the twenty-fourth annual report of the fibrodysplasia

May 2015

The Twenty-Fourth Annual Report of the Fibrodysplasia Ossificans Progressiva (FOP) Collaborative Research ProjectFrederick S. Kaplan, MDRobert J. Pignolo, MD, PhDEileen M. Shore, PhD

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2 FOP Collaborative Research Project Annual Report 2015

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FOP Collaborative Research Project Annual Report 2015 3

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Part I: IntroductionA. The Van Has Left the Driveway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5B. The Road Ahead: Infrastructure for a Cure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

PART II: Therapeutic HorizonsApproach #1: Blocking Activity of the Mutant Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Approach #2: Blocking Inflammatory Triggers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Approach #3: Blocking Connective Tissue Progenitor Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20Approach #4: Altering the Physiologic Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

PART III: Notable Developments in 2014When Something Expected Doesn’t Happen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24We Are Not Alone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Editor’s Choice – a Few Highlights from the Literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26The Tooth Ferry Program at the FOP Laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27The Cali-Weldon FOP Pre-Clinical Drug Testing and Biomarker Discovery Program . . . . . . . . . . . . . . . . . . . . 29The Cali Developmental Grants Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29FOP: The Spoken Word – 2014 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30FOP: The Written Word – 2014 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36FOP: What Can We Do to Help? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36Many Thanks to You . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

The Last WordBack to the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

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4 FOP Collaborative Research Project Annual Report 2015 FOP Collaborative Research Project Annual Report 2015 5

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“In my beginning is my end . . . the end is where we start from.” - T.S. Eliot

With the focus and resolve of a mission specialist, Ian Cali guided his motorized wheelchair on stage at the opening session of the IFOPA’s Drug Development Forum in Boston. The room fell silent as physicians, scientists, researchers, pharmaceutical company executives, regulatory experts, philanthropists, investment bankers, and FOP families directed their attention to Ian’s opening remarks – a profile in courage – and a plaintive appeal from FOP patients everywhere . . . .

A. The Van Has Left the Driveway

Since it was established in 1991, the FOP Collaborative Research Project has had a singular mission - to determine the cause of FOP and to use that knowledge to advance the treatment and a cure for FOP. During the past twenty-four years, we moved from the wastelands of a rare disease to the watershed of clinical trials. We identified the genetic cause of FOP and used that knowledge to spearhead worldwide research efforts to develop therapies that will transform the care of individuals with FOP.

In partnership with our benefactors, we have expanded the frontiers of discovery and drug development in this rare and catastrophically disabling condition, dismantled the physical and perceptual barriers that have impeded progress, and inspired global research in small molecules, antibodies, and gene therapy for FOP.

Here, at the Center for Research in FOP & Related Disorders, our work is broad and comprehensive while focused on seven spheres of FOP activity:

• ClinicalCareandConsultationWorldwide

• ClinicalResearchandInfrastructureDevelopment

• BasicResearch(IdentificationofTherapeuticTargets)

• TranslationalResearch(PreclinicalDrugTesting&BiomarkerDiscoveryProgram)

• DevelopmentalGrantsProgram

• ClinicalTrialDevelopmentandProof-of-PrincipleInvestigationinPatients

• Education

Dr. Kaplan along with his treasured 35 years of mementos, memories, and medical records on moving day

The Center for Research in FOP & Related Disorders is unique. It is the world’s first and only comprehensive program in FOP. Here at the Center, we have had a very busy year. In 2014, we achieved the following milestones in our FOP program:

1. Clinical Care and Consultation Worldwide

• Guidedpatients,familiesanddoctorsworldwideintheirdailybattleswithFOP.

• Directedtheworld’scurrentandhistoricallylargestFOPclinicandreferralcenter,nowinitsnewhomeatPennMedicine-UniversityCity,Philadelphia,Pennsylvania.

• CoordinatedmedicalmanagementanddentalcareofFOPpatientsworldwide.

• ConductedinternationalFOPclinicsforpatientsandfamiliesinGenoa,Italy;Belgrade,Serbia;Manchester,England;Marienheid,Germany;andMoscow,Russia.

Part I: Introduction

Photo Above Right: Mr. Richard Simcox (Banchory, Scotland) meets with Dr. Haitao Wong at the Center for Research in FOP and Related Disorders Photo Above Left: Greetings from Moscow (from left to right): Anastasia Vorobyeva (Professional interpreter), Dr. Margarita Polyac (Physician and professional interpreter), Dr. Frederick Kaplan, Svetlana Onishenko (Vice President, FOP Russia), Dr. Rolf Morhart, Michael Krivorotenco (seated; Director of Information Technology, FOP Russia), Svetlana Urvanova (President, FOP Russia), Vladislav Grachev (Director of the Central Federal District Branch of the Russian FOP community, "Living with FOP," and Member, IFOPA International President's Council), Tatiana Khodakova (Vladislav Grachev’s mother) and Dr. Svetlana Arsenteva (Federal Research Institute of Rheumatology, Moscow)

Below Center: Dr. Marelise Eekhoff (Amsterdam, Netherlands), Dr. Christiaan Scott (Cape Town, South Africa), Dr. Robert Pignolo (Philadelphia, USA) with Anisepho Stemela and her mother Phindiwe Stemela (Cape Town, South Africa) at the UK FOP Family Meeting and Conference (Manchester, UK)



Greetings from the Moscow Subway (left to right):Dr. Danees Safuanov (Moscow, Russia), IFOPA President’s Council Member Vladislav Grachev (Moscow, Russia), Mr. Harald Gerth (FOPeV; Hamburg, Germany), and Dr. Frederick Kaplan (Philadelphia, USA)

2. Clinical Research and Infrastructure Development (Natural History Studies Highlighted Here)

• CompletedaglobalsurveyofFOPflare-upsthatwillinformthedesignandevaluationofclinicaltrials

• Completedandvalidatedthefirstpatient-reportedLongitudinalNaturalHistoryStudyinFOP.

• DesignedandvalidatedtheFOPCumulativeAnalogueJointInvolvementScale(CAJIS).

• Consultedonthedesignanddevelopmentofapatient-reportedphysicalfunctionoutcomemeasureforadultsandchildrenwithFOP.

• ConsultedonthedesignanddevelopmentoftheClementiaLongitudinalNaturalHistoryStudy.

• AdvocatedtheprospectivedepositofdatafromTheClementiaLongitudinalNaturalHistoryStudyintotheIFOPARegistryDatabase.

• AdvisedtheIFOPAinplanningtheFirstDrugDevelopmentForum.

• ChampionedthedevelopmentofoneinternationalregistryforFOPbytheIFOPA,andownedbytheFOPcommunity.

3. Basic Research (Identification of Therapeutic Targets)

• InvestigatedmolecularmechanismsandimmunologictriggersofFOPflare-upsinstate-of-the-artknock-inmousemodelsofclassicFOP.

• IdentifiedanadultFOPpatientwiththeclassicFOPmutationwholacksheterotopicossificationandinitiatedbiochemical,immunologic,andgeneticstudiestodeterminewhy.

• Investigatedmolecularcross-talkbetweenthebonemorphogeneticprotein(BMP)signalingpathwaysandimmune-mediatedpathwaysintheconnectivetissueprogenitorcellsthatorchestratethedevelopmentofheterotopicossificationinFOP.

The boxes arrive at Dr. Kaplan’s new office at The Penn Musculoskeletal Center

• InvestigatedcellularinflammatorytriggersofearlyFOPlesionsusingnoveltripleknock-inFOPmousemodelsinordertoidentifykeyimmunologictargetsfortherapy.

• IdentifiedacellularresponsetotissuehypoxiathatamplifiesBMPsignalingandacceleratesheterotopicossificationinFOP.

• IdentifiedthecellularresponsetotissuehypoxiaasamajordrivingforceintheinductionandamplificationofFOPflare-ups,determinedthemolecularmechanismbywhichthisoccurs,anddiscoveredacurrentlyavailabledrugtopartiallyblocktheresponseinamousemodelofFOP.Furtheradvancedtestinginconditionalknock-inmousemodeloftheclassicFOPmutationwilldeterminewhetherthiscompound,alreadyscreenedforhumansafety,canadvancetoclinicaltrialsforFOP.

• PursuedahighlyinnovativeresearchprogramtoinvestigatetheinteractionoftheinnateimmunesystemwithtissueprogenitorcellsintheamplificationofBMPsignalingthatleadstoflare-upsandheterotopicossificationinFOP.

• InvestigatedtheroleofcellsoftheinnateimmunesystemintheinductionofheterotopicossificationinFOPconditionalknock-inmice.

• InitiatedcollaborativeinvestigationswithdevelopmentalneurobiologistsandpediatriconcologistsonmechanismsofdiseaseactivityinmalignantbrainstemgliomasandinFOP,twocatastrophicchildhooddiseasesassociatedwithcommonmutationsinACVR1.

Brooke and Brendan Scott (Adelaide, Australia) with Dr. Kaplan during a visit to the Center for Research in FOP and Related Disorders

• InvestigatedtheresponseofthedysregulatedACVR1signalingpathwayinFOPtobiophysicalfactorsintheearlyFOPlesionalmicroenvironment.ThisworkhaspotentialtoidentifynewtherapeutictargetsforinhibitingtheevolutionofFOPlesions.

• Characterizedthecellularandmolecularfeaturesofcartilageformationatthegrowthplateandinheterotopicendochondralossificationinanadvancedconditionalknock-inmousemodelofclassicFOP.

• InvestigatedgeneticandmolecularmechanismsofabnormalembryonicjointformationandfunctionaljointsurvivalinFOP-fundamentalknowledgethatwillbecriticalforunderstandingandidentifyingnewtherapeutictargetstotreatandpreventdisablingspinaldeformityanddegenerativearthritisinFOP.

• InvestigatedlimbpatterningandjointspecificationpathwaysrelevanttothecongenitalmalformationsandearlydegenerativearthritisofFOP-



studiesthatareprovidingcluestonewtherapeutictargetstopreservejointfunction.

• Investigatedmolecularmechanismsbywhichultra-rareFOPvariantstriggerpromiscuousBMPsignalingleadingtoFOPflare-ups.

• Designedanewconditionalknock-inmousemodelofFOPusinganovelgeneeditingapproach.

• ExpandedtheFOPSHEDCellToothFairyProgram.ThissubstantiallibraryofconnectivetissueprogenitorcellsiscriticalforongoingandfuturestudiesintherapeutictargetidentificationanddrugdiscoveryinFOP.

Postdoctoral fellow Dr. Julia Haupt describes her research to visitors at the Center for Research in FOP and Related Disorders

4. Translational Research (Preclinical Drug Testing & Biomarker Discovery Program)

• Completedthesecond-yearofacomprehensivepre-clinicaldrug-testingandbiomarkerdiscoveryprograminFOPmousemodels.Inthisprogram,wehaveidentifiedapromisingcompoundthatpartiallyinhibitsheterotopic

ossificationinamousemodelofFOP.Thedrugofinterestiscurrentlyapprovedforclinicaluseinotherindications.PendingresultsofongoingstudiesinadvancedanimalmodelsofFOP,thedrugmayberepurposedforasmallclinicaltrialinchildrenwithFOP.

