Celiac Disease and Non-Celiac Gluten Sensitivity
Novel and Emerging Therapies
In light of the limitations of the gluten-free diet, several new treatment strategies for celiac disease are currently under development. These novel and emerging therapies can be classified into four general categories: permeability inhibition, immunomodulation, grain modification, and gluten detoxification.
While ongoing research on novel therapies is targeting celiac disease, some of the dietary modification and gluten detoxification strategies described in this section may provide solutions for people with non-celiac gluten sensitivity.
Zonulin antagonism. Zonulin is a protein that regulates the tight junctions that “glue” intestinal cells together and control what passes through the gut wall. In celiac disease, overproduction of zonulin causes these tight junctions to come apart and remain open, increasing intestinal permeability (Tripathi 2009; Fasano 2012a). This “leaky gut” then allows large molecules, including gluten fragments, to enter the bloodstream, where they trigger an immune response and inflammation (Fasano 2012b; Fasano 2011; van Elburg 1993).
An investigational drug named larazotide acetate blocks zonulin from making the gut permeable, and appears to be effective in preventing gluten-related symptoms in celiac disease (Gopalakrishnan 2012). In a randomized controlled trial in patients with celiac disease, acute gluten exposure caused a 70% increase in intestinal permeability in the placebo group, while no change in permeability was seen in the larazotide group. The patients treated with larazotide tolerated the drug well and experienced fewer gastrointestinal symptoms. Moreover, larazotide-treated subjects exhibited a lessened inflammatory response to gluten in comparison with the placebo group, as determined by changes in levels of several inflammatory cytokines (Paterson 2007).
A more recent phase IIb trial evaluated larazotide in 342 celiac patients who did not respond to a gluten-free diet. Compared with controls, patients taking the zonulin-inhibitor at the lowest dose (0.5 mg daily) had significantly fewer gastrointestinal symptoms and headaches, as well as less fatigue. No changes in serum levels of anti-tissue transglutaminase or gliadin antibodies were seen (AGA 2014; Castillo 2014). The drug producer, Alba Therapeutics, is planning for phase III clinical trials of lazarotide’s efficacy and safety (AZO Network 2014). Larazotide acetate has been granted fast-track designation by the Food and Drug Administration (FDA), which is a process by which therapies that help address an unmet medical need may be approved and become available in the market more quickly (PR Newswire 2014).
Vaccination. A preventive vaccine may be one of the most attractive and exciting novel therapies for patients with celiac disease (Aziz 2011). The theory behind vaccination is that tolerance to gluten can be induced through repeated small exposures to strongly immunogenic fragments of gluten. The immune system becomes trained to not react to gluten, thus preventing an autoimmune attack in the small intestine (Bakshi 2012). Just this type of gluten vaccine (Nexvax2) is under development. Nexvax2 is a mixture of the three toxic peptides—gliadin (wheat), hordein (barley), and secalin (rye)—that provoke the immune system in individuals with HLA DQ2-positive genes. Nexvax2 was shown to be safe and well tolerated in a three-week phase I clinical trial in celiac patients (Castillo 2014; Rashtak 2012; Bakshi 2012). Phase II and III clinical trials will be necessary before FDA approval.
Inhibition of tissue transglutaminase 2. Tissue transglutaminase 2 (tTG2) is an enzyme that leaks out of damaged cells and modifies gluten. It is this modified gluten that is presented to immune cells, eventually leading to autoimmune and inflammatory responses in the intestine. As tTG2 is vital to the development of celiac disease, selective inhibition of tTG2 could be another potential therapeutic approach for celiac disease (Kupfer 2012; Esposito 2007; Siegel 2007).
However, tTG2 has many other diverse biological functions such as wound healing and assisting the ingestion of microbes or other foreign particles by immune cells (Siegel 2007). Therefore, inhibiting tTG2 may result in systemic side effects. Nevertheless, in animal studies a series of compounds called dihydroisoxazoles were shown to efficiently inhibit tTG2 with low systemic toxicity (Choi 2005; Watts 2006). Inhibition of tTG2 is still in the discovery phase with no clinical trials yet initiated.
