Posted by Karen
There are so many reasons to love the spring… For me, one reason is that May is when the annual report of the Fibrodysplasia Ossificans Progressiva (FOP) Collaborative Research Project is released. Yay! The report is written by Drs. Kaplan, Shore and Pignolo of UPenn for a lay audience, and it tells all about the research the group has done in the previous year. (“The group” is composed of the members of the FOP research lab at UPenn plus scientists in various other research centres.) The 2012 report came out a couple of weeks ago, and I’ll tell you all about it…
As a general comment, the best thing about this report is the degree of fantastic optimism expressed in it. Here’s a quote from the report:
“The FOP gene discovery and the advances it has inspired have transformed thinking and have altered horizons. It has been six years since that momentous milestone, and… the world no longer looks the same… The distinct structures that the doctors have told you are still there – genes, cells, pathways, models, triggers, treatments. But, they are not individual islands any more. They are a coherent skyline. An illuminating shift in perspective has deepened… It’s the difference between a countryside of castles and a city of skyscrapers.” (page 7)
Contrast this to the reports 4 and 5 years ago, when the metaphoric language was all about standing on top of a mountain (representing the gene discovery) and seeing multiple valleys and mountains ahead, with another mountain top (a cure or treatment for FOP) being visible on the far distant horizon. Wow… Big difference. Very big.
Moving to specifics – the report this year is set within the framework of a fictional university student writing a report for an arts course about “metamorphosis”. The student, Jenny, becomes interested in FOP because it involves the metamorphosis of healthy muscle tissue to bone. Jenny starts to investigate, and learns a whole bunch of stuff about FOP and what the scientists have researched in the past year. Here are the high points of what Jenny learned:
- In August of 2011, 27 FOP researchers got together and brainstormed about everything known to the science world about FOP, and they prioritized research directions for the short term (1 to 3 years) and long term (3 to 5 years). The research report contains the comment, “Never before has the scientific and medical community had both the repertoire of potential candidates and the sound scientific foundations for teting new drugs in animal models of FOP… (the scientists) have embarked upon a rational approach to prioritize the preclinical testing of these drugs.” (page 12)
- A very important first step before any clinical trials of drugs can be carried out will be for the group at UPenn to carry out a comprehensive survey of the features of the natural progression of FOP. In the near future, all FOP patients or their families will be asked to complete the survey, which will give the scientists as clear a picture as possible of exactly how FOP flare-ups start, progress and resolve in the real (ie, non-lab context) world of people’s daily lives. This information will be vital to help the researchers design effective clinical trials for drugs. (NOTE – my understanding “through the grapevine” is that the FOP Lab hopes to administer this survey within the next few months… I will SO be watching for it.)
- In 2011, the FOP Lab finally perfected its long sought-after FOP mouse, which they desperately need in order to test potential FOP drugs. The lab has had various mouse models of FOP in the past, but this is the best one they’ve been able to genetically engineer. “…the new knock-in mice developed by the Penn scientsits display all of the clinical and pathological features of FOP that are present in the human condition including the characteristic malformed toes and arthritic joints as well as the progressive and episodic heterotopic bone formation that is the devastating hallmark of the disease.” (page 18)
- The FOP Lab at UPenn is very keenly interested in a recent study which used something called “retinoic acid receptor gamma (RARg) agonists to prevent cartilege (ie, pre-bone) development. The scientists who carried out this research found that, “RARg agonists effectively inhibit heterotopic bone formation in FOP animal models during a wide treatment window that begins at the pre-cartilege phase and continues up to (but not including) the bone-forming phase.” (page 19) The report goes on to say that, “During the past year, robust work has continued on the development of an RARg agonist for use in a clinical trial in FOP. One of these compounds has been through human safety trial in adults, and efforts are currently being directed towards the devlopment of a clinical trial with this compound.” (page 20) My commentary – EXCITING EXCITING EXCITING!!!
- A research group at Harvard University was given funding in 2011 by the USA’s National Institutes of Health “Therapeutics for Rare and Neglected Diseases (TRND)” program to refine a substance discovered a few years ago called a “signal transduction inhibitor (STI) and develop it for clinical drug trials. The UPenn group are working with the Harvard group and another group from Vanderbilt University (where researcher Dr. Charles Hong discovered the substance) to move an STI into clinical drug trials. Me – more wow!
- In 2011, the UPenn FOP lab and another group from Baylor College of Dentistry independently sussed out that the nervous system has a role in FOP disease progression. “What was not known – unitl now – is that the same sensory nerves that carry pain signals to the brain also amplify the inflammatory response that leads to catastrophic explosions of new bone formation.” (page 23) Further studies showed that scientists could use agents to block points in the sensory nerve pathway and prevent bone formation from progression. This reveals yet another target for drug development.
- The UPenn lab and a group in Japan independently learned how to splice the bad FOP gene out of cells and replace it with a healthy gene, thus completely eliminating the FOP disease process. I have to say, this one sounds to me like the most splendiferously exciting discovery of them all! This is a CURE for FOP that we’re talking about, holy smokes, a cure. But – and there’s always a but – so far this has been done only in cells in labs, and before it can be used in people to cure (cure!) FOP, it has to be tested on lab animals and a safe technique must be developed for delivery into human cells (page 26/27). Still, what an amazing step.
- The FOP centre at Oxford University in the UK had an important develpment as well. The researchers at Oxford were able to uncovery the atomic microstructure of the FOP gene and the way in which the aforementioned STI works to turn off the gene. This information will help the Oxford group plus the UPenn group and the group at Baylor in their efforts to refine an STI which won’t have the nasty side effect of also shutting off other important biological processes (which is one of the problems posed by STIs in the past).
- Other important non-research stuff happened too. Ian Cali, a university student with FOP, made a moving and powerful speech at the August 2011 FOP research meeting, and Holly Pullano and Laura Rossano, two other young people with FOP who generously gave their time to talk to medical students at UPenn about the FOP experience. Apparently both presentations were very well received, and I have to give big kudos to these people for their efforts.
I have to admit, reading the report almost makes my head swim… There are about 750 people in the WHOLE WORLD who are known to have FOP (about 3500 suspected), and yet we’ve got important research going on at UPenn, Oxford University, Baylor College of Dentistry, Vanderbilt University, Harvard, a centre in Japan and elsewhere. I just about can’t believe it, and yet it’s happening. Why? Good question. The answer is at page 19 of the report, which tells us:
“Although FOP is exceedingly rare, affecting approximately one in two million individuals, it is illustrative of many more common conditions of extraskeletal bone formation that affect millions of individuals worldwide, and FOP may be a key to their understanding and solution. Such conditions include ectompid bone formation caused by brain and spinal cord injuries, atheltic injuries, peripheral nerve injuries, burns, high impact war injuries, total joint replacement, valvular heart disease, and atherosclerosis.”
Totally incredible research report. It gave us in our house so very much hope. If you’re interested in reading it, you can find the report at www.ifopa.org.
And now, from me, a plea – please, please, PLEASE remember FOP in your charitable giving this year! We are so close to getting an effective treatment (or maybe even more than one) for FOP, and we’ve got to keep up the momentum. In USA, charitable donations can go to the International FOP Association (IFOPA, see above), and in Canada, to the Canadian FOP Network (CFOPN, at www.cfopn.org). In the UK, you can donate to the FOP Action group (www.fopaction.co.uk). Both the IFOPA and CFOPN financially support the UPenn lab, and FOP Action donates to the Oxford FOP group.
My Miranda’s future depends on your help.
PS – Sorry no blog last week, in case anyone noticed. Computer issues.