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Therap Adv Gastroenterol. 2009 September; 2(5): 303–309.
PMCID: PMC3002532

New and Developing Therapies for Celiac Disease


The treatment for celiac disease, a removal of gluten in the diet, is safe and effective for the vast majority of patients. There is a large body of evidence that the diagnosis and treatment of those with celiac disease ensures considerable health benefits. Although a gluten-free diet is the principal treatment for celiac disease, it is relatively expensive, inconvenient and difficult to adhere to. For these reasons, there is interest in developing alternative therapies. Emerging research for the treatment of celiac disease has focused on three areas: to decrease gluten exposure, to modify intestinal permeability and to modulate immune activation. Therapies developed thus far consist of enzymes designed to digest gluten and the use of inhibitors of paracellular permeability to decrease the migration of gluten peptides into the lamina propria. Other potential therapeutic maneuvers include the binding of gluten by polymers, the use of tissue transglutaminase (TTG) inhibitors and DQ2 or DQ8 blockers, or modulation of cytokine production. While all represent new and exciting therapies, an ideal therapy should have virtually no side effects similar to a gluten-free diet. A pharmaceutical agent may be used on an intermittent basis, such as following occasional gluten exposure or on a chronic basis to mitigate the effects of potential inadvertent ingestion of gluten.

Keywords: celiac disease, gluten, gliadin, prolyl endopeptidases, therapy


Celiac disease is an autoimmune disorder resulting from exposure to gluten and a complex interplay of environmental and genetic factors [Green and Cellier, 2007]. While previously considered a rare condition diagnosed primarily in children with malabsorption, celiac disease has recently shown to be quite common. According to serologic population based studies, celiac disease may affect approximately 1% of the population [Green, 2007; Fasano et al. 2003]. Celiac disease has a worldwide distribution, detected not only in Europe and countries populated by Europeans, but also in North Africa [Ratsch and Catassi, 2001] the Middle East [Akbari et al. 2006; [Bitar et al. 1970] and India [Sood et al. 2006, 2001].

Current therapy — the gluten-free diet

The treatment for celiac disease is a gluten-free diet. This involves elimination of the grains containing gluten, wheat, rye and barley, as well as food products and additives derived from them [Green and Jabri, 2003]. Maintaining a gluten-free diet improves the health and quality of life for those with celiac disease, even in those with minimal symptoms [Casellas et al. 2008; Mustalahti et al. 2002]. Adherence to the diet improves symptoms [Murray et al. 2004] is believed to reduce the risk of malignancy [Holmes et al. 1989] and may reduce the risk of further autoimmune diseases [Cosnes et al. 2008; Ventura et al. 1999] though not all studies have demonstrated the latter [Viljamaa et al. 2005]. Other health benefits include improvement in bone mineral density, folate and homocysteine status and lipo-protein profile [Dickey et al. 2008; Brar et al. 2006a; Meyer et al. 2001].

Wheat is now consumed worldwide [Fasano and Catassi, 2001] and gluten is added to the regular diet in many and varied forms. Removal of exposure to gluten in the diet is safe and effective for the vast majority of patients. However, worldwide, adherence to the gluten-free diet is not uniform among those with celiac disease [Green and Cellier, 2007]. The highest rates of dietary adherence are reported for patients diagnosed at a very young age and those who were more symptomatic at presentation. Adherence to a gluten-free diet is improved in individuals with a thorough understanding of the diet and also those who participate in a celiac disease advocacy group [Leffler et al. 2008]. In France and Belgium, less than half of the adult patients who were studied strictly adhered to the diet for more than 1 year after diagnosis [Vahedi et al. 2003]. In the UK, compliance was low for both teenagers and adults [Kumar et al. 1988] and adolescents diagnosed via serologic mass screening in Italy had poor compliance [Fabiani et al. 2000]. Many diagnosed in childhood are not adhering to a strict gluten-free diet as adults [Bardella et al. 1994]. There are numerous reasons why there is low adherence to the diet. They include palatability, cost and availability, inadequate food labeling as well as social pressures and quality-of-life issues [Stevens and Rashid, 2008; Lee et al. 2007; Lee and Newman, 2003]. Due to cultural practices, certain ethnic groups may also have decreased adherence to a gluten-free diet [Brar et al. 2006b; Butterworth et al. 2004].

