molecular Therapy  , DOI: ( /mt ) Copyright © 2011 The American Society of Gene & Cell Therapy Terms and Conditions

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