• Examinedthetherapeuticeffectsandoff-targetside-effectsofcurrentdrugcandidatesinexistingmousemodelsofFOP.

• Screenednewcategoriesofcompoundsforefficacyinproof-of-principleexperimentsinadvancedFOPmousemodels.

• Usedaconditionalknock-inmousemodelofclassicFOPtotesttheabilityofaretinoicacidreceptorgammaagonisttoinhibitinjury-inducedandspontaneousheterotopicossification

• Evaluatedin vitromodelsystemsinapre-clinicaldrugtestingprogramusingmouseandhumanskeletalprogenitorcells.

• IdentifiedakeybiomarkerofheterotopiccartilageformationinFOPinmiceandhumansandincorporatedthestudyofthebiomarkerintothedesignofanongoingclinicaltrial.

5. Developmental Grants Program

• Awardedanew2-yeardevelopmentalgrantoninducedpluripotentstemcellmodelingforFOP.

6. Clinical Trial Development and Proof-of-Principle Investigation in Patients

• DevelopedwithClementiaPharmaceuticalsandtheFDAthedesignofthefirstrandomizeddouble-blindplacebo-controlledtrialinthehistoryofFOP.

• Commencedclinicaltrialsandproof-of-principleinvestigationwithPalovarotene,aninhibitorofendochondralboneformation,inadultFOPpatients.(Therationaleanddesignoftheclinicaltrialscanbefoundonanyorallofthefollowingthreewebsites):

• www.ifopa.org

• www.clinicaltrials.gov

• www.clementiapharm.com

• EnrolledadultFOPpatientsintwomajorinterventionalclinicaltrials.

• AdvisedpharmaceuticalandbiotechcompaniesonthedevelopmentofnoveldrugsforclinicaltrialsinchildrenandadultswithFOP.

• Advancedunderstandingofsmallmoleculeinhibitorsinphysiologicandpathologicchondrogenesis-knowledgeandapproachesthatarevitaltofutureclinicaltrials–involvingchildren.

7. Education

• MentoredthenextgenerationofphysiciansandscientistsworkingonFOPintheclassroom,clinic,andlaboratory

• Mentoredhighschool-,college-,medical-,andgraduate-studentsonresearchprojectstoexpandvitalknowledgeandscientificandpublicawarenessofFOP.

• Educatedphysicians,scientists,researchers,andregulatorsatmedicalandscientificforums,meetings,andconferencesworldwide.

Dr. Rolf Morhart, Olga Vishnevskaya with her daughter Marina, Dr. Irina Nikishina (Chairman, Pediatrics; Federal Research Institute of Rheumatology-Russian Academy of Medical Sciences), and Dr. Frederick Kaplan at the First International FOP Russia Family Meeting and Conference (Moscow, Russia)

Our work at the Center is at the forefront of the FOP world. The work is constantly evolving as we cross the bridge daily between the clinic and the laboratory and back again in a process that builds knowledge and deep understanding to help us accomplish the mission.

The collaborative activity and accomplishments of basic research at the FOP Laboratory are a key focus of the Center and focus on six major research areas:

http://clementiapharma.com



Immunologic and microenvironmental mechanisms that induce and amplify FOP flare-ups are conducted by graduate student Michael Convente, postdoctoral fellows Haitao Wang and Julia Haupt, and research specialists Vitali Lounev and Erika Wright. Stunning new therapeutic targets are emerging from their work, and it is possible that one or more such targets will become the basis for clinical trials with re-purposed drugs.

In vitro and in vivo FOP model development is conducted by post-doctoral fellows Julia Haupt and Salin Chakkalakal, by graduate students Michael Convente and Alexandra Stanley and by research specialists Vitali Lounev, Deyu Zhang, and Ruth McCarrick Walmsley. This work is a vital part of the infrastructure for drug discovery and development – the infrastructure for a cure.

Research Specialist, Ruth McCarrick- Walmsley at the Center for Research in FOP and Related Disorders

FOP progenitor cell studies are conducted by Vitali Lounev, Michael Convente, Salin Chakkalakal, Will Towler, Ruth McCarrick-Walmsley, and Robert Caron. These studies identify the specific cells and mechanisms that can be targeted to block heterotopic ossification.

Molecular pathway studies in ALK2 signaling in FOP are conducted by Meiqi Xu,

Salin Chakkalakal, Julia Haupt, Michael Convente, Haitao Wang, and Alexandra Stanley. This vital research enables the development of drugs that target these pathways.

Pre-clinical drug testing is conducted by Carter Lindborg, Haitao Wang, Vitali Lounev, Deyu Zhang, Erika Wright, and Salin Chakkalakal.

Graduate student Will Towler explains his research to visitors at the Center for Research in FOP and Related Disorders

Despite remarkable advances in FOP research over the past several years, we remain far from understanding some of the most basic and fundamental mysteries of FOP:

• Whattriggers FOPflare-ups?

• Howdoes FOPprogress inthe absenceof flare-ups?

• HowdotheimmunesystemandthelesionalmicroenvironmentinfluencetheprogressionofFOP?

• WhatistherelationshipbetweentheinnateimmunesystemandtheskeletalprogenitorcellsthatinitiateFOPflare-ups?

• Whatdotheultra-raregeneticvariantsofFOP(whichaffectonly2to3percentofFOPpatientsworldwide)teachusaboutthefunctionofthegeneticswitchthatdrivesheterotopicossificationinFOP?

These questions and more are under intense investigation in the FOP Laboratory, and their answers will help identify novel targets for drug discovery and development.

To paraphrase Rod Serling, creator of The Twilight Zone, we have entered a new dimension of space and time. The van has left the driveway; clinical trials have begun – a journey made possible by seminal discoveries in the FOP laboratory and by the monumental discovery

of the FOP gene in 2006. Nothing in the 300 year history of FOP has propelled us so fast or has taken us so far. But, to reach our destination, we will need a new infrastructure for a new era – an infrastructure for a cure.

B. The Road Ahead: Infrastructure for a Cure

While the commencement of clinical trials was a major milestone of 2014, a commitment to clinical trial infrastructure, necessary for any and all clinical advances in FOP, was the major story of the year.

In order for the FOP community to fulfill the promise of better treatments and eventually a cure, we will need an infrastructure for a cure – similar in concept to the highway networks, mass transit systems, power grids, and communication networks that allow societies to function.

Great scientific and medical enterprises, like great nations need a stable and robust infrastructure. The infrastructure for a cure is a vital priority of the Center, and will facilitate the discovery and development of drugs and the conduct of clinical trials that will allow the entire FOP community to navigate better treatments and a cure. Like a large public works project, it will take a committed effort of the entire international FOP community to accomplish this goal and we fully embrace that concept.

The infrastructure for a cure is composed of five essential components:

• Naturalhistoryinfrastructure

• Biomarkerinfrastructure

• Mousemodelinfrastructure

• Communicationsinfrastructure

• GlobalRegistryinfrastructure

In this section of the annual report, we will articulate our vision for the infrastructure for a cure and what we have done at the Center for Research in FOP & Related Disorders during the past year to facilitate its development.

1. Natural History InfrastructureThe successful design and interpretation of clinical trials requires a clear contemporary context for assessing the potential benefit of any possible new treatment. Before we can answer the question “Does a new drug reduce or prevent the complications of FOP?” we have to know with certainty the natural history (clinical course) of FOP, and the variability for each region of the body that is affected.

Postdoctoral fellow Dr. Salin Chakkalakal at the Center for Research in FOP and Related Disorders at the University of Pennsylvania

Flare-ups of FOP are usually sporadic and generally unpredictable, and there is great individual variability in the rate of disease progression. Several historical studies on the natural history of FOP have confirmed the extreme difficulty in predicting the onset, duration, or severity of an FOP flare-up, although characteristic

anatomic patterns of disease progression have been described. However, the data from these studies are more than twenty years old, come from an era when there were no more than 40 patient-members of the IFOPA, and from a time when the symptomatic treatment of FOP was very different than it is today. Now, nearly twenty times the numbers of individuals with FOP are known worldwide. Intervention can change outcome, and yesterday’s data may not reliably predict tomorrow’s therapy.



University of Pennsylvania graduate student Alexandra Stanley and Temple University medical student Jacques Greenberg meet with Kurt Kysar and his parents Carrie and David Kysar (Davenport, WA) at the Center for Research in FOP and Related Disorders

Experts from academia, international regulatory agencies, small biotech companies and large pharmaceutical corporations underscore that the most common cause for failure of clinical trials in rare diseases is not a lack of appropriate therapeutics targets or a dearth of potentially useful drugs, but a deficiency of knowledge of the natural history of the disease. “Natural history studies are not sexy”, said one federal regulator at a symposium on the natural history of rare diseases at The National Institutes of Health, “but natural history studies are of utmost importance in the design of successful clinical trials.” Before one can determine if a drug of interest alters the natural history of a disease, one must know what the natural history of the disease actually is!

In 2014, we completed a comprehensive international survey on the natural history of FOP flare-ups in every country and every continent where there are known individuals with FOP. The FOP flare-up survey consisted of 78 questions translated into 15 languages and distributed to 685 families in 45 countries. The survey was completed by 500 individuals with a remarkable worldwide response of 73 per cent.

The FOP flare-up study is one of five critical natural history studies completed by the Center for Research in FOP & Related Disorders in 2014. Other studies include a comprehensive evaluation of functional survival curves for all joints and regions of the body in five hundred FOP patients, a first-of-kind longitudinal self-assessment of mobility in FOP, a groundbreaking study on a novel physician-administered cumulative analog joint involvement scale for FOP, and an innovative scale for radiographic assessment of heterotopic ossification in FOP. These four additional studies have been completed, and represent a critical piece of the Natural History Infrastructure of FOP.

An additional sixth study completed by the Center for Research in FOP & Related Disorders includes a patient-reported physical function outcome measure for adults with FOP and was developed by Clementia Pharmaceuticals and Evidera in collaboration with the clinical research team at the Center. This important assessment vehicle has been validated in FOP patients and will be used in upcoming clinical trials, including the longitudinal natural history study in patients with FOP sponsored by Clementia Pharmaceuticals. We were proud to work with Clementia and their consultants at Evidera in designing this important patient outcomes assessment vehicle.

Young Doctor Sienna Otto (Rye, NY) takes Dr. Kaplan’s blood pressure during a visit to Penn

The longitudinal Natural History Study, announced by Clementia in December 2014, involves a multi-center, non-interventional, longitudinal design to measure disease progression over three years in patients with FOP.