Approximately 7–30% of patients fail to respond to a gluten-free diet [O'Mahony et al. 1996] with the most common reason for continued symptoms on a gluten-free diet being the continued ingestion of gluten [Abdulkarim et al. 2002]. This may result from either inadvertent or intentional ingestion of gluten. Expert dietary counseling is vital for celiac disease patients and can improve compliance, though the availability of expert dietary counseling is limited [Nelson et al. 2007]. In addition nongluten containing grains are not fortified as is wheat flour. As a result patients on a gluten-free diet for 10 years or more were shown to be deficient in vitamins [Hallert et al. 2002]. In a recent study of patient perception of the burden of celiac disease and its treatment, many patients regarded it as a substantial burden with a quarter of screen detected patients reporting regret at being diagnosed [Whitaker et al. 2009]. On follow-up biopsy adults rarely have a normal duodenal biopsy compared to children [Lee et al. 2003; Selby et al. 1999; Dissanayake et al. 1974]. The reasons for this are unclear, however possible causes include the difficulty in totally removing gluten from the diet.

For many of the above reasons patients and their physicians see benefit in a pharmaceutical agent to help them with the gluten-free diet, or even allow the ingestion of gluten. The concept of the development of a pharmaceutical agent to treat celiac disease has become a reality because of the rapid expansion in the knowledge of the pathological mechanisms of the damage induced by gluten in celiac disease. Nondietary therapies have focused on three main areas: to decrease gluten exposure, to modify intestinal permeability and to modulate immune activation. These therapies are illustrated in Figure 1. Several agents have reached the clinical study phase.

Figure 1
Developing celiac disease therapy. *TTG, tissue transglutaminase; **In human studies; #HLA, human leukocyte antigen.

Mechanism of injury in celiac disease

Gluten is the protein component of wheat, rye and barley and is poorly digested in humans secondary to its high content of glutamine and proline [Hausch et al. 2002; Shan et al. 2002]. As a result, high molecular weight peptides, such as the 33mer (a gliadin residue containing 33 amino acids), remain in the human digestive tract intact [Shan et al. 2002]. These high molecular gliadin peptides are particularly immuno-genic [Qiao et al. 2004; Hausch et al. 2002]. Gliadin peptides cross the intestinal barrier by both active transport (transcellular) processes [Bethune et al. 2009; Matysiak-Budnik et al. 2008] and via paracellular mechanisms [Lammers et al. 2008; Fasano et al. 2000]. Within the lamina propria, gliadin peptides are deamidated by the enzyme tissue transglutami-nase [Molberg et al. 1998; van de Wal et al. 1998]. This enhances immunogenicity [van de Wa l et al. 1998] by enabling a stronger interaction with human leukocyte antigen (HLA) antigen presenting cells in the lamina propria that express DQ2 or DQ8 molecules [Kim et al. 2004; Qiao et al. 2004]. This leads to T-cell proliferation and production of cytokines, particularly g interferon that appears to perpetuate damage and influx of gluten [Bethune et al. 2009; Schumann et al. 2008].

Reducing gluten exposure

Genetically engineering grains to eliminate immunogenic gluten fragments would eliminate celiac disease. The large number of peptide epi-topes located in different genetic loci of the wheat genome makes this approach challenging. Other potential challenges exist since the genetic modification of food is controversial and is not regarded favorably by the public. Another approach is the use of synthetic polymers that bind and neutralize gliadin. These have recently been studied and experimentally eliminate glia-din toxicity [Pinier et al. 2008].

A major approach that has been explored is the enzymatic degradation of the large, immunogenic gliadin peptides into small nontoxic fragments. This can be performed by prolyl endopeptidases (PEPs). These are proteases, found primarily in plants and microorganisms, able to degrade the proline-rich gluten peptides into smaller, less immunogenic fragments. This can be achieved by bacterial, or fungal enzymes that lend themselves to large-scale manufacturing [Stepniak et al. 2006; Piper et al. 2004]. Alternatively, pro-biotics have been demonstrated to degrade gluten and exert a protective effect on the damage exerted by gluten on cell cultures [Lindfors et al. 2008; De Angelis et al. 2006].

A technical concern is that the PEPs must not be inactivated, by the acidic milieu of the stomach. In addition, the bulk of gluten digestion should occur in the stomach. Groups in both the United States and the Netherlands have demonstrated efficacy of gluten digestion by different enzyme preparations [Gass et al. 2007; Stepniak et al. 2006]. To facilitate gluten degradation, a two-enzyme cocktail, consisting of a glutamine-specific cysteine protease derived from barley that has activity in the acid milieu of the stomach, and a bacterially derived PEP that acts in concert with pancreatic proteases for activity in the duodenum has been developed (ALV003, Alvine Pharmaceuticals Inc., CA) [Siegel et al. 2006]. The Netherlands group has developed a PEP preparation from Aspergillus niger (AN-PEP) with gastric activity [Stepniak et al. 2006].

Enzyme therapy is attractive because physicians are familiar with using enzyme preparations to treat lactose intolerance and pancreatic insufficiency. Therapy for celiac disease is however complicated because gluten must be completely prevented from interacting with the mucosa. Any remaining gluten peptides may lead to intestinal inflammation.

