Celiac disease, also known as gluten intolerance is a syndrome characterized by damage to the small intestinal mucosa, following exposure to either the gliadin fraction of wheat gluten or similar alcohol soluble proteins (prolamines) of barley and rye in genetically susceptible subjects. Celiac disease is a common autoimmune disorder that has genetic, environmental and immunologic components. The disease is closely associated with genes that code for human leukocyte antigens DQ2 and DQ8 (1). A 33-mer fragment of α-gliadin was identified that has several characteristics suggesting it is a possible initiator of the inflammatory response to gluten in celiac disease patients (2).
Symptoms of celiac disease can range from mild weakness, bone pain, and aphthous stomatitis to chronic diarrhea, abdominal bloating, and progressive weight loss (3). Because of the broad range of symptoms, celiac disease presence can be difficult to diagnose. Those affected suffer damage to the villi (shortening and villous flattening) in the lamina propria and crypt regions of their intestine (3). Furthermore, gastrointestinal carcinoma or lymphoma develops in up to 15 percent of patients with untreated or refractory celiac disease (4). A gluten-free diet can prevent almost all complications of the disease (5). Such a diet involves avoiding all products that contain wheat, rye, barley, or any of their derivatives. This is a difficult task as many hidden sources of gluten can be found in the ingredients of many processed foods.
Until now, aside from excluding gluten-containing foods from their diet, no pharmacological treatment is available for celiac patients. Surprisingly, relatively few treatment strategies are currently being explored. Approaches based on the tolerance of antibody and T-cell mediated response to the gliadin toxic peptides or on the development of anti-IL-15 neutralizing antibodies blocking the IL-15 mediated changes in the small intestinal mucosa are under investigation (6). A promising avenue lies in the discovery of exogenous enzymes, which could rapidly degrade toxic peptides in situ (7). However, the high cost associated to large-scale enzyme production and possible loss of activity after oral administration are potential constraints to their commercialization. Complementary strategies aiming to interfere with activation of gluten-reactive T cells include the inhibition of binding of gluten peptides to human leukocyte antigen (HLA) DQ2 (or DQ8). The crucial role of HLA in celiac disease development makes it an obvious target for therapeutic intervention. The recently solved X-ray crystal structure of HLA-DQ2 complexed with a deaminated gluten peptide has provided important information for the development of an HLA-DQ2-blocking compound (8). Zonulin antagonists have also been suggested as therapy for celiac disease. Zonulin is a protein involved in the regulation of intercellular tight junctions in the small intestine. Its expression has been shown to increase during the acute phase of celiac disease, a clinical condition in which the intestinal permeability is increased (9).
The development of grains that have low or no content of immunotoxic sequences, but with reasonable baking quality, has also been investigated. Such grains can potentially be developed by selective breeding of ancient wheat varieties (10), by transgenic technology involving mutation of sequences giving rise to immunostimulatory sequences (11) or by incorporation of nontoxic gluten genes into harmless organisms such as rice (12). Although these grains are technically challenging to engineer, and there is a possibility that cross-pollination with gluten-containing grains might lead to reintroduction of immunotoxic sequences, the availability of such grains could give patients with celiac disease a nutritionally better diet.
Polymeric Binders
A number of polymeric binders have been used for treating or preventing certain diseases.
The classic example of a polymeric binder is cholestyramine, a cationic resin that sequesters biliary acids in the gut and consequently lowers cholesterol blood levels. Recently, sevelamer hydrochloride, a novel aluminum and calcium-free polymeric phosphate binder with negligible side effects has been commercialized for the treatment of hyperphosphatemia in patients on dialysis. Perhaps the most interesting discovery in this field is an anionic high-molecular weight polymer, GT160-246, which was shown to neutralize Clostridium difficile toxin A activity both in vitro and in vivo (13). This endotoxin is the most commonly identified cause of infectious nosocomial diarrhea. GT160-246 offers a promising and safe nonantimicrobial approach to the treatment and prevention of C. difficile colitis in humans.
The idea that high molecular weight polymers could be of potential use in celiac disease stemmed from a study of Auricchio et al. (14), which demonstrated that mannan (mannose homopolysaccharide) and acetylglucosamine oligomers exhibited a protective effect on intestinal mucosa specimens of patients with active celiac disease (14). These findings suggest that the agglutinating and toxic peptides are bound by these carbohydrates. Secundo et al. (26) explored the effect of another polysaccharide, dextrin on the secondary structure of gliadins and hypothesized that dextrin might be used to prepare non toxic food derivatives for patients suffering from celiac disease. Despite these interesting preliminary data, no further investigations were carried out to confirm those findings in vivo. The main drawback of natural carbohydrates is their degradability under in vivo conditions which would make them inactive in situ.
The present invention seeks to meet these needs and other needs.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
USPTO Backgrounds
USPTO Backgrounds