Dr. Jennifer Wolfe from the University of Colorado Health Sciences Center in Denver, Colorado wrote in the journal Orthopaedics: "The identification of the specific gene mutation that causes bone to form in FOP has great implications. Knowing the genetic basis for this rare but catastrophic disorder of heterotopic ossification will guide us in the treatment of common entities. Imagine the ability to cause a tibia to heal, a spine to fuse, or a delayed union to stabilize in a predictable fashion by turning on the switch of bone formation. In the FOP community, the next goal is to learn how to block or bypass the damaged gene to stop the progressive heterotopic bone formation that occurs in these children. What we can learn from this process is how and when to simulate bone formation. The genetic key to FOP has the potential to demonstrate how to control and modify bone formation at the molecular level, which could revolutionize the way we perform surgery and treat patients." The FOP gene discovery is relevant to every disease that affects the formation of bone and every disease that affects the formation of the skeleton. Answers to FOP are relevant to many common conditions such as unwanted bone growth that forms after hip replacement surgery, brain injury, spinal cord injury, soft tissue injury, burns, war wounds, valvular heart disease, and even bone spurs from osteoarthritis. Eventually, it might be possible to harness the FOP gene, and create bone in a more controlled way where it is desperately needed such as in fractures that do not heal, surgical spine fusions, severe bone loss from trauma, osteoporosis, tumors, and congenital malformations. The FOP gene discovery is a great beacon of hope for all of us in the FOP community, and for all of us in a much wider community worldwide who are affected with common skeletal disorders.

Better treatments for FOP are not just a dream – they are now likelihood, and a cure is a distinct possibility.

During this past year, we have begun to turn the FOP gene discovery into insight, and insight into development. We have set our sights on the distant horizon. But, we won't get there by wishing it, and we cannot do it alone. We need your help.

What needs to be done? During this past year, we have expanded the network of physicians and scientists who are working on FOP through targeted identification and funding of those who can help most and who can help the fastest – wherever they may be. We need to expand that program, and we need your help.

What needs to be done? During the past year, we have begun to develop cellular and animal models to determine how the renegade FOP gene acts at the molecular level. We need that knowledge and those critical models to design new drugs and to test them. We need to continue that work, to expand it, and we need your help.

What needs to be done? During this past year, we have begun to crystallize the mutant FOP protein to study its atomic structure, its catalytic domains, and its interactions with other key proteins in the molecular relay-switch that triggers catastrophic amounts of new bone formation. Such knowledge will be needed to custom-design the best medications to block the mutant switch. We need to continue that work, and we need your help.

What needs to be done? During the past year, we have begun to model the active site of the broken switch, and are beginning to use that knowledge to design the best methods to block, jam, or bypass it. We need to expand that work, and we need your help.

What needs to be done? During the past year, we have begun to study the mechanisms by which the inflammatory microenvironment of an injury triggers the renegade FOP switch to form new bone. When we understand that better, we'll be able to use that knowledge to apply the brakes to a run-away process. We need to expand that work, and we need your help.

What needs to be done? During the past, year, we have begun to scour the world's available libraries of medicinal compounds to identify those that may block the abnormal FOP switch and its downstream molecular circuits. We need to expand that work, and engage the world's best medicinal chemists to help us modify those compounds for greater efficacy and safety. We need your help.

These goals and the tasks they imply are easy to articulate and all have been started, but they need funding to be fulfilled. We need your help to continue these vital programs and ensure their success, to do more, to do it faster, to expand our horizons, and to make sure that no clue is ignored.

Our research budget of 1.2 million dollars annually supports a core laboratory of 15 scientists as well as collaborators around the world. Each year, we struggle to find the funds to persist. But we need to do more than persist. We need to prevail. We need your continued help.

FOP is an uncommon condition of uncommon brutality, but there is finally a chance to do something intelligent and rational to interrupt the inexorable progression of what has been described as a "horrible nightmare disease." Chemistry combined with compassion will lead to orphan drug development, to more effective treatments for those with FOP, and for those with more common forms of heterotopic ossification. We have worked hard to get this far, and your

generosity has helped get us there. But, we need your help to go farther. We all know what needs to be done, and we need your help to prevail.

As we have said many times, cause and cure are the two words that propel us and provide the guiding principle for all we do: to discover the cause of FOP, and to use that knowledge to develop effective treatments and eventually a cure. In 2006, with your help, we reached the summit of a great mountain. We discovered the genetic cause of FOP. But more difficult work is ahead – the treacherous trip across the mountain range to the next summit.

What needs to be done? As David Ben Gurion, the first Prime Minister of Israel said, "The difficult we do immediately; the impossible takes a little longer." With your help, we plan to do the impossible. Finding an effective treatment and cure for FOP is not a job; it is a mission.

Clearly, there will be spin-offs of FOP research to more common diseases. However, all the work we have done, and all the knowledge we have gained is for one purpose - to cure FOP. A physician from sub-Saharan Africa, asked me recently. "Why do you do what you do?" The question is startling enough, but the answer is simple. "So that there will come a time when no child has to suffer from FOP - so that a terrible disease becomes nothing more than an inconvenience - so that childhood can be returned to children from whom it has been stolen - so that physical freedom can be restored to those from whom it has been taken – so that those who have been imprisoned in a second skeleton can be set free." This is not just a dream, it is a mission, and together we will achieve it.

What needs to be done? The answer is clear.

Thank you again for your wonderful help and generosity.

Sincerely yours,

Frederick S. Kaplan, M.D.

Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine

The University of Pennsylvania School of Medicine