“Until now, investigators seeing patients with FOP have relied primarily on basic research, case reports, and results from patient surveys to understand this disease,” noted Dr. Robert Pignolo, M.D., Ph.D. “This will be the first prospective, longitudinal study to perform total body imaging and other functional assessments in patients with FOP in a systematic manner. The synchronized data generated by the Natural History Study will guide ongoing drug development in FOP.” In summary, all six natural history studies:

• TheFOPFlare-upSurvey

• TheFOPJoint-SurvivalStudy

• ThePhysicalFunctioningOutcomeScaleforFOP(incollaborationwithClementiaandEvidera)

• TheLongitudinalSelf-AssessmentMobilityStudyinFOP

• TheCumulativeAnalogueJointInvolvementScaleforFOP

• TheRadiographicAssessmentscaleforHeterotopicOssificationinFOP

are all a critical part of the Natural History Infrastructure completed in 2014.

2. Biomarker InfrastructureBiomarker discovery and assessment is a vital component of the infrastructure for a cure.

Biomarkers are objectively measured indicators of biological processes or pharmacologic responses to an intervention. For example, blood cholesterol levels, blood pressure, and tumor size are biomarkers for heart disease, hypertension, and cancer respectively. In FOP, useful biomarkers will be ones that indicate whether an individual is having a flare-up (even perhaps before a flare-up is clinically apparent), and which lesional stage of a flare-up an individual is experiencing. Biomarkers could also be helpful in assessing progression of FOP is

the absence of a flare-up, and biomarkers will likely be used to assess effects of treatment. Importantly, biomarkers will enable faster, more efficient monitoring of clinical trials.

There are three compelling reasons why biomarkers are needed for successful clinical trial design and evaluation in FOP:

1. To measure and monitor the variability and progression of FOP in each individual and between individuals.

2. To measure and monitor the stages of disease activity during and between flare-ups and the absence of flare-ups.

3. To measure and monitor each individual’s response to the drug being studied.

Ashley Kurpiel (Peachtree, Georgia) and Christine Lichtenberg (Baldwin, NY) at Joshua’s Bingo For A Cure in Allentown, PA to Benefit FOP Research

Unlike in cancer, for which biomarkers may be the same or similar throughout the course of the disease, biomarkers will likely vary in FOP based upon the stage of the disease and the phase

of a flare-up. For example, biomarkers at the earliest inflammatory phase of an FOP flare-up may be very different from those in the later cartilage and bone formation phases of a flare-up.

Knowing when a flare-up is imminent would be vital in guiding the administration of preventative medications. For example, a drug might be effective but not apparent because the dose, duration of treatment, or


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stage-specific use of the drug was incorrect. Monitoring biomarkers during a flare-up might reveal such critical information. Without biomarkers, it would be impossible to know if a drug being studied might be useful, but not quite reach optimal timing, dosage, or potency. Thus, disease-specific, stage-specific, and drug-specific biomarkers will be essential in assessing the results of any clinical trial.

Carla Miranda (Buenos Aires, Argentina) and Dr. Kaplan during a visit to the Center for Research in FOP and Related Disorders

In 2014, we completed collection of serial urine samples over three months on 24 FOP patient volunteers for the comprehensive evaluation of biomarkers of disease activity. The study was sponsored by Novartis Institute for Biomedical Research (NIBR) in order to identify stage-specific biomarkers associated with FOP flare-ups. This work is vital to the design and implementation of future clinical trials. This evaluation of urinary biomarkers will help validate clinical findings of flare-up stages, and is currently underway. When the analysis is completed, the results will be published and available to all.

The Center for Research in FOP & Related Disorders has a large and valuable biobank of plasma samples on FOP patients from various stages of FOP flare-ups. In 2015, we will institute a comprehensive annotation and analysis of biomarkers on these samples under a sponsored research agreement. When completed,

the results of this study will be published and will be widely available to researchers worldwide. Biomarker infrastructure is a vital component of the infrastructure for a cure.

3. Mouse Model InfrastructureMouse model development, characterization and access are a critical part of the infrastructure for a cure. Mouse models of FOP are necessary for pre-clinical drug testing in FOP. Presently, five types of mouse models are in use: implantation of recombinant BMP into skeletal muscle, transgenic regulation of BMP expression under the control of various gene promoters, a constitutively active ACVR1 mutation (that does not exist in any known FOP patient but can lead to heterotopic bone formation), a chimeric knock-in animal model of genuine FOP, and a conditionally-active knock-in model of the classic FOP mutation.

Of these five mouse models of heterotopic ossification, the most relevant animal model for FOP research is the conditionally active knock-in mouse model of FOP. There are presently two such animal models known to exist and both are being fully characterized while even more advanced, informative models are being developed.

These newer FOP mouse models will be important in order to answer a myriad of clinically-relevant questions: Is a drug of interest effective once a flare-up occurs? Can the drug be stopped without a rebound effect? Does resistance to the drug occur over time? What is the proper window for treating an FOP flare-up? What is the correct dosage and duration of the drug for treating an FOP flare-up? Is the drug effective for spontaneous as well as induced flare-ups? What are the short-term and long-term side-effects of drug treatment in the context of the classic mutation? How do spontaneous flare-ups differ fundamentally from trauma-induced flare-ups? What is the mechanism by which disability in FOP progresses in the absence of flare-ups?

The design of alternative mouse models for classic FOP was initiated by the Center for Research in FOP & Related Disorders in 2014. Progress on one model, using a new gene-editing approach is highly promising

and we anticipate the development of a colony in 2015. Conditional knock-in mouse models of FOP must be refined, characterized, and shared. We intend to do so. We hope that other laboratories will do so as well. Mouse models of FOP are a necessary component of the infrastructure for a cure.

4. Communications InfrastructureOpen communication channels between FOP patients, clinicians and researchers are paramount to progress, a longstanding tradition in the FOP community, and an integral part of the infrastructure for a cure. The tradition of open communications in the FOP community harkens back to the very beginning of modern FOP research with the start of the FOP Collaborative Research Project in 1991. Even before the Center for Research in FOP & Related Disorders was officially established in the mid-1990s, seminal scientific, medical, and patient symposiums were held at the University of Pennsylvania in order to bring patients, physicians, and scientists together to educate each other about the questions driving FOP clinical and basic research and to stimulate clinical and basic research collaborations. International symposia and scientific workshops at the University of Pennsylvania in 1991, 1995 and 2000 set the stage for modern scientific exploration of FOP and heralded the discovery of the FOP gene in 2006. These international symposia, and an international scientific workshop held at Penn in 2011 supported in part by the IFOPA, set the standard for developing regional international patient and scientific meetings worldwide that further expanded the scope and depth of FOP research internationally.

In advancing this longstanding tradition of open communication channels among patients, clinicians, and researchers, the IFOPA conducted the first FOP Drug Development Forum in November 2014. As described by the IFOPA, “The forum was a groundbreaking event that brought together researchers from universities and pharmaceutical companies from around the globe to discuss the challenges of developing a treatment for FOP. The goals of the meeting were to address questions and knowledge gaps that exist in FOP Drug Development; stimulate new ideas to help advance development of

potential therapies as quickly and efficiently as possible; and facilitate dialogue, foster collaboration, and form connections among interested researchers.”

An IFOPA Legacy: Nick Bogard (Chairman and Organizer of the First IFOPA Fundraiser; 1990) and his daughter Ms. Betsy Bogard (Director, Global Research Development; IFOPA) at the IFOPA Drug Development Forum in Boston, MA

As with most other medical and scientific meetings on FOP, there was great value in unstructured time during the Forum so that physicians, scientists, regulators, patients, and representatives from pharmaceutical and biotechnology companies could mingle and exchange ideas and perspectives. Prior to the concluding session, attendees identified and discussed the gaps in knowledge that must be addressed in order to enable development of safe and transformative therapies for FOP. The following items were identified:

1. Advanced understanding of the natural history of FOP

2. Better understanding of the variable phenotype of FOP

3. Identification of biomarkers

4. Better understanding of the systemic nature of FOP



The Drug Development Forum was an important milestone in the history of the FOP community and a vital part of the communications infrastructure for a cure. The Center for Research in FOP & Related Disorders was proud to advise the IFOPA in planning this important event.

Drs. Charles Hong and Dan Perrien (Vanderbilt University; Nashville, TN) with Mr. Nick Mahler (Wylie, TX) at the IFOPA Drug Development Forum in Boston, MA

5. Global FOP Registry InfrastructureA global FOP registry owned and operated by the FOP patients is a keystone in the infrastructure for a cure.

Ms. Betsy Bogard, the global research director at the IFOPA, remarked: “Registries play a critical role in the development of therapies for rare diseases. One of the biggest challenges in rare diseases is limited patient and disease data. Building an international registry helps us overcome that challenge and takes an important step to support therapeutic development. Over time, and with the participation of the entire FOP community, we believe this registry will provide valuable insights into the prevalence, diagnosis, symptoms, impact, and treatment of FOP.”

In December 2014, the IFOPA announced that it would sponsor the development of a global FOP registry called The FOP Connection Registry. “There will be two portions to the registry: the patient portal where patients can share their own experience with FOP, and the medical portal: where doctors can enter data about FOP patients under their care. The registry will be available to the international FOP community and to

researchers as well as drug developers and regulators, and will help identify trends and provide new insights about FOP.”

The goals of the global registry, as described by the IFOPA are to:

• Empowerpatients

• ImprovecollectiveunderstandingofFOP

• Organizethecommunityforclinicalstudies

• Advancethedevelopmentoftreatments

The Center for Research in FOP & Related Disorders was proud to advise the IFOPA on developing this global FOP registry. “The international FOP community is small but mighty and speaks with one voice in one language understandable to all: we want a cure and we need one international FOP patient registry owned and operated by the FOP patients to help make that happen. It is one critical goal we can accomplish together and one critical way we can change our world,” said Dr. Fred Kaplan.

The Board of Directors of the IFOPA meet at the Center for Research in FOP and Related Disorders at the University of Pennsylvania (from left to right): Christopher Bedford-Gay (Manchester, UK), Moira Liljesthröm (Buenos Aires, Argentina), Gary McGuire (Midland, MI), Karen Munro (Burnaby, British Columbia), Nancy Sando (Petoskey, MI), Marilyn Hair (Chairman of the Board of the IFOPA; Redmond, WA), Paul Brinkman (Manhattan Beach, CA), Gail Weakland (Dunellon, FL), and Amy Gordon (Claremore, OK).

