In the coming weeks, I hope to provide up-to-the-minute updates (along with many frank opinions, since this is a blog!) about the status of all the various new treatments that have the possibility of disease modification in fragile X. I’ll do this in writing, since I do want to be fairly precise, and you may want to be able to copy these things; I’ll also reference much of what I say, except where the references are too numerous to list.
To do this, I’ll need to define a few terms, so let’s start there. First is the term “disease modification”, referenced above. We all are hoping for treatments which actually affect the course and the outcome of this single-gene disease we call fragile X. There are many available psychiatric drugs which can positively affect the behavioral manifestations of fragile X, and I’ve written plenty about them. But there is no indication that they change the long-term outcome in any significant way, as I noted in my last post. Obviously, the better kids do over the course of many years, the better their long-term prognosis, but the same can be said for any number of behavioral and educational interventions. There may very well be some kind of gray area here, but I think most of us can agree that we would like to see something much more specific, treatments which get to the very heart of the dysfunction in fragile X, and actually facilitate much more normal development. This is the mission of FRAXA, and it has become my life’s work, so I don’t consider these trivial distinctions. You’ll have to pardon me if I have some strong opinions in this area, and if I sometimes seem dismissive of ideas which are proposed that just don’t have the research backing to make them potentially “disease modifying” by accepted definitions.
So, how does one demonstrate that a particular treatment strategy might be disease modifying? Well, you could just give the treatment to patients and see what happens, based on some speculative theory of what’s wrong in the fragile X brain. This is the dominant model in autism studies today, and it carries over to some extent in fragile X. It is also quite common in psychiatry, and I’ve had the chance to observe the failure of this model on many occasions. For example, millions of children, adolescents, and adults take stimulant medications every day to enhance their attention (as well as decrease hyperactivity and other disruptive behaviors associated with ADHD.) Most parents hope, and assume, that this treatment will result in improved academic performance over the long term (we certainly see this in fragile X, too.) The drugs certainly work well in the short term, and efficacy is easy to demonstrate. However, most of the studies which have examined the long-term academic performance of kids with ADHD treated with stimulants show little, if any, advantage for the drugs. More recent studies have shown some benefits, but the results are debatable and more subtle than you might imagine (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629512/?tool=pubmed for a more thorough review.) In the fragile X field, we just don’t have the time or money to try this willy-nilly approach, and the number of research subjects is too small to make it work.
A better way, I think, is to develop treatments based on the observed abnormalities in the animal models of fragile X (mainly fruit fly and mouse), then test potential treatments in those animal models. This initial observation would be considered basic science; the attempt to find ways to reverse a defect might be termed “translational research”, and the actual testing of a specific drug in the animal model would be called “pre-clinical validation”, leading to clinical trials in people with fragile X. The “FRAXA Method”, as I like to call it, is to fund this kind of progression from basic research, through translational research, followed by preclinical validation, leading to clinical trials of medications that have genuine potential to change the outcome of fragile X. We didn’t invent this method, and it really isn’t anything new at all---it’s what every pharmaceutical company does every day. But you’d think it was some sort of radical new approach, compared to the half-baked and poorly reasoned trials coming from many areas (not just the autism field, either; many clinical trials in psychiatry, or in the broader rare disease field are little more than wishful thinking, with no real scientific basis.)
In the next few installments, I’ll talk about the results of this approach, then move on to discuss some other developments in clinical trials for fragile X. Stay tuned!