What Is the Main Idea?

The treatment of ulcerative colitis has traditionally focused on the control of symptoms. In the review article “Current and Emerging Targeted Therapies for Ulcerative Colitis”, published in the journal Visceral Medicine, the authors describe how advances in targeted treatments have the potential to improve the quality of life of people with ulcerative colitis.

What Else Can You Learn?

In this blog post, ulcerative colitis and emerging treatments for it are described. Different phases of clinical trials are also discussed.

What Is Ulcerative Colitis?

Ulcerative colitis is a form of inflammatory bowel disease. People with ulcerative colitis have chronic (long-term) inflammation and ulcers (sores) in the colon (also known as the large bowel and part of the large intestine, it removes water and some nutrients from partially digested food before the remaining waste is passed out of the body).

For many people with ulcerative colitis, the disease follows a “relapsing and remitting” course, which means that there will be times when their symptoms get worse and others when their symptoms partly or completely go away. Symptoms of ulcerative colitis include needing to go to the toilet frequently and urgently, abdominal pain, a general feeling of being unwell, and fatigue, which can combine to have a major impact on a person’s quality of life and ability to work.

What Causes Ulcerative Colitis?

The exact causes of ulcerative colitis are not fully understood, but it is known that a combination of factors cause inflammation to be activated by the immune system. Inflammation is a normal process through which your body responds to an injury or a perceived threat, such as a bacterial infection. In ulcerative colitis, a high level of inflammation taking place for too long results in tissue damage in the colon and disease-related complications that cause the symptoms described above.

Ulcerative colitis is thought by some to be an autoimmune condition, which means that the body’s immune system wrongly attacks normal, healthy tissue. The intestines contain hundreds of different species of bacteria, which are part of the “gut microbiome” (the term given to all of the microorganisms that live in the intestines and their genetic material). Although some of these species can cause illness, many are essential to our health and wellbeing, playing key roles in digestion, metabolism (the chemical reactions in the body that produce energy from food), regulation of the immune system, and mood.

Some researchers believe that in ulcerative colitis, the immune system may mistakenly identify harmless bacteria inside the colon as a threat and start to attack them, causing the colon to become inflamed. Genetic factors like changes in genes and environmental factors are also known to be involved in the development of ulcerative colitis, and recent advances in our understanding have enabled new targeted therapies to be developed that selectively block or reduce the activity of components involved in inflammation.

Treatment of ulcerative colitis has traditionally focused on symptom control, whereas the development of new targeted treatments aims to achieve remission (the signs and symptoms of disease are reduced either partially or completely) and the restoration of people’s quality of life. A number of new treatments are in phase 2 or 3 clinical trials and may soon add to the range of treatments available to people with ulcerative colitis.

What Are the Different Types of Clinical Trials?

To be approved, a treatment must be proven to be safe and better than existing treatments. New treatments have to successfully go through several phases of clinical trials before they are approved for use and cannot move on to the next phase unless that particular phase of trial has yielded positive results. Phase 0 and phase 1 trials are the earliest-phase trials. They usually involve a small number of people (usually up to 50 people), aim to determine whether a treatment is safe, and (if the treatment involves a drug being given) what happens to it in the body.

Once found to be safe, treatments enter larger phase 2 trials (usually up to 100 people) where they are assessed as treatments for specific illnesses and any side effects (an unintended effect of the drug) are investigated in more detail. Phase 3 trials include hundreds or thousands of people and test new treatments against an existing treatment to see whether it is better. Phase 3 trials are randomized and often take place over several years so that the long-lasting effects of the new treatment can be assessed.

Emerging Therapies for Ulcerative Colitis

Interleukin-23 (IL-23)

A protein called interleukin-23 (IL-23) is known to inhibit the responses of a type of white blood cell called regulatory T cells. These cells play an important role in the body by suppressing the response of the immune system, ensuring that its normal level of activity remains within set limits and that its activity is reduced once a threat has been dealt with. They are also critical in preventing the development of autoimmunity.

When IL-23 inhibits regulatory T cells, inflammation is able to continue unchecked. A particular form of IL-23 called IL-23p19 has been identified as being involved in the development of ulcerative colitis. Four IL-23p19 inhibitors are currently in or have completed phase 2 or 3 trials. They appear to be particularly effective in patients whose ulcerative colitis has become resistant to treatment with tumor necrosis factor (TNF) inhibitors, and their effectiveness in combination with TNF inhibitors is also being investigated.

S1P

S1P is a type of molecule called a “lipid mediator” and is produced in response to a cell receiving a stimulus, and then exported from the cell so that it can bind to a receptor to transmit a signal to target cells. S1P binds to five different S1P receptors expressed on various types of immune cell, resulting in lymphocytes (cells that make antibodies and help control the immune system) being able to travel toward inflamed tissue in the intestine. Drugs that bind to S1P receptors and cause them to be internalized back into the cell and broken down are called S1P agonists. One S1P agonist has already been approved for the treatment of ulcerative colitis and another is in clinical development.

Toll-Like Receptor 9 (TLR-9)

A receptor inside cells called Toll-like receptor 9 (TLR-9) recognizes and binds to bacterial and viral DNA that is present inside cells. It does this by recognizing components called CpG motifs, which are made of a cytosine and a guanine bound together (these are two of the four components of DNA that make up the “genetic code”). CpG motifs are known to be the components of bacterial and viral DNA that cause the immune system to be activated.

As a result, some researchers are investigating the use of short, single-stranded synthetic stretches of DNA (called CpG oligonucleotides) to stimulate the immune system. One such molecule, which activates TLR-9 on target cells, has been shown in clinical trials to suppress immune cells that promote inflammation and to activate immune cells that suppress it, and is undergoing further testing.

microRNAs

Another approach is investigating the potential use of microRNAs. Your genes are short sections of DNA that carry the genetic information for the growth, development, and function of your body. Each gene carries the code for a protein or an RNA. There are several different types of RNA, each with different functions, and they play important roles in normal cells and the development of disease. MicroRNAs are small RNA molecules that do not code for proteins and instead play important roles in regulating genes, for example by inhibiting (silencing) gene expression.

Some microRNAs also activate signaling pathways inside cells, turning processes on or off. One such microRNA is miR-124, which negatively regulates inflammation. Reduced expression levels of miR-124 have been reported in studies of patients with ulcerative colitis, and a treatment that has been designed to upregulate miR-124 is currently in clinical trials involving patients with a variety of inflammatory diseases, including ulcerative colitis and rheumatoid arthritis.

Interleukin-6 (IL-6)

Interleukin-6 (IL-6) is another molecule that promotes inflammation and has been shown to play a central role in the development of inflammatory bowel disease. The binding of IL-6 to its receptor results in uncontrolled accumulation of activated T cells that stop inflammation from being reduced. Results of a phase 2 trial investigating an IL-6 inhibitor have been positive and it will be investigated further to assess its safety and efficacy in treating ulcerative colitis.

Take-Home Message

It is hoped that the emerging treatments described above, and others, will increase the options available to patients with ulcerative colitis. In addition, their investigation will continue to improve our understanding of how ulcerative colitis is caused, enabling further targeted therapies to be developed and opening up the possibility of personalizing each patient’s treatment.

Note: This post is based on an article that is not open-access; i.e., only the abstract is freely available. Furthermore, in the Conflict of Interest Statement at the end of this paper, the authors make a declaration about grants, research support, consulting fees, lecture fees, etc. received from pharmaceutical companies. It is normal for authors to declare this in case it might be perceived as a conflict of interest.

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