PART II: Therapeutic Horizons Below: Graduate student Michael Convente describes his research to visitors at the Center for Research in FOP and Related Disorders

Above center: Bobby (Batman) Johnson (Warren, PA) visits Dr. Kaplan in Philadelphia Above Right: Dr. Richard Keen (London, England) and Dr. Frederick Kaplan meet Hamish Patel (Northampton, UK) at the UK FOP Family Meeting and Conference in Manchester, UK

Below: Dr. Isabelle Lemire (Director, Preclinical Research, Clementia Pharmaceuticals; Montreal, Canada) with Dr. Eileen Shore (Philadelphia, USA)Bottom Left: From left to right: Dr. Frederick Kaplan, Mr. Gary Whyte, Mrs. Maureen Pullano, Mrs. Holly LaPrade, Mrs. Gretchen Emmerich, and Mr. Patrick Doerr at Gary Whyte’s 13th Annual Comedy Night Fundraiser for FOP Research in Mountainside, NJ



Signal Transduction Inhibitor (STI strategy): STIs are important molecular tools for studying BMP signaling, and have the potential to be developed into powerful therapeutic drugs for FOP. Dorsomorphin (Compound C) was originally identified in a screen for STIs that perturb BMP-regulated embryonic pattern formation in zebrafish. Dorsomorphin and its derivatives inhibit all type I BMP receptors and block downstream BMP-signaling. However, a safe and effective STI for FOP must preferentially inhibit ACVR1/ALK2 (the FOP gene) over ALK3 and ALK6, rather than completely blocking all BMP signaling, and must not affect other critical cellular receptors such as ALK1 that are involved in vascular development. Highly selective STIs are currently being developed. STIs designed to specifically block ACVR1/ALK2 must have specificity, efficacy, tolerance to resistance, acceptable safety profiles, and be shown to lack toxic rebound effects before they can enter clinical trials for FOP.

Further extensive testing in animal models of classic FOP will be necessary to more completely evaluate potential efficacy, safety, dosage, duration, timing, treatment window and rebound issues. A number of university laboratories, government agencies, pharmaceutical and biotechnology companies are vigorously pursuing this approach.

Monoclonal Antibody Strategy: Although the mutated ACVR1/ALK2 receptor in FOP demonstrates leaky BMP signaling, it importantly exhibits ligand responsiveness; thus the opportunity for developing blocking antibodies to ACVR1/ALK2 or its ligands in the prevention and treatment of FOP. The development of monoclonal antibodies specific for ACVR1/ALK2 or its ligands make this approach particularly appealing. Work is presently underway in numerous independent laboratories, pharmaceutical and biotechnology companies on this exciting area of FOP therapeutics.

Small Inhibitory RNA (siRNA): A novel proof-of-principal approach using siRNA to specifically block the mutant FOP allele was pioneered by researchers at the Center for Research in FOP & Related Disorders. In a recent study, we generated specific inhibitory RNA

duplexes capable of suppressing the expression of the mutant copy of the gene in connective tissue progenitor cells from FOP patients and showed that this approach decreased the elevated BMP signaling in FOP cells to levels observed in control cells. The cells used in our study were adult stem (or progenitor) cells obtained directly from deciduous teeth of FOP patients and thus preserve the exact imbalance of mutated and normal ACVR1/ALK2 receptors found in all classically-affected FOP patients worldwide.

While this approach provides proof-of-principle for the use of allele-specific inhibition of ACVR1/ALK2 in the treatment of FOP, the in vivo utility of this approach must be confirmed in mouse models of classic FOP. Additionally, other hurdles impair human application at the present time, most notably safe delivery of the small RNA duplexes to cells in the human body. However, advances are rapidly being made in siRNA delivery, and this approach holds great promise for the future. At least five biotechnology companies are exploring this approach to FOP therapeutics.

Approach #2: Blocking Inflammatory Triggers

Several mouse models of heterotopic ossification strongly support the roles of inflammation in triggering FOP flare-ups and heterotopic ossification. In one study, local muscle inflammation was sufficient to induce heterotopic ossification in a transgenic mouse model in which BMP4 was over-expressed at the neuromuscular junction. In a related study, the activity of circulating monocytes and tissue macrophages was inhibited pharmacologically and genetically and substantially abrogated heterotopic ossification in a mouse model of FOP. In another study, the activation of inflammatory pathways in a constitutively active ACVR1/ALK2 mouse model led to heterotopic ossification at sites of inflammation whereas activation of the mutant ACVR1/ALK2 gene alone did not. Together, these finding strongly support that an inflammatory microenvironment enables heterotopic ossification in the setting of dysregulated BMP signaling.

Erica Wright (Philadelphia, PA) at the Center for Research in FOP and Related Disorders

Therapeutic horizons for the treatment of FOP are based on seminal discoveries over the past quarter-of-a-century by the FOP Collaborative Research Project and the Center for Research in FOP & Related Disorders.

Worldwide interest in FOP

research skyrocketed in the wake of the historic discovery of the FOP gene in 2006 at the Center for Research in FOP & Related Disorders. FOP research is now a worldwide enterprise. In 2014, nearly 40 distinct venues performed research on some aspect of FOP, a dramatic 25% increase over the previous year. The core activity of this effort and the only comprehensive FOP program in the world is located at the Center for Research in FOP & Related Disorders at the University of Pennsylvania.

Research scientists, physicians at university laboratories, pharmaceutical companies, biotechnology firms, and international government agencies have expressed keen interest in FOP and are engaged in an arms race to create better treatments and a cure for FOP. At least nine independent laboratories, pharmaceutical or biotechnology companies are now working on the development of kinase inhibitors for FOP, at least five are working on the development of ligands traps or antibodies, and at least eight are pursuing the development of small inhibitory RNA technology – all propelled by the discovery of the FOP gene and by the identification of its robust therapeutic target – the ACVR1 receptor kinase.

In an article entitled, “From Mysteries to Medicines: Drug Development for Fibrodysplasia Ossificans Progressiva (FOP),” in Expert Opinion in Orphan Drugs, we describe a critical unmet need for transformative therapies for FOP and outline therapeutic horizons for the treatment of FOP.

The discovery of the FOP gene in 2006 was a transformative event in the history of FOP and immediately revealed at least four approaches to the treatment and/or prevention of FOP. These approaches include:

1. Blocking activity of the mutant receptor (ACVR1/ALK2) that causes increased BMP pathway signaling (through four possible strategies which include: monoclonal antibodies, signal transduction inhibitors (STIs), inhibitory RNA, and secreted antagonists).

2. Inhibiting triggers of FOP flare-ups.

3. Directing FOP stem cells to an alternate tissue fate other than cartilage or bone.

4. Blocking the body’s response to microenvironmental signals that promote the formation and/or amplification of FOP lesions.

Approach #1: Blocking activity of the mutant receptor

(ACVR1/ALK2) that causes increased BMP pathway signaling in FOP (four strategies include: signal transduction inhibitors (STIs), monoclonal antibodies, inhibitory RNA, and secreted antagonists)

The discovery of the FOP gene identified ACVR1/ALK2, the mutated type I BMP receptor, as the prime pharmacologic target for the treatment of FOP. Therapeutic strategies for inhibiting BMP signaling in FOP include inhibitory RNA technology to knock-down the mutant allele, blocking monoclonal antibodies directed against ACVR1/ALK2 or its ligands, orally administered small molecule signal transduction inhibitors (STIs) of ACVR1/ALK2, and secreted antagonists for BMP signaling.



Ongoing research at the Center for Research in FOP & Related Disorders is focused on the role of the innate immune system in triggering disease flare-ups and progression in the setting of the FOP mutation. This exciting research, supported by the IFOPA, holds much promise for inactivating highly vulnerable targets in the induction and amplification of FOP lesions.

Approach #3: Blocking Connective Tissue Progenitor Cells

Retinoids, used for the treatment of acne, are known to cause skeletal birth defects because they interfere with the formation of the cartilaginous scaffold on which the embryonic skeleton is built. The idea of using retinoids to treat FOP flare-ups was simple, and elegant: if retinoids cause birth defects by disrupting the formation of the cartilaginous scaffold of the normal skeleton, perhaps they could impair the formation of heterotopic endochondral ossification in FOP.

Dr. Deyu Zhang at the Center for Research in FOP and Related Disorders

In the mid-1980s, a clinical trial of isotretinoin (13- cis-retinoic acid; accutane), was conducted for the prevention of FOP flare-ups. Although the outcome of the clinical trial was equivocal, the idea of using a

retinoid to prevent or treat FOP flare-ups was far ahead of its time. Over the past 30 years, nuclear retinoid receptors have been discovered, and specific agonists that possess far greater specificity and far fewer side effects than isotretinoin have been developed.

A novel approach to inhibit heterotopic ossification, not prior to induction, but after the commencement of

Dr. Masahiro Iwamoto (Children’s Hospital of Philadelphia) during a lecture on RAR-gamma agonist action on heterotopic ossification

building a second skeleton has been reported. In their landmark study, Shimono and colleagues, now at the Children’s Hospital of Philadelphia, show that the early chondrogenic stage of the pre-osseous scaffold is

exquisitely sensitive to the inhibitory effects of retinoic acid receptor gamma (RAR-γ). By using compounds that specifically activate the RAR-γ receptor, the authors targeted the pre-cartilage and cartilage cells that respond to the inflammatory start signals and that form the scaffold for mature heterotopic bone. In their mouse experiments, the authors employ a comprehensive approach using implanted stem cells, BMP induction of heterotopic endochondral ossification, and a conditional transgenic mouse that forms FOP-like heterotopic endochondral ossification to show that RAR-γ agonists potently inhibit heterotopic endochondral ossification. Remarkably, when the RAR-γ agonists are stopped, no significant rebound effect occurs, indicating that the RAR-γ agonist effect may be irreversible.

Importantly, the authors showed that this class of compounds is effective in inhibiting heterotopic endochondral ossification in animal models during a wide treatment window that included the pre-cartilage mesenchymal stem cell phase, up to, but not including, the bone formation phase. These findings suggested that the successful inhibition of heterotopic endochondral ossification in patients is possible even after the clinically elusive induction phase has occurred. Most remarkably, the authors showed that this class of compounds may

actually redirect cell fate decisions in mesenchymal stem cells to a non-bone lineage, an observation with wide-reaching implications for skeletal oncology, vascular biology, and tissue engineering. Taken together, the authors identified a potent, orally available class of compounds that can prevent heterotopic endochondral ossification in animal models by inhibiting the cartilage scaffold, and by diverting stem cells to a more benign soft tissue fate while avoiding the rebound phenomena seen in other classes of experimental medications.

The authors additionally showed that the RAR-γ agonists dramatically and irreversibly down-regulate BMP signaling by promoting the degradation of phosphorylated BMP-pathway specific Smads.

The beauty of this approach is that it does not broadly target the BMP signaling pathway in many tissues in the body, but instead targets a specific biological process of tissue development (cartilaginous scaffold formation) that requires the over-active BMP signaling pathway to cause disabling disease. Thus, it has the desired features of targeting the molecular basis of FOP in the very cells that form heterotopic endochondral ossification, hopefully with minimal collateral damage.

Dr. Maurizio Pacifici (Children's Hospital of Philadelphia) and Dr. Clarissa Desjardins (CEO, Clementia Pharmaceuticals)

In 2014, Clementia Pharmaceuticals, after several years of consultation with The Center for Research in FOP & Related Disorders at the University of Pennsylvania, began a phase II clinical trial as well as an open label extension trial of Palovarotene in adults with FOP. Palovarotene, a RAR-gamma (RAR-γ) agonist, prevents

heterotopic bone formation in mouse models of FOP, as described above. Clementia’s Phase II clinical trial was designed to determine whether Palovarotene would have the same effect in patients with FOP. The Center for Research in FOP & Related Disorders, through its contributions to current and evolving clinical study design, have made these Palovarotene trials possible.

