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  Antisense oligonucleotides (odn) against smad7 and uses thereof in medical fieldUSPTO Application #: 20070042985Title: Antisense oligonucleotides (odn) against smad7 and uses thereof in medical field Abstract: The invention relates to antisense oligonucleotidic sequences (ODN) against Smad7 suitably modified, and their uses in medical field as therapeutic biological agents, in particular in the treatment of chronic inflammatory bowel disease, such as Crohn's disease and ulcerative colitis. (end of abstract) Agent: Young & Thompson - Arlington, VA, US Inventor: Giovanni Monteleone USPTO Applicaton #: 20070042985 - Class: 514044000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Nitrogen Containing Hetero Ring, Polynucleotide (e.g., Rna, Dna, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20070042985. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates to antisense oligonucleotides (ODN) against Smad7 and uses thereof in medical field [0002] Particularly the invention refers to Smad7 antisense ODN sequences suitably modified, which show a surprising biological activity of specific inhibition of Smad7 expression and are therefore usable in medical field as therapeutic biological agents, in particular in the treatment of chronic inflammatory bowel disease (IBD). [0003] Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of chronic inflammatory bowel disease in human. Both diseases are complex clinical entities, whose pathogenesis is strictly dependent on the interaction between different genetic, environmental and immune factors. [0004] Despite CD and UC show marked differences both on the pathophysiological and clinical level, the therapeutic approach to suffer g patients shares many common elements. Variability of the clinical presentation, of the type and the extension of the lesions, and of the kind of complications influences the therapeutic choice, even though the pharmacological treatment would represent the first predominant approach. [0005] Salicylazosulfapyridine and 5-aminosalicylic acid are drugs of proven efficacy in the management of the mild form of IBD and in the remission maintenance therapy. [0006] In the phases with moderate to severe activity and in the cases in which the general state is involved, it is necessary to turn to the use of corticosteroids. From the medium and long-term analysis of the main worldwide case histories, it appears that clinical remission is obtainable only in two thirds of patients receiving corticosteroids, and only in 50% of these patients it does not occur any relapse after drugs suspension. [0007] The continuous administering of corticosteroids, beside inducing drugs dependence phenomenon, is worsened due to a very high risk of side effects. [0008] Also immunosuppressive treatment, which often accompanies or replaces corticosteroidal therapy, does not always ensure phlogosis containment and control of symptoms, and further has the disadvantages of numerous contraindications and severe side effects (Podolsky, 2002). [0009] The new drug generation that became available in the 1990's, are biological agents. The more in-depth knowledge of IBD natural history and of the main pathophysiological mechanisms has contributed to steer medical intervention in a concrete way. Thus, a development of biotherapies aimed at controlling specific inflammatory "pathways" occured through the use of recombinant human proteins, monoclonal chimeric humanized antibodies and fusion proteins. Contextually, agents which have showed a better efficacy in CD treatment are monoclonal chimeric antibodies directed to block TNF-.alpha., a pro-inflammatory cytokine overproduced during IBD (Seegers et al., 2002). This compound, which is at present in phase IV of clinical trial, is effective in the inflammation containment in about 60-70% of the treated patients. Nevertheless, some side effects have been pointed out with a considerable frequency of incidence and recognizable in reactivation of latent microbial infections, hypersensitivity phenomena and formation of autoantibodies. The latter phenomenon could be based on the fact that anti-TNF-.alpha. neutralizes the cytokine TNF-.alpha. which has numerous biological functions. [0010] In addition to its inflammatory effect, TNF-.alpha. takes part also to those mechanisms involved in the induction and maintaining of immunological tolerance. Therefore a block of TNF-.alpha. activity could paradoxically encourage excessive immunological reactions (Sandborn et al., 2002). [0011] All these remarks suggest the-need of new studies on animal models of IBD through which it is possible to identify new active principles to be used in a better and durable treatment of