Treatment and Disease Management

The only effective and clinically relevant treatment to date is a lifelong adherence to a gluten free diet. In the absence of the gliadin proteins found in gluten, the body can completely reverse any negative effects associated with the autoimmune response to gluten. A gluten free diet involves avoiding any foods that contain wheat rye or barley (Niewinski, 2008). In the United States, oats that are not steel cut should be avoided given that they are processed with wheat, but oats themselves do not contain any gluten peptides. Mechanistically, by removing the environmental factor that induces any immune response, it is easy to see how this therapy is so effective at eliminating symptoms.

Despite this being the only relevant treatment to date, there are multiple opportunities to develop therapies that inhibit the pathogenic pathway of Celiac disease, and there are several treatments currently being researched that attempt to do just that. For example, both Larazotide acetatehave and several endopeptidases are being tested and have shown promising results in reducing symptoms of Celiac disease (Vanga, 2014). Larazotide acetate functions by modulating the integrity of tight junctions and thereby reducing the passage of gliadin through the intestinal mucosa, whereas the endopeptidases function to further digest any gliadin fragments, reducing the prevalence of any potential epitopes that could incite an immune response.

, 2011

Visualization of all the areas that are capable of being used as points of treatment in Celiac disease Source: Khosla, 2011
Visualization of all the areas that are capable of being used as points of treatment in Celiac disease Source: Khosla, 2011

In general, there are a vast number of ways to attack this disease. Anything from oral proteases to drugs that target zonulin expression, to enzymes that inhibit the function of tissue transglutaminase, to gluten sequestering polymers that bind gliadin under gastric and intestinal conditions are being developed and undergoing tests to be clinically approved (Khosla, 2011). Speicifally, a drug cocktail called STAN1, which incorporates an oral protease, is now being developed and has reached clinical trials(Khosla, 2011). There are also a few individual oral protease drug therapies that are currently in clinical trials as well. In any event, the majority of the treatments being developed focus on either reducing the permeability of the membrane, reducing the binding ability of HLA-DQ2 or HLA-DQ8, or reducing the bodies ability to incite an immune response in the presence of gliadin (Khosla, 2011). Below is a graphic that shows the vast number of treatments that are being developed. The abbreviations used from the paper have been included in the picture.

Visualization of the vast number of treatments either approved or being developed to treat Celiac disease (Khosla, 2011)
Visualization of the vast number of treatments either approved or being developed to treat Celiac disease (Khosla, 2011)

Besides these drug treatments, there are a few more alternative therapies that have received some attention. Gluten tolerization, for example, is now in clinical trials(Khosla, 2011). This is essentially the process of introducing a peptide vaccine to reduce the bodies immune response against various epitopes of gliadin. There is currently a a prototypical vaccine, NexVax, in trials that is designed to increase the bodies resistance against multiple epitopes of gliadin(Khosla, 2011). The variety of possibly immunogenic epitopes pose a problem for this treatment, however, given that it is difficult to design a vaccine that could provide resistance to upwards of 50 epitopes.

Genetic modification to remove the immunogenic gliadin portion of the wheat plant is a more radical therapy that does not necessarily focus on the individual with the disease (Vanga, 2014). This would effectively reduce any T-stimulatory epitopes in circulation after an individual consumes wheat, and would therefore reduce any immunogenic effects. A related study in which pretreatment of flour with lactobacteria, which are capable of digesting the highly immunogenic 33-mer gliadin peptide, unfortunately, still showed enhanced permeability of the small intestine (Vanga, 2014). This is most likely due to the vast amount of epitopes in gliadin capable of inducing an immunogenic response.

Jump to other pages about Celiac disease

Title Page

History and Metabolic Context

Molecular Basis of the Disease State

Conclusions and Proposals for Future Work

 

6 Replies to “Treatment and Disease Management”

  1. Nice work, Tommy. I had some other ideas in mind about treatment options and wanted to see what you thought about them. Do you think it would be possible to design specific proteases that could be administered in order to increase the breakdown of gliaden? Maybe specific proteases that could “get past” the tough proline structures? The immune aspect of Celiac also interests me. I wonder if it would be possible to design a type of “vaccine” for Celiac patients. Could we design a safe version of the antigen that could be administered to Celiac patients to develop a type of resistance? That would be pretty cool.

    1. Hey Zach,

      The answer to both your questions is actually yes. There have been promising results that suggest that oral proteases could in vivo could reduce the amount of circulating gliadin eptiopes and ultimately reduce the severity or presence of Celiac associated symptoms. There is also a “vaccine” of sorts in trials that works to desensitize individuals to a variety of gliadin epitopes. The problem with this therapy, however, is that it is difficult to design a vaccine to cover the over 50 immunogenic epitopes gliadin boasts.

      Links I referenced:

      http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02376.x/abstract

  2. Hey Tommy, nice analysis – I’ve certainly learned a lot by going through your pages. One broader question I have for you is – are there extra drawbacks to having a gluten-free diet? Is wheat an important source of another nutrient that would need to be supplemented when a patient starts a gluten-free diet? Next, in terms of the proposed treatment that would act by affecting the inflammatory response – do you know how potent these treatments would be? Celiac symptoms are due to inflammation gone awry, but inhibiting or decreasing the efficacy of the inflammatory response could be harmful and make the patient more prone to infection. Alternatively, maybe there could be something similar to the lactulose pills lactose-intolerant individuals take? Maybe a Celiac patient could take an inflammatory-depressant right before they eat something that they may suspect came into contact with gluten, for temporary effects? Just wanted to hear your thoughts. Thanks!

    1. Hey Besher,

      To answer your first question, wheat is really just a carbohydrate, so there is not real need for the body to consume it. It is actually common now for individuals looking to lose weight or gain muscle to go on a low carb gluten free diet. Also, from personal experience, I can tell you donuts may look really really good, but its probably a good thing I can’t eat them.

      To answer your second question, it is entirely possible that there may be complications involved in any of the treatments used to treat Celiac disease as most of them target global processes. This is also why my favorite treatment options is to target zonulin, as it seems the most idiosyncratic. Unfortunately, since most of the drugs and what not are still in clinical trials, I can’t specifically comment on the nature of any side effects. I don’t exactly know the exact nature of the lactose intolerance pill, but there discourse about using anti inflammatory pills. Generic versions of this drug unfortunately target the lower intestine, so more specific versions that target the upper intestine need to be developed to completely hit Celiac disease.

      Links I referenced:

      http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02376.x/abstract

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