The Phase II clinical trial is a double-blind placebo-controlled study to evaluate the safety and efficacy of Palovarotene during and after an FOP flare-up in 24 patients with FOP of 15 years of age or older. Three clinical trial sites are now open and enrolling patients and include the Center for Research in FOP & Related Disorders at the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania led by principal investigators, Drs. Robert Pignolo and Frederick Kaplan, the University of California - San Francisco led by principal investigator Dr. Ed Hsiao, and the Necker Hospital in Paris, France led by principal investigator, Dr. Genevieve Baujat.

Approach #4: Altering the Physiologic Response to

Microenvironment Signals that Promote Heterotopic Ossification We recently demonstrated that generation of a hypoxic tissue (oxygen starved) microenvironment in skeletal muscle is a critical step in the formation of an FOP lesion. To better understand the physiological implications of hypoxia in the context of the FOP mutation, we tested the hypothesis that a hypoxic microenvironment enhances signaling through the mutant ACVR1/ALK2 receptor and demonstrated that BMP signaling was both enhanced and prolonged in the presence of the FOP mutation under hypoxic conditions compared to normoxic (normal oxygen) conditions. We recently discovered the molecular mechanism by which this process occurs and used both genetic and pharmacologic approaches to reverse it in vitro and in vivo. Our studies indicate that blocking the cellular response to hypoxia with a currently available drug partially abrogates the resultant



heterotopic endochondral ossification in a mouse model of FOP. Detailed explanation of the findings and their implications for future clinical trials will be forthcoming later in the year.

As these four therapeutic approaches demonstrate, there are many potential ways to harness FOP. The long-term treatment of FOP is likely to involve not one, but several complementary approaches that acknowledge molecular mechanisms involved in the induction and progression of the disease. We are proud to have unveiled many of these targets that are now the prime focus of broad international activity on the discovery and development of therapeutics. As we delve deeper into the profound mysteries of FOP, even more therapeutic targets will inevitably emerge.

Mrs. Lisa Gardo (Chief Clinical Research Nurse) and Dr. Robert Pignolo confer on the first randomized double-blind placebo-controlled trial for FOP at the Center for Research in FOP and Related Disorders

PART III: Notable Developments in 2014

Mrs. Kay Rai with research assistants Evan Bannister and Patrick Hesketh in Dr. Kaplan’s office at Penn

Penn undergraduate student Andrew Chang and graduate student Alexandra Stanley at Joshua’s Bingo For A Cure to Benefit FOP Research in Allentown, PA

Kathy Hall (Somers Point, NJ) and Dr. Kaplan meet at Joshua’s Bingo For A Cure FOP Research Fundraiser in Allentown, PA

Angelis Veliz (Annandale, VA) during a visit to Penn

Right: Dr. Marelise Eekhoff (Amsterdam, Netherlands), Dr. Robert Pignolo (Philadelphia, USA), Dr. Donna Grogan (Clementia Pharmaceuticals; Montreal, Canada), Jeff Packman (Clementia Pharmaceuticals; Montreal, Canada); Dr. Richard Keen (London, UK), Dr. Eileen Shore (Philadelphia, USA), Dr. Zulf Mughal (Manchester, UK), and Dr. Fred Kaplan (Philadelphia, USA) at the UK FOP Family Meeting and Conference (Manchester, UK)

Right: Help Freeze FOP: Jordyn Bugarin (Baltimore, MD) displays her colorful poster with Dr. KaplanBelow Center: Meiqi-Xu in the FOP Laboratory at the Center for Research in FOP and Related DisordersBelow Left: Eric, Ellecia and Johanna Klein (Grove City, Ohio) during a visit to Penn

Joey Hollywood (Bridgewater, NJ) and Dr. Kaplan display a new collection of plastic bones



When Something Expected Doesn’t Happen: Finding the

Unsung Genetic Heroes

“We study those who are sick. But, if we are trying to develop therapies for prevention, maybe we should study those who don’t get sick - those who stay well.”

- Stephen Friend, M.D.

A healthy, 27 year-old man with the classic FOP mutation recently came to Philadelphia for clinical evaluation of FOP. He has congenital malformations of the thumbs and toes that prompted the consultation and indicate that his FOP mutation was active before birth, as occurs in others. However, his extraordinary lack of flare-ups and the complete preservation of joint function and mobility suggest that FOP progression is now inactive in this man. But, why?

Plausible causes of disease quiescence in this 27-year-old man with the classic FOP mutation include protective second site mutations, environmental factors, epigenetic effects, innate immune system modulation, circulating antibodies, or other circulating inhibitory factors.

As Drs. Stephen Friend and Eric Schadt of the Resilience Project at Mount Sinai Hospital in New York noted, “Screening resilient individuals for second site mutations or factors that prevent disease causing alleles from manifesting their effects will pinpoint new targets for drug development.”

Clearly, we need to generate new ideas from new observations. Vast unknowns remain about FOP, and we will never cross new frontiers if we avoid them.

The patient described here is being studied intensively at the Center for Research in FOP & Related Disorders. Whole exome sequencing is being performed to screen for second-site mutations and additional

biochemical and molecular studies are being conducted to identify factors that may be preventing flare-ups and heterotopic ossification.

A.J. Gonzales (Bellmawr, NJ) and his “AJ Avengers - Fighting for a Cure to FOP” with Dr. Kaplan and Kay Rai at the Center for Research in FOP and Related Disorders

We will keep you informed as the studies progress. The astounding case of this asymptomatic 27 year-old man with classic FOP was presented at the FOP Drug Development Forum in Boston in November 2014.

As Dr. William Harvey (discoverer of the circulatory system) wrote in 1657:

“Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows tracings of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual laws of Nature by careful investigation of cases of rarer forms of disease.”

We Are Not AloneIn an editorial entitled, “Shared Mutation for Two Childhood Diseases,”in the July 9, 2014, issue of the Journal of the National Cancer Institute, Catheryn M. Delude wrote: “The rare genetic disease fibrodysplasia

ossificans progressiva (FOP) turns a child’s muscle tissue into bone, forming a second skeleton that is eventually fatal. In 2006, a mutation in ACVR1/ALK2, which encodes a cell surface receptor for bone morphogenetic proteins (BMPs), was identified as the cause of FOP. Eight years later, there was a bizarre coincidence: Four research teams independently found the same mutation in almost 25 per cent of children who had a rare, inoperable, and incurable pediatric brainstem tumor called diffuse intrinsic pontine glioma (DIPG). Each year, about 200-300 US children are diagnosed with DIPG. DIPGs belong to a group of pediatric high-grade gliomas (HGGs) that look identical to glioblastoma. Traditionally, biopsies are not performed, since results would not change therapy. Of all the dismal pediatric outcomes for HGGs, DIPGs are the most devastating.”

“Median survival of the kids is 9 months. Everyone is dead within 2 years,” said Mark Kieran, M.D., Ph.D., of Boston’s Dana-Farber Cancer Institute, a co-investigator of one of the studies.

“All of a sudden, we have an explosion of insight that occurs when the cancer world and the developmental world meet,” Dr. Fred Kaplan said. “There’s nothing worse than horrible diseases that affect children, and here are two catastrophic childhood diseases linked by a connection to the same mutation. We now have scientists in the pediatric cancer field consulting with scientists in the FOP field to gain insights into mechanisms and treatments that will hopefully help children with both diseases.”

“FOP researchers had learned that when BMPs bind to the receptor that ACVR1 encodes, they activate a pathway that ultimately affects cells in different locations and stages of development,” Delude wrote. “The DIPG studies show that the identical mutation in DIPG cells also aberrantly activates downstream genes in the BMP pathway.”

“The ACVR1 mutation only mildly activates the BMP pathway, so how it leads to cancer isn’t clear,” said Adam Resnick Ph.D., a researcher at the Children’s Hospital of Philadelphia, “It doesn’t work like a classical oncogene.”

UK FOP Heroes. Rachel Almedia, Allison Acosta Bedford, Helen Bedford-Gay and Chris Bedford-Gay (the Organizing Committee of the UK FOP Family Meeting and Conference; Manchester, U.K.) with Drs. Kaplan and Shore

“Now the cancer and FOP communities can only speculate about how the same ACVR1 mutation may connect both wildly different diseases”, Delude continued.

“After 40 years of frustration in empiric treatment approaches in DIPG,” one investigator said, “these reports offer a more rational approach in developing new therapies, and hope for the children and families affected by this devastating disease.” And Kaplan added, “and for those affected by FOP.”

In a related review entitled, “ACVR1 mutations in DIPG: Lessons learned from FOP,” published in Cancer Research, Kathrin R. Taylor and colleagues wrote: “The surprising link between the seemingly unrelated diseases of DIPG and FOP suggested by common mutations in ACVR1 represents a unique opportunity for collaboration between researchers in disparate fields to fast-track drug development for both entities. Although each disease has its own requirements and obstacles, we ought to be optimistic that our shared experiences, insights, and approaches can lead to synergies in tackling the desperate unmet clinical needs of two groups of children.”

A robust collaboration has been established between the Resnick Laboratory at the Children’s Hospital of



Philadelphia and the Center for Research in FOP & Related Disorders on possible common disease mechanisms in FOP and DIPG. This collaboration is providing novel insights that will hopefully benefit children who suffer from both DIPG and FOP.

Editor’s Choice – a Few Highlights from the Literature

Numerous review articles and case reports on FOP were published in 2014. A few original articles, however, warrant additional attention.

1. ACVR1/ALK2 is required for cartilage formation during developmentKaren Lyons and colleagues from the University of California, Los Angeles reported that the BMP type I receptor ACVR1 (the receptor that is mutated in FOP) is required for cartilage formation during normal development. The paper, published online in the Journal of Bone and Mineral Research reported the clinical features of mice lacking ACVR1 in cartilage. Mutant mice were viable but exhibited defects in the development of the head and spine. The study is important because it demonstrates that although we know something about ACVR1 in FOP, we still know very little about the role of ACVR1 during normal development and beyond.

2. New cell models for FOPDr. Takenobu Katagiri and colleagues from Saitama, Medical University in Japan reported in the Biochemical and Biophysical Research Communications Journal, “Establishment of a Novel Model of Chondrogenesis Using Murine Embryonic Stem Cells Carrying FOP Associated Mutant ALK2 (ACVR1).” In this study, the authors described the use of embryonic stem cells from FOP mice to study molecular mechanism potentially relevant to heterotopic ossification in FOP. The authors propose that their in vitro model system may be useful for screening drugs for FOP. This paper compliments a previously reported study by Andria Culbert from the Center for Research in FOP & Related Disorders.

