The IFOPA hosted the second Drug Development Forum Oct. 24 to 25 in Boston, Mass. The very popular Forum brings together both academic and pharmaceutical researchers to address important questions and challenges of therapeutic development for FOP.
The meeting’s agenda was designed to share learnings from active research and drug development efforts worldwide, stimulate new ideas to help advance therapeutic development as efficiently as possible, and facilitate collaboration among interested researchers. (Photo - Left to right: Sienna Otto, Dr. Kaplan and Raina Halford)
Moira Liljesthrom, IFOPA Board Member and Chair of the IFOPA Research Committee, says these events are important because they “bring together researchers, pharmaceutical companies, clinicians and FOP families to facilitate the exchange, the discussion and the sharing of information…In doing so, Forums promote the understanding of FOP and accelerate the way to a treatment.”
The Forum also included two patient panels. Ensuring that researchers hear the experience of those living with FOP, as well as their perspective, is critical to research, drug development and clinical trials.
The next Drug Development Forum will be held in Italy in 2017. Learn more about the academic institutions and pharmaceutical companies that were represented at the event, see feedback on the Forum, view photosand see a presentation on Forum outcomes.
Thank you so much to all of the supporters of Hayden's Hope Dipsea run. We raised $10,000 for the International FOP Association (IFOPA). The IFOPA provides research funds, education and support to patients and family. Below is a small snapshot of programs and services that the IFOPA offers for the FOP community.
Please support me on my Dipsea run honoring Hayden and FOP research by donating to the International FOP Association. Click here to make a donation.
3rd flight of the Dipsea Steps in
On Sunday June 12th, I will run the 106th Dipsea Race in honor of Hayden, to bring awareness for FOP and to raise funds for research. The Dipsea Race is a 7.4 mile trail race from Mill Valley through Muir Wood and ending in Stinson Beach. 600+ stairs are scattered throughout the race. Fibrodysplasia Ossificans Progressiva is a rare and debilitating genetic condition that essentially turns muscle into bone, creating a second skeleton in the body. Currently there is no known cure. There are 800 people in the world affected with FOP - 285 of those people are here in the United States. Hayden was diagnosed with FOP almost 14 years ago. Since then, the FOP lab at the University of Pennsylvania, has discovered that the ACVR1 gene causes FOP. Armed with that information, the FOP Lab in conjunction with the International FOP Association, have reached out to pharmaceutical companies to explore the possibility of a cure.
Hayden and his sister Elsa
Today, we are in Phase 2 drug trails with Clementia Pharmaceuticals for a drug called Palovarotine. The drug is showing much promise. Hayden is currently in the process of enrolling in Clementia's Natural History Study which will help researchers understand the progression of FOP and how an investigational treatment might affect the course of the disease. FOP is designated as a rare disease by National Organization for Rare Diseases. Few rare diseases have a therapy or cure. Most funds for research for a rare disease come soley from family fundraisers. The FOP lab at the Department of Orthopaedic Surgery at U of Penn has a budget of $1.5 million/year for research. 75% of these funds come from family fundraising and donations. 25% come from institutional support (NIH/NIAMS, Orthopaedic Research & Education Foundation).
Hayden and his cousins on
his 16th birthday this year.
Please support me on my Dipsea run honoring Hayden and FOP research by donating to the International FOP Association. Click here to make a donation.
To learn more about the International FOP Association go to www.ifopa.org.
Quieting cells' low-oxygen alarm stops flare-ups in rare bone disorder
UNIVERSITY OF PENNSYLVANIA SCHOOL OF MEDICINE
PHILADELPHIA - The cellular response to the lack of oxygen fans the flames of flare-ups in a rare bone disorder. In fibrodysplasia ossificans progressiva (FOP), a mutation triggers bone growth in muscles, which limits motion, breathing, and swallowing, among a host of progressive symptoms.
