By NORBERT HERZOG and DAVID NIESEL
Crohn’s disease is a chronic, inflammatory bowel disease that occurs when the body’s own immune system attacks the lining of the digestive tract, causing deep inflammation that can be debilitating, even life-threatening. Current treatments often use drugs that suppress the immune system, but they aren’t always successful and have potentially serious side effects. A new treatment uses a molecule based on cellular RNA to regulate the activity of a protein in the gut and suppress the immune response in the hope of successfully treating Crohn’s disease.
Crohn’s usually affects the end of the small intestine and the start of the large intestine or colon, but it can affect any region of the gastrointestinal tract from the mouth to the anus. Crohn’s disease can penetrate the entire thickness of the walls in the bowel, and patches of inflammation can be separated by areas of normal tissue. The inflammation can cause scarring or a fistula, a tunnel leading from one loop of the intestine to another or from the intestine to the bladder, vagina, or skin, all of which require surgery. Although symptoms vary among patients, they can include persistent diarrhea, rectal bleeding, the urgent need to move bowels, abdominal cramps and pain, sensation of incomplete evacuation or constipation, fever, loss of appetite, weight loss, fatigue, night sweats, loss of normal menstrual cycle, and increased risk of colon cancer. Like many autoimmune diseases, patients experience periods of flare-ups and periods of remission with no symptoms.
A specific protein called SMAD7 is overproduced by people with Crohn’s disease. SMAD7 suppresses the activity of another protein, TGF-Beta, which helps control the immune response and maintains the barrier between the gut and the rest of the body. Scientists hypothesized that if they could somehow reduce the activity of SMAD7, they could keep TGF-Beta working properly and control the inflammation.
Instructions for controlling proteins like SMAD7 are contained in messenger RNA. Messenger RNA is created by transcribing DNA, the genetic information that resides in the center of every cell. Once the DNA’s instructions are properly transcribed, the messenger RNA leaves the cell’s center to be translated into protein. Scientists wanted to attempt to control SMAD7 by making an RNA molecule that could complement the messenger RNA containing instructions for SMAD7. The lab-created RNA would block the messenger RNA, preventing it from ever being used to make SMAD7 protein. And without too much SMAD7 in the digestive system, TGF-Beta would be able to do its job of keeping inflammation in check.
In a phase II clinical trial of 166 patients, 55-65 percent of those receiving higher dosages of the new medication were in remission two weeks after starting the treatment and stayed in remission for two weeks after stopping with few side effects. In this study, patients reported how they felt and did not undergo invasive testing to determine the state of their disease. Future studies with larger groups of patients will need to conduct endoscopies and biopsies to establish that the new treatment does reduce inflammation and resolve Crohn’s disease.
Professors Norbert Herzog and David Niesel are biomedical scientists at the University of Texas Medical Branch. Learn more at medicaldiscoverynews.com.