In a seminal paper in Stem Cells entitled, “ALK2 (ACVR1) regulates early chondrogenic fate in FOP heterotopic endochondral ossification,” Culbert and colleagues showed that the classic FOP mutation directly enhanced early stages of cartilage formation. This key finding established a direct role for the FOP mutation in promoting heterotopic ossification through a cartilage intermediate, and identified ACVR1-specific BMP signaling at the onset of cartilage formation as a robust therapeutic target for the prevention of heterotopic ossification in FOP. The work, performed using embryonic fibroblast cells from FOP mice, established a powerful in vitro system for drug screening and showed that ACVR1 is required for ectopic cartilage formation, an obligate precursor of bone formation in FOP.

3. Mouse Models of FOP are Not All the Same or Equally Informative

Ms. Betsy Bogard (Boston, MA), Dr. Frederick Kaplan (Philadelphia, PA), Mrs. Marie Hallbert Fahlberg (Eskilstuna, Sweden) and Dr. Takenobu Katagiri (Saitama, Japan) at the FOP Italia Family Meeting and Conference in Genoa, Italy

In a paper in Human Molecular Genetics, Petra Seemann from the Berlin-Brandenburg Center for Regenerative Therapies and Charité Hospital in Berlin, and Julia Haupt from the Center for Research in FOP & Related Disorders at the University of Pennsylvania and their colleagues reported, “ACVR1 (Q207E) causes classic FOP and is functionally distinct from the engineered constitutively active ACVR1 (Q207D) variant.” In this important paper, Seemann, Haupt, and

Meet & Greet for Friends and Families in Allentown, PA.

Front Row (from left to right): Joey Hollywood (Bridgewater, NJ), Dr. Frederick Kaplan (Philadelphia, PA), Bobby Johnson (Warren, PA). Back Row (from left to right): Jeannette Bordeau (Kintnersville, PA), Lisa Bordeau (Kintnersville, PA), Karina Chaikhoutdinov (seated; Brooklyn, NY), Christine Lichtenberg ( Baldwin, NY), Lindsay Ruiz (Somers, NY), Ashley Kurpiel (Peachtree, Georgia), A.J. (Superman) Gonzales (Bellmawr, NJ), Patrick Doerr (King of Prussia, PA), Kathy Hall (Somers Point, NJ ) and Joshua Scoble (Emmaus, PA).

colleagues establish that the ultra-rare Q207E mutation in ACVR1 can also cause classic FOP, but more importantly that the commonly used and genetically engineered Q207D constitutively active ACVR1/ALK2 mouse model has severe limitations as a model for FOP. By contrast, the naturally-occurring mutations (R206H and Q207E) facilitate receptor activation in a reversible manner, and are a far better model for classic FOP. The study emphasizes that the commonly used Q207D model has a distinctly different activation mode compared to the naturally occurring classic FOP mutations (R206H and Q207E). Importantly, the Q207D mutation does not exist in nature, and has several limitations as a model for FOP. The study strongly supports that the R206H knock-in mouse models are best suited to perform pre-clinical drug testing in FOP.

Jamie Turvey (Hampshire, UK) with parents Clive and Surekha Turvey at the UK FOP Family Meeting and Conference (Manchester, UK)

The Tooth Ferry Program at the FOP Lab:

SHEDding Light on FOPThe participation of so many patients and families who contribute blood/DNA samples to advance FOP research has been invaluable and is enormously appreciated. These samples were critical for discovering the FOP gene and for identifying the specific DNA sequence changes that occur in classic and variant forms of FOP. Although much FOP research can now be conducted using mouse models of FOP, FOP patient cells and tissues will always be essential in order to confirm that the information that we learn from mice holds true in humans.

We relied on blood samples from patients for many years since blood can be safely obtained without risk of triggering an FOP flare-up. However, blood cells provide limited information about FOP lesion formation. Fortunately, recent advances have identified additional types of human cell and tissue samples that can be obtained safely and are vitally important to our work. One of these cell types is “SHED cells.”

SHED stands for Stem cells from Human Exfoliated Deciduous teeth – a long name that describes the stem-like progenitor cells that are inside primary or baby teeth. When a baby tooth falls out naturally, we can recover the cells from inside the tooth. We have used baby teeth from FOP patients to show that these cells can



be grown in our lab and treated in special ways to form cartilage and bone cells, providing us with an informative system to examine how the FOP mutation affects the differentiation potential of cells involved in an FOP lesion.

Demid Prohorov with his parents Olga and Vladimir and Dr. Kaplan at the First International FOP Russia Family Meeting and Conference (Moscow, Russia)

A few years ago, the FOP Center started a “Tooth Ferry” program to encourage families to send FOP baby teeth to us so that cells from these teeth could be used for FOP research. These cells have already given us bountiful information about the effects of the FOP mutation on cartilage and bone cell formation. These cells were used in our recent studies to down-regulate the mutant (damaged) copy of the FOP gene by siRNA and are being used in our ongoing studies on the effects of microenvironment factors on FOP flare-ups and lesion formation. Thus, SHED cells continue to be extremely vital for many of our laboratory experiments. Because the cells have a limited lifespan and since multiple samples from a person are very informative, we continually need additional “donations” to continue to conduct our studies with SHED cells.

Anyone with a child who is losing teeth can participate in “The Tooth Ferry Program.” When your child loses a tooth or needs to have one pulled at the dentist’s office, you can send it to us in a preassembled kit that we will provide to you. Teeth from siblings and non-family members are also welcome for comparison. In addition to baby teeth, we are also happy to receive wisdom and

other permanent teeth from people with FOP. Permanent teeth also contain stem cells and we are currently investigating their use and applicability in FOP research.

Ruth McCarrick-Walmsley is heading up our effort to collect the teeth and study SHED cells. There is a brief window of opportunity for receiving the teeth with still-healthy cells, so we have developed specific instructions for their handling and shipping. If you decide to participate, we will send you a kit including all of the necessary return packaging (for several teeth), return FedEx labels, Ruth’s contact information, a tooth diagram to fill out and return, and a copy of instructions. We are also providing information about the program on the IFOPA website, (www.ifopa.org) however it is very important that you contact us before sending a tooth – if teeth arrive by surprise at the lab, we may not be ready and able to prepare them optimally.

Dr. Eileen Shore meets with Elena Stolica and her mother Danijela from Bileca, Bosnia

The tooth ferry kit is very simple to use. This is an IFOPA supported program and there is no cost to you. If you have children with teeth still to lose or are being pulled, please contact Ruth by phone (610-513-4470) or email ([email protected]) and a “Tooth Ferry Kit “ will be on its way to you soon!

The Cali-Weldon FOP Pre-Clinical Drug Testing and Biomarker Discovery Program

Novel targets for therapeutic intervention in FOP strongly suggest that existing drugs may be repurposed for proof-of-principle pre-clinical studies in FOP mouse models. If promising, such drugs could rapidly advance to clinical trials while more specific targeted approaches are under long-term development. Our preclinical drug testing program and biomarker discovery program at the Center for Research in FOP & Related Disorders was initiated in 2012, and is funded in large part by the generosity of the Cali and Weldon families.

The mission of this program is to test the most promising available drugs and those most likely to be validated for clinical trials in the foreseeable future. Some of the compounds already tested are commercially available for use in other indications and could be repurposed for FOP while other drugs, such as small molecule kinase inhibitors, are being developed specifically to target FOP.

The specific aims of this novel program are to:

1. Test the efficacy of currently available drugs and experimental compounds to inhibit heterotopic ossification (HO) in animal models of FOP.

2. Identify disease-specific and stage- specific biomarkers of FOP mouse models and patients.

Recently, we identified an approved medication that appears promising in partially inhibiting heterotopic ossification in an FOP mouse model. Thanks to additional funding from the Brinkman family, advanced testing of this compound is being conducted in knock-in animal models of classic FOP. Pending results of these investigations, a small clinical trial may be initiated in FOP using this approved/repurposed drug. With the funds from the Brinkman family, we have hired an

additional research specialist to help implement the mandates of this unique program.

The Brinkman family: Paul, Maureen & Kyle Brinkman and Dr. Aarti Madan (Manhattan Beach, CA) at the IFOPA Drug Disease Forum in Boston, MA

The Cali Developmental Grants Program

Dr. Kristi Wharton (Brown University) discusses FOP research with Dr. Ed Hsiao (University of California - San Francisco)

In 1997, the Cali Family, in consultation with Dr. William N. Kelley, M.D., then Dean of the University of Pennsylvania School of Medicine, established the Center for Research in

FOP & Related Disorders at the University of Pennsylvania. This was and still remains the only such Center of its kind in the world. Simultaneously, the Cali Family, inaugurated the vanguard Extramural Developmental Grants Program which is administered by The Center. The mission of the Developmental Grants Program is to foster collaborative research between the Center and other research laboratories of excellence at Penn, and at other universities in the United States and



around the globe. The program has been in place for nearly 18 years and has been extremely successful in fulfilling its mission of dismantling the physical and conceptual barriers that impede progress in this compelling area of human need.

(From left to right) Mr. William Weldon, Mr. John Cali, Dr. Eileen Shore, Mrs. Hillary Weldon, and Mrs. Amanda Cali

Over the past 18 years, the Cali Developmental Grants Program has awarded 18 grants of 100,000 dollars each for a total support of 1.8 million dollars. This innovative program has expanded horizons in FOP research well beyond the physical boundaries of the FOP laboratory at Penn into a true worldwide co-laboratory.

Research partners include other laboratories within the University of Pennsylvania as well as other universities and institutions including Baylor, Brown, Harvard, Northwestern, Texas A&M, Vanderbilt, University of California-San Francisco, Children’s Hospital of Philadelphia, and the Max Planck Institute for Molecular Biology in Germany.

The Cali Family Fund and Developmental Grants Program has funded work that led to the discovery of new therapeutic targets for FOP and to the development of kinase inhibitors, antibodies, extracellular traps, cellular pathway inhibitors, and inhibitory RNA for critical proof-of-principle studies in FOP.

Importantly, more than 80 per cent of the scientists and researchers who participated or were represented at the recent IFOPA Drug Development Forum in

Boston have been direct or indirect beneficiaries of a Cali Developmental Research Grant from the Center for Research in FOP & Related Disorders.

During the past year, the Cali Developmental Grants Program funded research on kinase inhibitors in the laboratories of Dr. Charles Hong at Vanderbilt University and Dr. Jay Groppe at Texas A&M University, and research on induced pluripotent stem cell models for FOP in the laboratory of Dr. Ed Hsiao at the University of California – San Francisco.

Additional information on the Cali Developmental Grants Program can be obtained from Dr. Kaplan at: [email protected], or Dr. Eileen Shore at: [email protected].