such pathologies (Fiocchi, 2001). [0012] Anti-TNF-.alpha. treatment, as far as the other biotherapies, such as the administration of anti-inflammatory cytokines, for example IL-10, represents a therapeutic extracellular approach aimed at controlling biological effects of molecules secreted by inflammatory cells. [0013] The study of the signal-transduction pathways activated by cytokine interaction with their receptors has outlined the chance to use new therapeutic strategies capable to modulate specifically and selectively the intracellular expression of important inflammatory and non inflammatory molecules. [0014] Under normal conditions, the intestinal mucosa is the seat of a "physiological" inflammatory infiltrate, which is tightly controlled by various counter-regulatory mechanisms. [0015] In relation to the above, an important role is played by TGF-.beta.1, a multifunctional cytokine capable of regulating the growth, differentiation and activity of many immune and non immune cells. [0016] Both in vitro and in vivo studies have demonstrated that TGF-.beta.1 acts as a potent immunoregulator able to control mucosal intestinal inflammation, and that the inhibition of its activity results in the development of colitis which shows immunomorphological similarity with CD or UC (Powrie F. et al., 1996; Neurath M. Fet al., 1996; Ludviksson B. R. et al., 1997). [0017] In fact, TGF-.beta.1 genes deficient mice display severe multifocal inflammatory responses, also involving the intestine, associated with an excessive inflammatory cytokines production by numerous cell types, including T cells (Shull M. M. et al.,1992; Christ M. et al. 1994). [0018] Similarly, inhibition of TGF-.beta.1 signalling in mouse by expressing a dominant negative mutant form of the TGF-.beta.1 receptor RII, results in an enhanced susceptibility to develop experimental colitis (Hahm K. B. et al., 2001). [0019] Finally, it was shown that specific inhibition of TGF-.beta.1 signaling in T cells by the expression of a dominant negative TGF-.beta. receptor type II causes an autoimmune disease characterised by severe inflammatory infiltrations in lung and colon and the presence of circulating autoimmune antibodies (Gorelik L. et al., 2000). These data indicate that the loss of activity of a single anti-inflammatory molecule could be sufficient to alter intestinal homeostasis and to allow immune responses leading to tissutal damage. [0020] TGF-.beta.1 anti-inflammatory activity starts with the interaction of the molecule with a complex of heterodimeric transmembrane serine/threonine kinases receptors consisting of two subunits, named TGF-.beta.1 R1 and TGF-.beta.1 R2 respectively. Upon TGF-.beta.1 binding, the receptors rotate relatively within the above mentioned complex, resulting in a trans-phosphorylation process and subsequent activation of TGF-.beta.1 R1 by the constitutively active TGF-.beta.1 R2 and capable of autophosphorylation. [0021] The propagation of the TGF-.beta.1-triggered signal to the nucleus is mediated by proteins belonging to the Smad family. Activated TGF-.beta.1 R1 directly phosphorylates Smad2 and Smad3 proteins, which become able to interact with Smad4, thus enabling the complex Smad2-3/Smad4 to translocate to the nucleus, where it participates to the transcriptional control of some genes (Heldin C-H. et al., 1997). [0022] The role of Smad3 in the TGF-.beta.1 anti-inflammatory activity was supported by studies in animal models, which show that the deletion of the encoding gene for Smad3 is associated with diminished cell responsiveness to TGF-.beta.1, and with a related development of inflammatory disease characterized by a massive infiltration of T-cells and pyogenic abscesses formation at gastrointestinal level (Yang X. et al., 1999). [0023] Also other intracellular proteins, for example Smad7, belong to the Smads protein family. Such protein occupying TGF-.beta.1 R1 interferes with the binding of Smad2/Smad3 to the receptor, thus preventing the phosphorylation and the activation. Hence, an increased expression of Smad7 protein is associated with an inhibition of the TGF-.beta.1-mediated signaling (Hayashi H. et al., 1997). [0024] The evaluation of the TGF-.beta.1 expression in intestinal mucosa from IBD patients shows that said molecule production is paradoxically enhanced in comparison to what can be proved in the gut of normal patients (Lawrance I C. et al., 2001). Continue reading... Full patent description for Antisense oligonucleotides (odn) against smad7 and uses thereof in medical field Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Antisense oligonucleotides (odn) against smad7 and uses thereof in medical field patent application. 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