25th Annual FOP Research Report!

Posted by Karen - June 19th, 2016

Happy Father’s Day, everyone. We’re definitely enjoying it at my house… My kids, Miranda (age 11) and Owen (age 14) gave their dad a gift in honour of this day, and I made pancakes and bacon for breakfast. After a phone call to my dad, we went out with my kids’ grandmother to the yearly Scandinavian Midsummer Festival. Later on today, we’ll be watching a hotly anticipated episode of our favourite cable TV show (the one that rhymes with “Fame of Scones”, ha ha). It’s all good.

My kids and their dad, Pete.

My kids and their dad, Pete.

To top it all off, earlier this week we had the pleasure of receiving a gift from (in part) another father – the “father of FOP research”, Dr. Fred Kaplan. Yes, it’s that time of year again, when Dr. Kaplan, together with co-authors Dr. Eileen Shore and Dr. Robert Pignolo, provide us with the annual report of the Fibrodysplasia Ossificans Progressiva Collaborative Research Project. Amazingly enough, this was the 25th such report! For 25 years, the research team spearheaded by Dr. Kaplan and centred at the University of Pennsylvania has been diligently and dedicatedly producing an annual report to update us about their ongoing studies into FOP.

I can’t begin to express what it means to FOP families to receive this report every year. I recall that the 2007 report was issued just a few months after my daughter Miranda’s diagnosis, and my husband and I devoured every word like starving dogs on a pile of bones. And, every year since then, it’s been almost as exciting to read the report as it was that first time. The time, care, and effort poured into this annual publication illustrate one of the many reasons why Dr. Kaplan is considered the father of FOP research.

So what did our FOP father and his excellent colleagues tell us about this time around? ALOT. In fact, it was 67 pages worth of research goodness. I always try to discuss the report in this blog, and this year it’s harder than ever to try and pare it down to a succinct summary. That being said, here goes my attempt…

First, the team told us about a research breakthrough from Regeneron Pharmaceuticals which revealed that a previously unsuspected substance called Activin A interacts with the mutant FOP gene to cause FOP flare-ups to occur (Activin A has no comparable effect on the non-mutated version of the gene). Activin A had not been suspected in the past, but now it has been revealed to be a vital and essential component to instigating the monstrous work of FOP. This was a very important discovery, because it revealed an important potential druggable target. And, if you can believe this, Regeneron ALSO happens to have access to a substance which was shown to block the effect of Activin A – and thus eliminate ossification – in a mouse model of FOP! At present, the FOP Lab at Penn is working on applying the Activing-A-blocking substance to actual FOP cells obtained from the discarded baby teeth of human FOP patients. While there is still plenty of work to do to prove the efficacy of this approach for treating FOP, the Activin A discovery is considered to be an extremely important breakthrough (see pages 13 through 16 of the report).

Second, the team discussed its ongoing investigation into the connection between low oxygen in FOP cells and the progression of FOP flare-ups. This is a complicated thing to explain, but in a nutshell, the team has learned that FOP flare-ups are characterized by, and perpetuated as a result of, extremely low oxygen in involved cells. This low oxygen results in stopping or preventing the production of something called Rapabtin 5, a substance which is necessary to turn off the production of FOP proteins which eventually lead to bone. The team has also been able to identify 3 existing substances which restore the Rabaptin 5 levels to normal in mice with FOP, thus stopping bone production. Importantly, 2 of these 3 substances (if I understood this correctly) are substances already used in treatment of other diseases, meaning that they are currently approved medications. After the team has done more work around safety and proper dosage issues, it may be that this is another approach to treating FOP (see pages 16 through 20).

Third, the team told us about work this year into whether or not a substance currently in clinical testing, Palovarotene, is safe for use in children. Because of the mechanism by which this potential drug operates, which is disruption of pre-bone cartilage formation, there was a concern that it could interfere in normal skeletal development. However, interestingly, the team discovered that Palovarotene is indeed a concern for children who DON’T have FOP, the evidence with mouse studies thus far suggests something quite different for children WITH FOP. You see, apparently the FOP gene causes long bone formation (femur, humerus) to be somewhat stunted in mouse fetal development, resulting in FOP mice which are slightly shorter in measurement than their non-FOP peers. Strangely enough, administering Palovarotene to baby mice with the FOP gene resulted in young mice with virtually normal bone length measurements. The scientists believe that Palovarotene somehow restores full functioning of the growth plates to essentially normal levels. This was definitely a surprise – a very welcome one, and one which has potentially important positive ramifications to children using Palovarotene (see pages 24 through 27).

The team had lots of other stuff to discuss, but these were the 3 main areas of focus. That said, they did discuss one other matter which seriously blew my mind. Specifically, they reported that applied work by pharmaceutical and biotechnology companies on FOP has EXPLODED in recent years. Apparently, there are currently 8 such companies working on “kinase inhibitors”, 6 developing  “antibodies or ligand traps”, 4 focusing on on “small inhibitory RNA technology”, and 2 looking at “alternate cell and microenvironmental approaches” (p. 23 of report). As the team points out, every bit of this is because of the identification of the mutant FOP gene, which was announced in 2006.

There you have it. This report is incredibly informative, tantalizing, and amazing. What an amazing early Father’s Day gift, a present from the father of FOP research and his scientific colleagues. If you’d like to read the report yourself, click here: http://www.ifopa.org/news-and-events/latest-news1/610-25th-annual-report-of-the-fop-collaborative-research-project.html

Miranda, Karen & Dr. Fred

Miranda, age 4 (chewing on a candy), me, and The Man himself, Dr. Kaplan.

 

PS – More than anything, we want basic foundational research on FOP to continue and help us get to the finish line – a treatment or cure for FOP. At present, there’s NOTHING. When my beloved daughter experiences an FOP flare-up, we know that it will almost inevitably lead to the development of more loathed and unwanted FOP bone, because it can’t be treated. Just recently, Miranda had a flare-up under her chin, and now she has a palpable bone stretching from her chin to her throat. Please help us out by contributing to our upcoming FOP fundraiser, the Walk for FOP, which will take place on July 31, 2016. To donate on-line, go to www.walkforfop.com and click on either “General Donations” or “Donate to Participant”. Or, you can also donate by cheque made out to: Canadian FOP Network. If you’d prefer to donate by cheque, please contact me and I’ll give you my address. Thanks!

 

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