Decrease intestinal permeability Another therapeutic target is to prevent the migration of luminal gluten peptides across the intestinal epithelium. The transport mechanisms involved are not completely understood but are considered to involve both transcellular and para-cellular mechanisms. Intercellular tight junctions are altered in celiac disease. [Ciccocioppo et al. 2006]. Zonulin, an endogenous peptide involved in tight junction regulation, is amplified in celiac disease and increases intestinal permeability [Fasano et al. 2000]. Although the mechanisms of intestinal permeability and gliadin transport are not completely understood, potential therapeutic agents have been developed. AT-1001 (Alba Therapeutics Corporation, MD), a peptide that inhibits the action of zonulin, and the increase in intestinal permeability induced by gluten has been used in clinical studies [Paterson et al. 2007]. In a randomized, double-blinded, placebo-controlled study by Paterson and colleagues, subjects with celiac disease were challenged with gluten and given either 12mg AT-1001 or placebo. Patients treated with AT-1001 had no increase in intestinal permeability while patients treated with placebo had a 70% increase. The patients treated in this study also experienced decreased gastrointestinal side effects and proinflammatory cytokine levels. The drug appeared to be safe and well tolerated [Paterson et al. 2007]. Further phase II studies are currently underway. The agent (AT-1001) is currently called larazotide.

Decrease immune activation

While therapies currently being investigated aim to decrease the amount of gluten reaching the small bowel or its migration across the intestinal epithelium, another potential target of drug therapy is modulation of the immune response to gluten. This may be achieved by preventing glia-din deamidation through the inhibition of tissue transglutaminase, by preventing HLA presentation through blocking the HLA DQ2 or DQ8 molecules, or by modulating cytokine production. Other proposed therapeutic methods include vaccine development and immune modulation using hookworm. Hookworm infection may decrease gluten sensitivity in individuals with celiac disease via modulation of the immune response [Sollid and Lundin, 2009]. While some of these therapies are promising, they also may pose an increased potential for side effects.

There are several therapeutic studies currently underway as evidenced by the NIH website (¼celiac+disease) these are shown in Table 1.

Table 1.
Therapeutic studies for celiac disease Listed at the NIH website as accessed March 2009.


Although celiac disease is an autoimmune condition with a recognized environmental trigger, there is interest in developing nondietary therapies. Millions of people worldwide are affected by the condition and a large potential market exists for these agents. It is feasible that a new medication may be utilized. It is unclear whether these medications would be used continually to cope with inadvertent gluten ingestion, or intermittently, such as when an individual dines out of the home. There is potential that they may be used to mitigate the effects of intentional gluten ingestion. There are several challenges inherent in developing treatments for this condition. It has been difficult to develop an animal model to study celiac disease, though recently enzyme therapy was tested in a susceptible monkey model [Bethune et al. 2008]. Most studies have been conducted in-vivo, ex-vivo, and eventually in small numbers of human volunteers. A drug must be resistant to degradation in the acidic environment of stomach as well as pancreatic and intestinal proteases and remain active in the small intestine. Objective endpoints are also difficult to define for therapeutic trials in celiac disease. Endpoints may consist of a combination of antibody levels, clinical symptoms, histologic scores, and functional assays of absorptive or permeability function. While useful, all of these approaches have limitations. The marked phenotypic variability in celiac disease makes the disease difficult to study.

Therapies to decrease gluten exposure, to modify intestinal permeability and to modulate immune activation, represent exciting emerging treatments for celiac disease, but a gluten-free diet is virtually without side effects. The gluten-free diet still represents the best and safest treatment for celiac patients. Once the diagnosis of celiac disease is established, the therapy is adherence to a gluten-free diet for life. Any new potential treatment must have a similar safety profile to the gluten-free diet. Clinical studies, consisting of 3 months duration, may not detect all side effects. Therapies resulting in increased infection, malignancy or severe gastrointestinal side effects would not be tolerated by clinicians or patients.

Conflict of interest statement

Dr Tennyson: none; Dr Lewis: none; Dr Green is on the Clinical Advisory Board of both Alba Pharmaceuticals and Alvine Therapeutics.

Contributor Information

Christina A. Tennyson, Celiac Disease Center, Department of Gastroenterology, Columbia University, New York, USA ; ude.aibmuloc@8932tc.

Suzanne K. Lewis, Celiac Disease Center, Department of Gastroenterology, Columbia University, New York, USA.

Peter H. R. Green, Celiac Disease Center, Department of Gastroenterology, Columbia University, New York, USA.


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Articles from Therapeutic Advances in Gastroenterology are provided here courtesy of SAGE Publications