Tuesday, October 11, 2011

Update on new treatments for fragile X---Part 4: MMP-9 inhibitors

In 2007, Iryna and Doug Ethell of UC Riverside made the seminal finding of excessive activation of the enzyme Matrix Metalloproteinase-9 (MMP-9) in fragile X. They showed that excessive MMP-9 activity maintained dendritic spines in an immature state, and that this contributed to the behavioral abnormalities seen in the fmr1 KO mouse. Most importantly, they showed that the known inhibitor of MMP-9, the available antibiotic minocycline, could rescue all the abnormalities they found in the mouse model. This made minocycline an attractive off-the-shelf treatment for fragile X. Shortly thereafter, I started experimenting with the judicious off-label prescription of minocycline in a small number of carefully selected patients; the results were impressive, to say the least! Indeed, the effect of minocycline was too good, and too rapid to be solely the result of normalized developmental trajectory. Minocycline appears to have an early psychotropic effect which is independent of its fragile X-specific mechanism; this has been utilized in several studies of minocycline as a treatment for schizophrenia and obsessive-compulsive disorder (which leads to the intriguing possibility that minocycline could be an excellent treatment for autism spectrum disorders in general.) Keep in mind that, in the mice, treatment was a very long-term affair---the equivalent of years in human terms.

After conferring with Carlo Paribello, of the Fragile X Research Foundation of Canada, we quickly began organizing a clinical trial. This first trial was an open trial, designed to examine the pattern of responses in high and low dose minocycline treated subjects. The trial achieved excellent results, with substantial decreases in aberrant behaviors over 8 weeks of treatment. Long-term follow-up of these subjects was also done, and results of that phase of the trial are now being analyzed. Very few side effects were seen in either high or low dose groups, and the therapeutic effect seemed similar (though the number of subjects could not discriminate subtle differences.) This is not unexpected, since studies by surgeons have shown that typical antibiotic doses of minocycline (100 mg/d) inhibit MMP-9 levels by 50-75%. That is just about exactly what we want. One unexpected result from the study was that ¼ of all the subjects followed for a year had an increase in Anti-Nuclear Antibodies (ANA), a rather non-specific indicator of autoimmune reactions. None of these subjects had any actual symptoms, though serious autoimmune reactions to minocycline are seen (fortunately, only rarely.) We’re still not entirely sure what to make of this finding, as it’s not known just what percentage of people in the general population develop elevated ANA levels with chronic minocycline treatment. However, it could be a useful indication of impending autoimmune problems, and may be worth checking as a screening test. Interestingly, none of the patients that I treat directly have developed this kind of reaction to minocycline, though I have talked to a number of parents around the country who have encountered this problem.

A larger, placebo controlled trial is under way at the MIND Institute to follow up on these initial findings, and we look forward to these results. In the meantime, another bit of confirmatory evidence came from the lab of Kendal Broadie at Vanderbilt. His group has published results showing dramatic rescue of fragile X fruit fly abnormalities with minocycline---all the more impressive because the fly model is essentially a knockout of 3 genes (fmr1, fxr1, and fxr2.) This group also showed that genetic reduction of the fly equivalent of MMP-9 yielded similar results; this is significant, because minocycline does several different things, but MMP-9 inhibition does seem to be the active ingredient.

So, we have an excellent off-the-shelf treatment in the form of minocycline, a cheap generic medication with a long history and fairly benign safety profile. But some people, perhaps as many as ¼, have trouble taking it, and it’s not recommended for kids under 8 because of dental discoloration (which is not directly related to MMP-9 inhibition.) We at FRAXA are continuing to explore more specific alternatives to minocycline; there is interest in pharmaceutical companies in drugs which can inhibit MMP-9 specifically without some of the other effects of minocycline. However, this is a niche market, and only a few companies have active programs in this area, so it may be a while before we find anything better than minocycline in this area.