Targeting MMPs in Crohn’s disease
I’ve been meaning to write about this article for a few weeks: Synthetic Molecules Treat Autoimmune Disease in Mice. The synthetic molecule in question is an antibody to the enzyme matrix metalloproteinase-9 (MMP-9). Since my research project involved manipulating MMPs in controlled drug delivery, I make it a point to check out related topics.
This particular article is about a treatment for Crohn’s disease. Crohn’s is a disorder in which the body’s own immune system (hence, autoimmune) attacks the intestines, causing inflammation and lots of unpleasant symptoms I’m not going to mention in case you’re eating. The exact cause of Crohn’s disease is unknown. Crohn’s can be treated with lifestyle changes and medications, but some cases are severe and refractory to all known treatments. I saw a few severe cases in my old job as a medical records coder. Severe or mild, this is Not Fun.
Now a little about MMPs. MMPs are a family of enzymes that degrade the extracellular matrix (ECM), the proteins in your body between the cells. Collagen is one type of ECM protein. They’re all identified by numbers, so MMP-1, MMP-2, MMP-3, and so forth. In normal function, MMPs contribute to many normal body functions, such as growth and wound healing. In certain diseases, including cancer and Crohn’s disease, MMP expression and activation is well above normal levels. In inflammatory bowel diseases such as Crohn’s, the overactive MMPs (namely, MMP-2, 9, and 13) have been suggested in the breakdown of the intestinal walls, leading to the ulceration or fibrosis (1). So, by stopping the MMPs, we should have a treatment for the disease, right?
Well, yes and no. MMP inhibitors were examined in the 1990s as a cancer treatment. Since MMPs contribute role to the growth of cancer by creating space for tumors to grow, aiding the formation of new blood vessels, and being involved in metastasis, inhibition seemed like a good route to pursue. The MMP inhibitors did well in studies with animals, but poorly in trials with humans. The actual picture of the relationship between MMPs and tumors was much more complicated than previously thought; some MMPs had a protective effect against cancer (2). Also, the MMP inhibitors stopped the spread of cancer, but weren’t able to attack the tumor that was already present (3).
This particular paper seems more promising. The research group developed molecules that when injected, would cause the body to develop antibodies to MMP-9 (which they dubbed metallobodies). The researchers tried this in a mouse model of Crohn’s disease and were able to detect metallobodies in the mice’s blood and prevent the symptoms of Crohn’s. The metallobodies bound to MMP-2 and MMP-9, which isn’t surprising since MMP-2 and MMP-9 are very similar in structure and function (The enzyme I worked with for my research was MMP-2, so I’m well acquainted with both). The specificity is encouraging, as the inhibitor won’t interfere with the normal functions of the other MMPs.
Other questions remain to be answered: the human immune system is more complex than that of a mouse, will this molecule have the same effect? What effect will the molecule or the metallobodies have on the rest of the Crohn’s disease process? We’ll see how this pans out.
1. Altadill, et. al. “Comparative Analysis of the Expression of Metalloproteases and Their Inhibitors in Resected Crohn’s Disease and Complicated Diverticular Disease ” Inflammatory Bowel Diseases, 2012, 18 (1) 120-130.
2. Martin and Matrisian. “The other side of MMP: Protective Roles in Tumor Progression” Cancer Metastasis Reviews, 2007, 26(3-4), 717-724
3. Coussens et. al. “Matrix Metalloproteinase Inhibitors and Cancer: Trials and Tribulations” Science, 2002, 295(5564): 2387