FOP: The Spoken Word – 2014During 2014, major lectures on FOP were presented at the:

• AlexionPharmaceuticals;Cheshire,Connecticut

• AmericanSocietyforBone&MineralResearchAnnualMeeting;Houston,Texas

• BoneResearchSocietyAnnualConference;Sheffield,UnitedKingdom

• BoneResearchSocietyRareBoneDiseaseWorkshop;Sheffield,UnitedKingdom

• ClementiaPharmaceuticals;Montreal,Canada

• UKFOPConference;Manchester,UnitedKingdom

• FOPevAnnualMeeting;Marienheid,Germany

• FOPItaliaAnnualMeeting;Genoa,Italy

• InternationalBMPConference;Berlin,Germany

• MayoClinic;Rochester,Minnesota

• PerelmanSchoolofMedicineattheUniversityofPennsylvania;Philadelphia,Pennsylvania

• RussianInterregionalPublicOrganizationtoHelpPatientswithFOP-FirstCongress;Moscow,Russia

• StanfordUniversity;Stanford,California

• UniversityofBelgrade;Belgrade,Serbia

• UniversityofZagrebandCroatianAcademyofSciencesandArts;Zagreb,Croatia

Drs. Frederick Kaplan and Eileen Shore with Jelena Milosevic, her mother Snezana Milosevic (Belgrade, Serbia) and Dr. Sonya Pavlovic (Professor of Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, The University of Belgrade; Belgrade, Serbia)

We would like to acknowledge the extraordinary medical, scientific, and patient meetings in Genoa, Italy; Belgrade, Serbia; Manchester, United Kingdom; Marienheid, Germany; and Moscow, Russia in 2014 that we were honored to attend and in which we were

honored to participate. It was a wonderful opportunity to meet with scientists, researchers, physicians, students, and especially patients at these various venues and to participate so meaningfully in these stimulating meetings.

During 2014, highlights of FOP research were presented at local, regional, national, and international FOP family meetings and gatherings in:

• Allentown,Pennsylvania

• Belgrade,Serbia

• Boston,Massachusetts

• Genoa,Italy

• Manchester,UnitedKingdom

• Marienheid,Germany

• Montreal,Canada

• Moscow,Russia

• Mountainside,NewJersey

• Orlando,Florida

• Philadelphia,Pennsylvania

Dr. Robert Pignolo with Sonja Spolare (Luxemburg) at the FOPeV Family Meeting and Conference in Marienheid, Germany



Dr. Eileen Shore with Kirsten and Fred Müehlhoff at the FOPeV Family Meeting and Conference in Marienheid, Germany

Jasmin Sanderson and her mother Kelly (Hartlepool, UK) meet with Dr. Kaplan and a Minion at the UK FOP Family Meeting and Conference (Manchester, UK)

Christine Lichtenberg (Baldwin, NY) and Dr. Kaplan at Joshua’s FOP Bingo For A Cure Research Fundraiser in Allentown, PA

Sabrina Ajieva and her brother Islam with Dr. Kaplan at the First International FOP Russia Family Meeting and Conference (Moscow, Russia)

Drs. Robert Pignolo and Frederick Kaplan meet with Millie Barker (Suffolk, UK) at the UK FOP Family Meeting and Conference in Manchester, UK

Liam Rump (seated; Littleton, CO) with his parents, brother, and sister at The Center for Research in FOP and Related Disorders

With Rachel Hopwood (Rochdale, UK) at the UK FOP Family Meeting and Conference (Manchester, England, U.K.)

Laura Rossano (Cold Spring Harbor, NY) and members of the freshman class of The Perelman School of Medicine at the University of Pennsylvania after Laura’s commanding lecture to the medical students (August, 2014)

Matthias Sommer with his mother Petra Sommer (President, FOPeV) at the German FOP Family Meeting and Conference in Marienheid, Germany

Dr. Kaplan and Mya Watts (Marietta, Georgia) at Penn

Kelsey Rettinger (Ashtabula, Ohio) extends greetings during a visit to Penn

Drs. Frederick Kaplan and Tina Bales with Joey Hollywood (Bridgewater, NJ) at the FOP Bingo For A Cure Fundraiser in Allentown, PA

Gary Whyte’s “Let’s Cure FOP” cake honoring the LaPrades and the Kaplans at the 13th Annual Comedy Night Fundraiser in Mountainside, NJ



Dr. Frederick Kaplan meets with Zoë Buxton, her husband Mike, Lucy Fretwell and her friend Edward (all from Belfast, Northern Ireland) at the UK FOP Family Meeting and Conference (Manchester, UK)

Drs. Robert Pignolo and Frederick Kaplan meet with FOP Sweden at UK FOP. Hugo Fahlberg and his mother Marie Hallbert Fahlberg (IFOPA International President’s Council Member and President FOP Sweden; Eskilstuna, Sweden), Mrs. Brigitta Camelfelt, Pontus Camelfelt and his sister Sara Camelfelt (Tyreso, Sweden)

Julie Elmquist Christensen (Odder, Denmark), Julie’s father David Elmquist (Malling, Denmark) and Julie’s friend Liv Krobgaard Hansen (far left; Skanderborg, Denmark) meet with Kay Rai and Shannon Chester at the Center for Research in FOP and Related Disorders

Greetings from Belgrade (from left to right): Jelena Milosevic (Belgrade, Serbia), Dr. Frederick Kaplan, Dr. Eileen Shore, Ivitza Petrovic (Serbia) and Viktorija Penova (Macedonia)

Timur Dautov and his mother Munira with Drs. Kaplan and Morhart at the First International FOP Russia Family Meeting and Conference (Moscow, Russia)

Infrastructure for A Cure

Dr. Christiaan Scott (Cape Town, South Africa) and Moira Liljesthröm (Buenos Aires, Argentina) at the FOP Italia Meeting and Conference Genoa, Italy

Dr. Charles Hong (Vanderbilt University; Nashville, TN) and his staff greet Sharon Kantanie (seated; Nashville, TN) and Dr. Patricia Delai (striped shirt; Sao Paulo, Brazil)

Adam O’Shaughnessy and his mother Antoinette (Limerick, Ireland) with Dr. Kaplan at the UK FOP Family Meeting and Conference in Manchester, UK

Drs. Frederick Kaplan and Petra Seemann at the FOPeV Family Meeting and Conference in Marienheid, Germany

Lindsay Ruiz (Somers, NY) presents Dr.Kaplan with a new skeleton tie to augment his wardrobe

Charlie Boyer-White (Chesterfield, UK) and Oliver Bedford-Gay (Manchester, UK) with Dr. Kaplan and Dr. Pignolo at the UK FOP Family Meeting and Conference (Manchester, UK)



FOP: The Written Word – 2014

Moira Liljesthröm (IFOPA Board Member & IPC Chair) and Manuel Robert (Buenos Aires, Argentina) with Dr. Kaplan at the IFOPA Drug Development Forum in Boston, MA

In 2014, publications from numerous groups on FOP and FOP-related issues appeared in peer-reviewed journals including:

• AmericanJournalofMedicalGenetics

• AnesthesiaandAnalgesia

• Biochemistry,Biophysics,ResearchCommunications

• CancerResearch

• ExperimentalCellResearch

• ExpertOpiniononOrphanDrugs

• HumanMolecularGenetics

• IntractableRareDiseasesResearch

• JournalofBiologicalChemistry

• JournalofBone&MineralResearch

• JournalofMedicinalChemistry

• JournaloftheNationalCancerInstitute

• MolecularEndocrinology

• MolecularSyndromology

• NatureGenetics

• Organogenesis

• PrenatalDiagnosis

• StemCells

As of January 1, 2015, the classic paper in Nature Genetics (April 2006) describing the discovery of the FOP gene has been cited in 450 major scientific publications worldwide.

Dr. Frederick Kaplan, Vladislav Grachev (Director of the Central Federal District Branch of the Russian FOP community "Living with FOP", and Member, IFOPA International President's Council), and Dr. Rolf Morhart in Red Square; Moscow, Russia

FOP: What Can We Do to Help?Patients, families, friends, even casual visitors to the Center for Research in FOP & Related Disorders often ask: “What can we do to help?” The answer is simple. “Anything you can.”

As Kate Griffo and John Glick at The University of Pennsylvania’s Perelman School of Medicine said, “In philanthropy, as in medicine, even brief inaction can do harm. A hiatus in research funding may mean that a promising treatment or a new line of inquiry may come to an untimely and devastating end. A break in efforts could halt progress toward finding a treatment that could relieve suffering or save lives.”

Research is laborious, time consuming, often frustrating, and costly, and is filled with false starts, blind alleys, glimmers of hope and the fog of frustration, but so too is the FOP we are trying to cure. Formidable enemies require formidable opponents, and teamwork requires resources. When seminal discoveries are made and ignorance is extinguished, the fog lifts, and the summits and the paths between them become clear. When knowledge advances, it illuminates the next horizon. It is a powerful beacon that changes the world like nothing else can. The feeling of accomplishment for all who contribute to this endeavor lights a fire of personal fulfillment and brings knowledge that they have contributed something important and enduring for other human beings for generations to come.

When modern FOP research began 24 years ago in a small laboratory at the University of Pennsylvania, there was little knowledge about this terrible disease, and little hope outside an infinitesimally small circle of believers who knew in their heart that something could be done to change it. Hope prevailed - hope fueled by the faith and commitment of a dedicated and persistent few who year after year funded studies to create and sustain a team devoted to make a difference. Over the years, that team has grown and expanded and its reach now extends around the world.

Through a sustained effort at the Center for Research in FOP & Related Disorders, research is eradicating the stifling ignorance that was prevalent just two decades ago. Barrier after barrier has fallen and achievable goals are in reach. FOP research holds real promise of preventing, treating, and curing FOP. It is no longer an imaginary dream. We need your help now more than ever to make this a reality.

The often-heard comment, “Call us when you have a treatment or a cure,” is an option, but not one that will help us find a cure. Everyone has a stake in this effort. We need your help in getting there: bake sales, swimming events, Burns’ Suppers, barn dances and bingo; chicken barbeques and spaghetti dinners, garage sales and silent auctions; country fairs and benefit concerts at the Metropolitan Opera; raffles and rodeos, sales of

holiday cards and embroidered quilts, 5K runs and ice fishing contests; chamber music benefits and Hard Rock concerts; horse-plowing contests and competitive swims; golf tournaments and bowling parties; wine tasting events and lemonade stands on busy street corners.

No idea or endeavor is too small or too outlandish to help. Every second counts. Please help cure FOP.

Many Thanks to You

Mr. Richard Simcox and Mrs. Gail Simcox (Banchory, Scotland) visit the Center for Research in FOP and Related Disorders at the University of Pennsylvania

The members of the Center for Research in FOP & Related Disorders at the University of Pennsylvania and at collaborating laboratories around the world are extremely proud to be a part of this mission, and are enormously grateful to all of those who support this vital research effort to find better treatments and a cure:

• TheInternationalFOPAssociation(IFOPA)

• TheNationalInstitutesofHealth(ThePeopleoftheUnitedStatesofAmerica)

• TheCaliFamilyEndowmentforFOPResearch

• TheWeldonFamilyEndowmentforFOPResearch



• TheIsaacandRoseNassauProfessorshipofOrthopaedicMolecularMedicine

• TheCali-WeldonProfessorshipofFOPResearch

• TheRoemexFellowshipinFOPResearch

• TheJesseDavidHendleyFoundation

• TheBrinkmanFamily

• TheCanadianFOPFamilies&FriendsNetwork

• FOPItalia

• TheFOPeV(Germany)

• AGenerousandAnonymousDonorfromCaldwell,NewJersey

• Andthemanyindividuals,families,friends,andcommunitiesthroughouttheworldwhocontributegenerouslyandtirelesslytotheFOPeffort.

