Sunday November 22 2009 | Biotechnology feed | All feeds
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Sunday November 22 2009 | Biotechnology feed | All feeds
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Return to introduction on drug discovery ~ LeadDiscovery Reports Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Role of the intestinal
tight junction modulator zonulin in the pathogenesis of type I diabetes in BB
diabetic-prone rats.
(Source: Proc Natl Acad Sci U S A.) Full Citation:Proc Natl Acad Sci U S A. 2005
Feb 22;102(8):2916-21. Epub 2005 Feb 14.
Publisher's
Abstract ----------------
Despite the availability of insulin, in 2002 more than 50% of Americans with diagnosed type 1 diabetes failed to meet target levels of glucose control and consequently the risk of microvascular complications associated with the disease, and resultant cardiovascular problems, kidney failure, amputation and blindness remains a major problem. Although glucose tolerance remains normal until the clinical onset of diabetes, beta-cell function and insulin release decrease even during the preclinical period. It is thought that approximately 90% of beta-cell mass must be destroyed before overt hyperglycemia will occur. Attention is now being focused on the "honeymoon period", the critical period between the times of clinical diagnosis and ample destruction of beta-cell mass, which may be exploited to find avenues that could prevent insulitis and obviate the need for insulin restoration. A full evaluation of unmet needs in autoimmune diabetes as well as other autoimmune diseases can be found in our report Autoimmune Disorders & Transplant Rejection - Opportunities for the Drug Development Sector, It is now clear that inherited susceptibility to type 1 diabetes depends on several genes at different loci, however it is believed that an environmental trigger is also necessary to promote autoimmunity and these may include viruses, toxic chemicals, and various dietary components such as cow's milk. The ability of dietary components to act as triggers may be facilitated by increased intestinal permeability, increasing the exposure of intestinal contents to the immune system. Indeed increased gut permeability has been observed in numerous human autoimmune diseases. The paper featured here focuses on the pathophysiological role of zonulin, a protein that regulates intercellular tight junctions. Zonulin is involved in the innate immunity of the gut and, when inappropriately up-regulated, appears to play a key role in the increased intestinal permeability and pathogenesis of autoimmune diseases such as celiac disease. The objective of this study was to establish whether zonulin-dependent increased intestinal permeability plays a role in the pathogenesis of type 1 diabetes. The study led by Alessio Fasano, CSO and co-founder of Alba Therapeutics, reported that diabetic-prone rats displayed a 35-fold increase in intestinal intraluminal zonulin levels. Zonulin up-regulation was followed by the production of autoantibodies against pancreatic beta cells, which preceded the onset of clinically evident type 1 diabetes about 25 days. Blockade of the zonulin receptor using a peptide inhibitor (AT-1001) reduced the cumulative incidence of type 1 diabetes by 70%, despite the persistence of intraluminal zonulin up-regulation. This study offers excellent proof of concept to support the development of zonulin blockers as an approach to type 1 diabetes. A number of further studies are however eagerly awaited. Firstly, and perhaps most obvious is a study to determine whether zonulin levels increased in patients. This should be a relatively simple study to conduct if the animal study described here reflects the clinical situation, as a clear increase in serum zonulin was measured in rodents. If zonulin levels do increase during the development of diabetes then this molecule could represent a useful marker of disease development. Second and perhaps more important, it will be important to see how long zonulin blockade can be delayed before this approach becomes ineffective in preventing the development of diabetes. In the present study, blockade was initiated prior to an increase in anti-islet antibodies. Antibody development occurred concomitantly with zonulin over-expression and this preceded the development of diabetes. It would be interesting to determine the efficacy of zonulin blockade when commenced just after levels start to increase. This would have a number of clinical implications; not least, if zonulin is a marker of disease onset, at-risk individuals could be monitored for zonulin overexpression and then treated accordingly once increases are observed. Finally increased gut permeability has been observed in numerous human autoimmune diseases and the over-expression of zonulin as well as its blockade could have far reaching implications. Indeed Alba Therapeutics are currently developing AT-1001 for the treatment of celiac disease. This lead compound is currently undergoing pre-clinical toxicology studies prior to being advanced into the clinic. Studies conceptualizing the targeting of zonulin for the treatment of celiac disease will be highlight in an upcoming issue of DailyUpdates Source: LeadDiscovery LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report. This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider. |
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