Thursday, July 24, 2014

More on fragile X and MMP-9

Just in case we're all getting despondent about the prospects for fragile X treatment, it's worth remembering that there are many potential disease-modifying strategies---it's not just mGluR5! Another major article from the Ethell lab at UC Riverside has shown the therapeutic potential of drugs that inhibit MMP-9. A nice lay description of the new paper is here and the abstract of the article is here.

This latest work shows that human fragile X tissues have elevated levels of the extracellular enzyme MMP-9, as well as an increase in the active fraction of that protein (like most enzymes, MMP-9 can exist in an inactive form which can be switched on rapidly; this kind of regulation is important in most biological pathways.)

The Ethell lab also showed that genetic reduction of MMP-9 rescues most fragile X phenotypes in the mouse model. Previous work had shown that inhibition of MMP-9 with minocycline also had similar effects, but minocycline has many different actions. These experiments demonstrate conclusively that MMP-9 inhibition is the active ingredient. This is important, because pharma companies are working on drugs which inhibit MMP-9 without the antibiotic effects. They also showed that inhibition of this extracellular enzyme can normalize the activity of many of the intracellular signaling pathways (i.e. mTOR) that have been the focus of so much fragile X research. And, perhaps most interesting of all, they showed that genetic reduction of MMP-9 rescues the macro-orchidism phenotype in fragile X, something which has been relatively resistant to rescue with other therapeutic strategies. Since MMP-9 is a gelatinase, we have previously hypothesized that excessive MMP-9 activity in fragile X was responsible for the well-described lax connective tissue; confirmation that MMP-9 activity is indeed elevated in human fragile X tissue lends support for this idea, though this phenotype is difficult to measure in mice, so rescue effects were not assessed in this study.

All in all, this latest article adds to the growing body of evidence that MMP-9 dysregulation is a critical part of the pathology of fragile X, and MMP-9 should be considered a major treatment target for fragile X.