THE PRIMER

Imagine the tantalizing scent of freshly baked bread. Now, think about even a single scrumptious slice wreaking havoc on you: stomach pain, bloating, and other digestive consequences. Welcome to Planet Celiac— home to the millions of Americans diagnosed with celiac disease. This article looks at this autoimmune disorder and how biotech companies are working to make life much more comfortable for celiac patients.

Celiac disease is triggered by gluten proteins found in wheat. Typically, our bodies break down proteins into their chemical building blocks (amino acids). Our intestines then harmlessly absorb them to make the new proteins essential to cellular function.

Glutens, however, contain unusually high levels of proline. This amino acid endows glutens with the power to resist digestive enzymes. The resulting incomplete digestion causes us to produce short amino acid chains or peptides. In people with celiac disease, peptides provoke their bodies’ immune systems to attack their own small intestines. Ow.

Symptoms of celiac disease range from diarrhea, weight loss, and malnutrition to the less obvious such as isolated nutrient deficiencies. Some people with celiac disease suffer no symptoms at all.

So, gluten is a protein. And very bad for celiac disease patients. But what is it? Glutens are the proteins in wheat, barley, and rye. Those grains are in bread, of course—but in lots of other food and drinks, including cereal, beer, malted milkshakes, and salad dressing!

So, what’s a citizen of Planet Celiac to do? Currently, the only recourse is totally avoiding food and drink containing gluten. It sounds simple, perhaps, but gluten is a tricky foe—salad dressing? Beer? Really? Really.

A peptide is a chain of amino acids consisting of fifty or fewer amino acids.

Peptides are part of us. Or at least inside us—as mentioned above, they come from protein digestion. Our bodies also produce and put to work several other peptides too. For example, the pancreas pumps out the peptide hormone glucagon in response to low blood sugar. Glucagon signals the liver to release stored glucose into the bloodstream. Other powerful peptides include amylin, which slows our stomach’s emptying, and prolactin, which stimulates milk production in nursing mothers.

Celiac disease and gluten sensitivity each involve the body’s response to peptides derived from gluten proteins. However, the details of that response differ significantly.

Celiac disease patients mount “an antigen-specific immune response.” They generate antibodies that recognize gluten peptides and unleash T-cells (a type of white blood) to fend them off. The trouble is that the overzealous T-cells also hone in on the patient’s small intestine, often causing significant damage and discomfort.

In contrast, gluten-sensitive patients launch an “innate immune response” toward gluten. While they don’t produce gluten-specific antibodies or activate gluten-specific T-cells, their immune system recognizes gluten peptides as foreign and potentially harmful, leading to inflammation that can cause celiac-like symptoms. The significant takeaway difference is that people with gluten sensitivity suffer no direct damage to their intestines. The two disorders can be differentiated by testing for celiac-specific antibodies.

Biotech may have a few fixes for the more than twenty million Americans dealing with celiac disease or gluten sensitivity. Scientists are approaching the problem from two different angles. One, they’re working on modifying wheat and other grains, so they don’t kick the body’s immunity into action. And two, they’re exploring ways to treat patients, so their immune systems respond more mildly.

Eat That Wheat?

Wheat glutens contain two proteins: gliadins and glutenins. Gliadins give rise to problematic peptides and rev up the immune system. Researchers from the Spanish Institute for Sustainable Agriculture used CRISPR/Cas9 genome editing to develop a strain of wheat without gliadin proteins. The new-fangled wheat scored high marks from a panel of trained assessors compared to traditional wheat. Anokion SA (Switzerland) has completed its Phase 1 clinical trial for KAN-101, which is intended to treat celiac disease. This drug is designed to re-educate immune cells that drive celiac disease, preventing them from responding to gluten antigens. The trial demonstrated that KAN-101 is safe and effectively reduces the body’s immune response to gluten in patients with celiac disease. A Phase II clinical trial for KAN-101 is planned, and its successful completion will make it significantly more likely for the drug to reach the market.

ImmusanT (Cambridge, MA) is developing a desensitization therapy in which patients are systematically exposed to peptides that elicit the celiac disease immune response. Researchers hope to “reprogram” T-cells to no longer freak out over the problematic peptides. This approach echoes desensitization therapies for allergies such as pollen, pet dander, and dust mites. Once considered too risky for food allergies, new studies support the benefits of gradual exposure to food allergens. ImmusanT’s product, Nexvax2, has completed Phase Ib studies, however, the Phase II clinical trial for Nexvax2 was halted due to interim analysis revealing that the vaccine did not offer statistically significant protection against gluten exposure when compared to a placebo. Despite this outcome, ImmusanT has emphasized the potential value of the data collected, which could help inform future treatments for celiac disease.

PvP Biologics (San Diego, CA) is developing KumaMax, an enzyme that breaks down gluten in the stomach before it damages the small intestine. Now in preclinical testing, KumaMax is derived from an enzyme called kumamolisin. Kumamolisin is found in Alicyclobacillus sendaiensis, a type of bacteria that grows in acidic conditions – similar to those found in the stomach, meaning that the enzyme can be delivered orally and should be able to function efficiently in the stomachs of celiac patients.

[wpcode id=”14822″]

Alicyclobacillus sendaiensis is an extremophile. These bacteria grow in—you guessed it–extreme environments. Humans, most plants, animals, and fungi have adapted to a minimal range of conditions such as body temperature, pH (acid level), and atmospheric pressure. Extremophiles have instead evolved to survive crazy environments. One of the most famous extremophiles you’ve probably never heard of is the Taq polymerase. All sorts of biotech use Taq in the polymerase chain reaction (PCR). This reaction uses a DNA-copying enzyme to amplify DNA and requires temperatures near boiling. Most DNA-copying enzymes can’t handle the heat.

In contrast, Taq is literally hot stuff. Taq’s affinity for steamy temperatures isn’t surprising. After all, its bacterial “parent” came from the hot springs at Yellowstone National Park.