Craig Hendley Memorial Dedication at the Center for Research in FOP and Related Disorders (from left to right): Robin Gambaiana, Dr. Frederick Kaplan, Craig Hendley’s sister Terri Hendley, Mark Gambaiana (Chairman Emeritus of the Board of the IFOPA), and Dr. Eileen Shore

Rada Borzova (Director of Siberian, Ural, and Far Eastern Federal District Branch of the Russian FOP Community; Siberia, Russia) with her parents and Dr. Kaplan at the First International FOP Russia Family Meeting and Conference (Moscow, Russia)

Dmitry Baranov with his parents, Alexy and Lena and Dr. Kaplan at the First International FOP Russia Family Meeting and Conference (Moscow, Russia)

The Last Word

Above: Drs. Eileen Shore and Frederick Kaplan meet with Dr. Sonja Pavlovic (5th from right), Professor of Molecular Genetics and her staff at the Institute of Molecular Genetics and Genetic Engineering, the University of Belgrade; Belgrade, Serbia

Above: IFOPA International President’s Council Member

Mrs. Marie Hallbert Fahlberg (Eskilstuna, Sweden) and IFOPA Board Member Mrs. Lori Henrotay (St. Louis, MO) with Dr. Kaplan at the IFOPA Drug Development Forum in Boston, MA

Below: Dr. Rolf Morhart (Garmisch Partenkirchen, Germany) with Dr. Carmen DeCunto (Buenos Aires, Argentina) and Dr. Robert Pignolo (Philadelphia, USA), at the FOP Italia Family Meeting and Conference in Genoa, Italy

Below: Dr. Kaplan with Jarvis Budd from Queensland, Australia



“What we call the beginning is often the end. And to make an end is to make a beginning. The end is where we start from.” -T.S. Eliot

Each year, we conclude the Annual Report by acknowledging the incredible generosity of our donors and benefactors without whom there would be no research, no progress, and no hope for the future. But, not this year. This year, the acknowledgments are the penultimate word. This year, the last word belongs – not to the donors and benefactors - not to the physicians, scientists, researchers, journalists or historians - but to the patients - whose deep, personal struggle with FOP drives this entire enterprise.

The patient’s voice was the inspiration for the historic Drug Development Forum last November. Ian Cali, an articulate 24-year-old man living with FOP, was chosen to deliver the opening address.

Ian Cali

With the focus and resolve of a mission specialist, Ian Cali guided his motorized wheelchair on stage at the opening session of the IFOPA Drug Development Forum in Boston. The room fell

silent as physicians, scientists, researchers, pharmaceutical company executives, regulatory experts, philanthropists, investment bankers and FOP families directed their attention to Ian’s opening remarks - a profile in courage – and a plaintive appeal from FOP patients everywhere.

Ian’s words resonate deeply in the parlors of philanthropy, in the offices of doctors and deans, in the boardrooms of pharmaceutical and biotechnology companies, in the corridors of FOP research, and in the living rooms of FOP families worldwide. Here, from

his original written version, are Ian Cali’s complete and unredacted opening remarks – the ones that he had wished to deliver - and the last word:

Back to the Future“Based on historical records, the population of the entire world in the early 1920’s was estimated to be right around 2 billion people. Back then, for most people, there were few choices of doctors. Research and medicine was cheap, limited and often ineffective, and communication was dependent largely upon geographic proximity.

As foreign as that is compared to the world we live in today, up until Penicillin was discovered in 1928, there were few effective treatments that the medical world had to offer. Treatments and symptom lists were so limited that the average doctor was able to keep nearly everything in their head, then just cross-reference their mental data-base with a patient’s circumstances.

We now live in a world where as a whole, our 7 billion people have discovered approximately 4,000 medical and surgical procedures, 6,000 prescribable drugs and yet there are still hundreds, if not thousands of rare and common diseases and conditions without a treatment or cure. The days when a general practitioner could keep the bulk of current medical knowledge in his or her head, are definitely over.

My name is Ian Cali, I’m 24, and if you haven’t figured it out yet I have one of those yet-to-be-cured diseases - FOP. I was misdiagnosed with Scleredema when I was 4 and properly diagnosed with FOP when I was 5. Being diagnosed at such a young age, I didn’t really comprehend the impact it would have on the rest of my life. My parents sat me and my brother down to try and explain what my diagnosis meant and both of our responses were very different. My brother is three-and-a-half years older than me, so he understandably asked if I was going to die. My parents assured him that everybody dies eventually, but that FOP wouldn’t be the reason. At this point, it was my turn to react. At that time, my

innocence was fully intact so I turned to my parents and asked if I’d still be able to eat candy. From that point on, I think my parents knew that I’d be okay.

However, that’s not to say that living with FOP has been easy, for any of us. FOP is one of those things that your brain struggles to fully wrap itself around. I know this, because I’ve dealt with FOP for 20 years and I’m still trying to wrap my head around it. I’ve been lucky enough to have parents who are willing and able to let me live my life and deal with the consequences of my decisions, regardless of how brutal they may be. Although I’ve definitely had my moments of regret, I’ve come to realize that in the end, we’ll regret the things we didn’t do, far more than we’ll regret the things we did.

I've had a traditional progression of FOP. I was lucky enough to not have experienced any medical intervention that caused harm to me (no biopsies). In the first 10 years of my life, I experienced ossification in my neck, back, shoulders and due to trauma-related incidents, partial ossification of my jaw as well. In the second decade, I have lost movement in my elbows, hips, and knees. Yet, I am grateful for the movement I have today that allows me to maintain any degree of independence with the most common and unlikely tasks using tools and gadgets.

FOP has given me an extra appreciation for the little things in life, because the little things are what FOP has gradually taken away from me behind the scenes. Things like getting myself in or out of a chair, dressing myself, running around with friends, exercising, walking up or down stairs, taking a taxi or hitching a ride with a friend are all things that I’ve had to let go of being able to do. It’s crazy to deal with something as volatile as FOP and not lose yourself along the way, but I’ve always said that FOP is part of what I am, but no part of who I am.

There was a radio hit song in the past year that had a line in the chorus that hit home for me. The line reads “I’m friends with the monsters that are under my bed, I get along with the voices inside of my head.” While that line may seem one-dimensional and juvenile in the context of the song, it summarizes what living with

FOP is like as much as any words can. On a daily basis I am dependent on someone else to help me with the majority of my daily activities like cutting or preparing food, getting dressed, washing my hair, getting in or out of bed, driving anywhere, or simply reaching anything outside of my immediate personal space.

On that mental-emotional note, I’d like to talk about some of the things that I believe make problem solving more difficult in the medical and research arena. Much of the medical and research community today is motivated by economics, corporate, or other pressures to operate as independent and self-sufficient entities as opposed to functioning as an integrated whole. This approach often leads to coveting information, retaining credit for discoveries and bits of knowledge, and often reporting only successes, not failures.

I totally understand the desire and pressure as a researcher, scientist, physician, or pharmaceutical company to want to be the best at what you do. To the majority of people, being the best at something means making the fewest mistakes. I have a different opinion, based on my own experience . . . perhaps being the best at something just means making mistakes and learning from them. It is part of human nature to resist the things we don’t know or understand because hindsight is 20-20 and nobody likes to look back on an experience and think “wow I could’ve done that better.” However, if we learn from our mistakes, then we almost guarantee that we do that thing better next time.

This is where I want to challenge you all. From this point on, I dare you . . . no . . . I ask you . . . to embrace humility, discipline and teamwork because we will not figure out FOP if all of those things don’t happen. As one of the rarest diseases in the world, FOP has proven to be one of the most complex mysteries known to the medical community - so complex and rare in fact, that a lot of the medical community isn’t even aware of it yet. As individualistic as all of us may be at times, . . . dealing with complexity often demands the success of a group, not the individual. That collaborative success can be an accumulation of individual successes, but it’s up to you to share them.



I speak for the FOP community when I say that we need you to collaborate, take a new angle, and ask questions that you may think are silly or irrelevant or old news because it may lead to something new.

I would like to share my FOP perspective on time and the importance of your collaboration in helping to solve the mysteries of my condition.

Using five years as a benchmark. Five years may be how many years you spent in med-school, or the amount of time you’ve spent researching something that sparks your interest.

It’s been more than five years since I’ve touched my face.

Ten years ago, the companies you now work for may not have even existed, you may have been deciding what you wanted to research or study, or perhaps you were in a different industry all together.

Ten years ago I was a 14 year old kid faced with reinventing the wheel of my own life a few months after my left hip had ossified and rendered me more immobilized than my brain ever could have comprehended being.

Twenty years ago, many of you were probably still in college or med-school, embarking on the journey to figure-out what made you tick, and what you were passionate about . . . whether that was medicine or something completely different.

Twenty years ago, I was an innocent, fully able-bodied 4 year old, who was gloriously oblivious to the fact I was about to nearly die after spiking a 106.4 degree fever, then spend the rest of my life bewildered at the challenges I’d be faced with.

After exposure to that timeline, perhaps you can begin to understand why this weekend is such a precious opportunity for the FOP community.

Today, here in Boston, we have esteemed representatives of the scientific world, which we know holds all the answers, but has been stymied by FOP for over 300 years. We also have the patients, like me, who know a fraction of the scientific intricacies, but experience FOP every second of every day. As much as I wish I could, I can’t daydream about a cure and have it spontaneously appear, while all of you must keep looking at FOP from new angles in order to discover something revolutionary. We need each other, because separately, we both fall short of our goals; but together, we can both win.

I challenge you - and I ask you from the bottom of my heart - to embark on a humble search for gaps in knowledge so that we can all learn from them. Share your failures as well as your successes, and maximize this opportunity to consider something new, with new people. When it comes down to it, I hope you all accomplish your goals - gain that recognition you need to get published, make the discovery that will give you great personal satisfaction, or earn you millions of dollars . . . but I want the treatment or cure for FOP to be the discovery that triggers that cascade of success. To all of you, time is often just another variable scattered throughout all of the equations your lives are filled with, but to the FOP community, time is what we’re running out of.”

Thank you for your support, from the Center for Research in FOP and Related Disorders at the University of Pennsylvania

(Seated left to right): Drs. Frederick Kaplan, Eileen Shore, Robert Pignolo(Standing left to right): Patsy Hooker, Kamlesh Rai, Dr. Girish Ramaswamy, Ruth McCarrick-Walmsley, Will Towler, Dr. Annamarie Horan, Shannon Chester, Michael Convente, Dr. Deyu Zhang, Dr. John Fong, Alexandra Stanley, Dr. Vitali Lounev, Meiqi Xu, Dr. Salin Chakkalakal, Dr. Haitao Wang, Niambi Brewer, Dr. Julia Haupt, Andrew Chang, and Bob Caron

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