Blocking HLA DQ2 and HLA DQ8. In celiac disease, the human leukocyte antigens HLA DQ2 and HLA DQ8 bind with gluten peptides and induce an immune reaction that leads to disease development. Blocking the binding sites of these HLA antigens may provide yet another treatment alternative. Various gluten analogues (structurally similar to gluten) have been developed that effectively bind and inhibit HLA DQ2, which is present in over 90% of cases of celiac disease (Juse 2010; Huan 2011; Kapoerchan 2008; Xia 2007). The primary concern with these HLA antagonists is the possibility of interfering with other similar HLAs that are involved in normal immune surveillance. This strategy is still in the discovery phase (Rashtak 2012).
Anti-interferon-gamma and anti-TNF-alpha therapies. Interferon-gamma and tumor necrosis factor-alpha (TNF-α) are cytokines (signaling molecules) that are activated by gluten’s interaction with T cells of the immune system. These cytokines contribute to the inflammatory cascade in celiac disease. Interventions that block these cytokines have been investigated in celiac disease. Infliximab (Remicade), an anti-TNF-α monoclonal antibody used in the treatment of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, was beneficial in two case reports of unresponsive celiac disease (Guo 2013; Nilsen 1998; Pena 1998; Gillett 2002; Costantino 2008; Woodward 2013).
Anti-interleukin-15 therapy. Interleukin-15 (IL-15) is another cytokine that plays a significant role in the development of celiac disease. Genetically altered mice that produce excess IL-15 in intestinal cells develop inflammation along with flattening of the villi in the small intestine, much like the damage that occurs in celiac disease. One trial showed that in mice, blocking IL-15 with antibodies reversed this autoimmune damage (Yokoyama 2009). AMG 714, an anti-IL-15 antibody, is being evaluated in phase II clinical trials for the autoimmune diseases rheumatoid arthritis (Amgen 2007) and psoriasis (Amgen 2014). Targeting IL-15 is a plausible treatment strategy for celiac disease as well, though human trials are still lacking (Sollid 2011).
CCR9 antagonists. The chemokine receptor CCR9 acts as a trafficking or homing molecule that selectively causes T cells to move to the small intestine, where they promote persistent inflammation. This homing receptor has been associated with celiac disease (Olaussen 2007). An antagonist to CCR9 called CCX282-B induced a clinical response and maintenance of clinical remission in Crohn’s disease (Keshav 2013). A phase II trial of CCX282-B in celiac disease has been completed, but results are pending. Due to a lack of specificity, this drug may increase the risk of gastrointestinal infections (Stoven 2013; Sollid 2011).
Wheat variants. The development and production of variant wheat strains that contain reduced levels of toxic gluten proteins is one novel approach currently under exploration. Success in this endeavor might allow people to consume wheat while reducing their exposure to gluten. Several studies have reported that various species of ancient wheat (einkorn) and some strains of pasta wheat (durum) contain little to no immunogenic gluten peptides. It appears that ancient forms of wheat contained less total gluten and toxic gluten fragments than modern bread wheat (Molberg 2005; Spaenij-Dekking 2005).
Research efforts are focused on breeding wheat strains similar to ancient wheat that lack harmful gluten peptides. Identification and breeding of grain varieties with less immunotoxic profiles is in development (Molberg 2005).
Enzyme therapy. Enzyme therapy is a promising new intervention designed to detoxify gluten. Certain protein-digesting enzymes (proteases) derived from plants and microorganisms can completely break down gluten peptides into harmless fragments. One such enzyme preparation, AN-PEP, is a proline-specific protease extracted from the common fungus Aspergillus niger. This enzyme specifically cleaves the proline-rich gliadin peptides, making them less immunogenic. Experiments with cell cultures demonstrated that AN-PEP can withstand the strongly acidic environment of the stomach, and fully digest gluten and immunogenic peptides (Stepniak 2006). Human clinical trials are underway to confirm this.
Another protease, ALV003, is further along in development and appears to have greater therapeutic potential. Composed of a proline-specific protease and a glutamine-specific protease called EP-B2, this two-enzyme combination was shown to be superior to either enzyme alone (Siegel 2006; Siegel 2012). According to a phase II trial, ALV003 appeared to reduce gluten-induced small intestinal damage in patients with celiac disease who were challenged with up to 2 g gluten per day while following a gluten-free diet (Lähdeaho 2014). A 500-person multi-center trial is currently ongoing (Adelman 2014).