New approaches to type 1 diabetes and other autoimmune diseases
Yesterdays edition of DailyUpdates (19th Dec, 2005) featured a paper looking at the efficacy of etanercept as a treatment of psoriasis. Both this condition and also type 1 diabetes are the focus of our recent drug discovery report, Autoimmune Disorders & Transplant Rejection - Opportunities for the Drug Development Sector,
Although psoriasis is almost 8-fold more prevalent than type 1 diabetes, it now represents a relatively minor clinical problem. This is due in part to the success of TNF blockers including etanercept. According to the study highlighted yesterday, patients rated disease severity as improving from moderate/severe to minimal/good.following treatment with etanercept and a quantitative measure of efficacy as measured by the Dermatology Life Quality Index reported that etanercept produced a 65-70% improvement. There remain a number of unmet clinical needs in the treatment of psoriasis however in general a disease once associated with uncontrollable discomfort and disfiguration of the skin as well as loss of mobility is now managable. This contrasts with type 1 diabetes.
Type 1 diabetes accounts for approximately 10% of all cases of diabetes and is characterized by the destruction of insulin-secreting beta cells in the pancreatic islets of Langerhan. This results in a loss of insulin production exposing the patient to the effects of both acute and chronic deviation in glucose balance. The therapy of choice for the disease is to inject insulin and before the discovery and isolation of insulin in the 1920s, having this type of diabetes meant certain death.
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.
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 in today’s edition of DailyUpdates (20th Dec, 2005) focuses on the pathophysiological role of zonulin, a protein that regulates intercellular tight junctions (Watts et al, 2006). 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
posted by Jon Goldhill at 2:07 PM
2 Comments:
To date, serum zonulin expression has been examined in six autoimmune disorders. Zonulin appears to be significantly over-expressed in patients with type I diabetes, celiac disease, autoimmune hepatitis and primary biliary cirrhosis, when compared to healthy controls.
Oral administration of AT-1001 after development of anti-islet antibodies in diabetes prone BB/wor rats increased diabetes-free survival, from about 40% at the 129 day mark, to 70%.
The first human dose exposure study for oral AT-1001 in normal volunteers was successfully concluded in Oct 2005 under a celiac disease IND, which application has now received fast-track designation by the FDA. Single dose proof-of-concept studies in celiac patients are currently underway, as well as multiple dose safety studies in normal volunteers.
Interesting data - does this mean that we may have to rethink the etiology of these diseases?
In the past autoimmune diseases have been considered to depend on 2 preconditions - a mix of genetic predisposition to autoimmunity and exposure to an environmental trigger.
The zonulin data suggests to me that a third precondition may exist - ie leaky barriers. In other words the data suggest that at least some autoimmune conditions may depend on an ongoing, inappropriate presentation of environmental antigen through the gut wall.
One thought that springs to mind however - the gut wall represents just one barrier between the environment and the immune system. Can the findings in the gut be extended to the airway and even the blood brain barrier (for MS). Likewise dietary antigens represent just one class of trigger - how does the hypothesis of viral infection being a trigger fit into the zonulin story.
Just one final comment - what is the cause of zonulin overexpression - could this be related to a polymorphism that extends susceptibility to multiple diseases in a similar fashion to CTLA-4? All interesting stuff!!
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