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‘Goodbye to the Gluten-Free Diet...'

...trumpeted La Repubblica, Italy’s largest circulation newspaper, after the International Coeliac Disease Meeting in Genoa in September. Alex Gazzola examines whether such a headline could be justified.

end gluten-free diet cartoon

Some of the world’s leading coeliac disease experts attending the International Coeliac Disease Meeting (held during the 20th annual conference of the Association of European Coeliac Societies (AOECS), in Genoa in September) unveiled some startling new research results concerning the prevention and cure of coeliac disease.

Although the news was largely ignored by mainstream media in the UK, and indeed much of Europe, their Italian counterparts showed no such reservations.

‘The cure for coeliac disease has been found’ and ‘a vaccine is ready’ announced Primocanale, a Genoa-based TV channel. ‘Goodbye gluten-free diet – the anti-coeliac pill has arrived’ headlined La Repubblica, Italy’s largest circulation general newspaper. The coverage was unprecedented in a land of 75,000 diagnosed coeliacs, with an estimated further half million undiagnosed, and where an inability to eat pizza and pasta is incomprehensible to many.

Although obviously pleased by the unexpected coverage, the AIC (Associazione Italiana Celiachia – the Italian Coeliac Association) sounded a note of caution to temper the excitement generated, and felt compelled to issue statements and press releases clarifying the state of play to their members and the media. So how justified and accurate were those promising headlines?

Here’s what was revealed in Genoa and what the AIC had to say – and what it might mean for the coeliac community in the UK and worldwide.

Coeliac Drugs

The results of phase 2 trials on a promising new drug, larazotide acetate (AT-1001), were announced. Discovered by Dr Alessio Fasano, medical director of the University of Maryland Center for Celiac Research, Baltimore, United States, the drug inhibits a human protein called zonulin, which regulates intestinal permeability. Tests on 110 coeliac patients revealed that 86% of those taking the drug and exposed to gluten remained symptom free.

‘Three years ago we trialed the drug on diabetic rats, and we found the treated animals kept their intestinal barrier intact and did not produce the auto-immune antibodies that trigger immune reactions,’ says Fasano. ‘These observations were so positive we’re already now trialing on humans. In this most recent phase, coeliacs treated with a placebo (dummy) pill and exposed to gluten developed classic symptoms in 75% of cases, but those treated with the real drug and exposed to gluten only developed symptoms in 14% of cases – the same number as those exposed to ‘fake’ gluten and a placebo pill, or ‘fake’ gluten and a real pill. More detailed research is under way on 180 patients, and we’ll know the results by the end of the year.’

The drug, developed by Alba Therapeutics, and which is designed to be taken prior to the consumption of a gluten-containing meal, effectively blocks the toxic effect of the protein. ‘Zonulin is a type of “key” which opens doors from one cell to another in the intestinal wall,’ says Fasano. ‘The intestine is covered by a single layer of cells that form a considerable barrier against outside attack, but coeliacs lose this ability because they produce too much zonulin.

The problem with producing too much zonulin is the cell ‘doors’ remain too ‘ajar’, allowing improperly digested fragments of gluten to enter the body, which in turn gives way to an immune system response that triggers the typical coeliac symptoms. The inhibitory anti-coeliac drug works by temporarily “shoring up” the cell wall, thus breaking a link in the chain of reactions.’ The results have since been presented at the 2008 American College of Gastroenterology Annual Scientific Meeting, held in early October. Phase 3 clinical trials are now being planned to evaluate safety, efficacy and the maintenance of the effect of AT-1001. Researchers are upbeat, and have predicted a revolution in patients’ lives within five years. Alba Therapeutics have also conducted preclinical studies on the drug showing potential in the treatment of inflammatory bowel disease.

It was also announced that a separate study on a newer drug is also ongoing, co-ordinated by Frits Koning from the Leiden University Medical Centre, Netherlands. This is based on a protease, a type of enzyme which breaks down proteins, in this case one able to completely dismantle gluten, rendering it non-toxic to coeliac patients.

Early results on the phase 1 human trials currently taking place will be out within the year. The approach is known to work, according to Fasano, but it remains undecided how the drug may be best eventually used: whether to employ it to ‘predigest’ gluten before bread-making, creating new free-from products that will be cheaper and tastier than the gluten-free foods presently available on the market, or whether to use it as a pill administered prior to eating a gluten meal, to help the body digest and assimilate it.

Some probiotics also produce enzymes capable of dismantling gluten, and research and experiments are currently being undertaken at the Department of Applied Microbiology at Bari University, Italy, to evaluate their use. Fasano says early results there are promising too.

Coeliac Vaccines

By the end of the year, phase 1 trials on the vaccine being developed by Nexpep will be carried out on a dozen patients, co-ordinated by Dr Robert Anderson of the Walter & Eliza Hall Institute of Medical Research in Melbourne, Australia. It will be the first clinical human trial on a curative (rather than preventative) vaccine for an auto-immune disease.

The mechanism is complex, but it is intended that the vaccine will work by reprogramming the immune system of coeliacs to tolerate gluten by ‘introducing’ fragments of gluten to the immune system in a particular way, ‘re-educating’ it to tolerate the protein, and not produce the cytokines which go on to harm the intestinal lining in coeliac patients.

The AIC additionally reported that scientists are monitoring the effects of the introduction, in Italy, of a new anti-rotavirus vaccine and whether this may have any impact on the manifestation of coeliac disease. Rotavirus causes gastroenteritis, and the vaccine in question, RotaTeq, has been given to most Italian infants for almost three years – and that of course includes both babies who are genetically at risk of coeliac disease and those who aren’t.

‘Coeliac disease does not always appear as soon as a susceptible individual is exposed to gluten – in some cases, symptoms may not manifest until decades later,’ observes Fasano. ‘In these patients, the immune system tolerates gluten for a while, but then something happens which tips the balance towards an anomalous, auto-immune response. For some, the triggering factor can be stress, for others pregnancy, for others surgery. In a sizeable number, the blame appears to be a rotavirus infection. The vaccine should therefore be able to block the development of coeliac disease in these patients.’

So far, babies treated with the vaccine have not shown an incidence of coeliac disease lower than those from earlier generations who have, of course, never been vaccinated. Fasano speculates that this may be because not enough babies have been vaccinated for the beneficial effect to yet show up statistically, given that rotavirus- triggered coeliac disease constitutes only a fraction of the wider coeliac population. So might an anti-rotavirus vaccine have an eventual role to play in the prevention of coeliac disease – if only in part?

‘Only time will tell,’ he says.

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Comment from Sarah Sleet - Chief Executive - Coeliac UK

I think these results are very interesting and there is real potential there. But it’s important to stress that a pill has not yet arrived, and a vaccine is not yet ready. As with anything concerning medical development, especially drug development, there are strict safety procedures to go through, which take a lot of time. Inevitably, not all of the treatments will clear all the hurdles.

Another important issue to address is how receptive the coeliac population is going to be to taking a drug or vaccine-based treatment when they’ve already got the risk-free alternative of a gluten-free diet. I suspect the answer will be different for different individuals. Some coeliacs will wonder why they would want to take any kind of risk on a treatment when there is a safe alternative, and others, who find the diet burdensome, will feel the risks are far outweighed by the potential benefits.

There is a need to offer options to manage long-term conditions. Research should definitely be pursued, but ultimately treatment may not necessarily be for everybody.

Click here for more articles on the management of coeliac disease

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