Scientists from the Center for Research in FOP and Related Disorders at the Perelman School of Medicine at the University of Pennsylvania and colleagues examined the critical role of tissue hypoxia, or oxygen starvation, in the induction and amplification of FOP lesions, also called flare-ups.
The research team, led by Haitao Wang, PhD, a senior research investigator, Robert Pignolo, MD, PhD, an associate professor in the division of Geriatrics and the Ian Cali Distinguished Clinician-Scientist at the Center, and Frederick S. Kaplan, MD, the Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine and Chief of the division of Molecular Orthopaedic Medicine, published their findings in the Journal of Bone and Mineral Research this month.
They showed that cells from FOP lesions in humans and in a mouse model of FOP are markedly oxygen-starved and that this hypoxia triggers a molecular alarm orchestrated by the HIF-1α protein. Surprisingly, HIF-1α dramatically amplifies the already mutant bone morphogenetic protein (BMP) signaling in the oxygen-starved cells and stimulates heterotopic ossification, the abnormal metamorphosis of muscle to bone that occurs in FOP. Most importantly, when the team disabled the HIF-1α cellular alarm, BMP signaling in human FOP bone progenitor cells was restored to levels comparable to cells in normal oxygen. This adjustment profoundly reduced heterotopic ossification and the resulting disability in the FOP mouse.
A Tantalizing Lead
In 2006, Penn researchers led by Kaplan and Eileen Shore, PhD, the Cali-Weldon Professor of FOP Research and a co-author on the current study, discovered how a mutation in the gene for a BMP receptor called Activin Receptor A type I (ACVR1) occurs in all individuals who have classic FOP. The mutation in ACVR1 (mACVR1) causes the ACVR1 protein, a cell surface receptor, to be mildly overactive, thereby stimulating the BMP pathway continuously, like a faucet that drips water when it should be turned off. However, despite the presence of mACVR1 in all FOP patients, individuals with FOP do not form bone continuously but rather episodically during flare-ups, an important clue that suggested that something else fuels the process of lesion formation.
A tantalizing lead came from studying FOP lesions themselves. Importantly, all FOP flare-ups, whether spontaneous or triggered by trauma, are associated with inflammation, also a well-known cause of oxygen starvation in cells.
"Hypoxia can occur for many reasons, but in early FOP flare-ups, we speculated that hypoxia might result from the inflammatory microenvironment in lesions," Kaplan said. "This happens when oxygen supply to the damaged tissue is impaired and oxygen demand by the damaged cells greatly exceeds its supply."
Indeed, every cell continuously produces HIF-1α but rapidly destroys it when the cell has an adequate supply of oxygen. When a cell is oxygen starved, the enzymes that inactivate HIF-1α instantly cease to function, allowing HIF-1α to escape destruction, enter the nucleus of the cell, and trigger an alarm that instructs genes to adapt to a low-oxygen microenvironment. This chain of events allows the cell to survive.
The current study showed that HIF-1α inhibitors, specifically the cancer drug imatinib (Gleevec), the natural product apigenin, and the small molecule PX-478, potently inhibit dysregulated BMP signaling induced by HIF-1α in cells, as well as heterotopic ossification following tissue injury in a mouse model of FOP.
"The implications for targeted clinical trials and for compassionate clinical use of HIF-1α inhibitors in the treatment of FOP flare-ups are promising, however we need more data on dosing, duration, timing, rebound, resistance and long-term safety," Pignolo said.
"Our study provides profound insight into the role of cellular hypoxia in FOP flare-ups and shows that cellular oxygen sensing through HIF-1α is a critical regulator of the BMP pathway and heterotopic ossification in FOP," Kaplan said.
The findings support the hypothesis that FOP lesions thrive in a hypoxic microenvironment, not simply due to oxygen deprivation, but also because of a maladaptive response to hypoxia by the HIF-1α molecular alarm, similar to that seen in cancer. Most importantly for individuals with FOP, the study identifies HIF-1α as a therapeutic target -- knowledge that will likely contribute to the development of more effective treatments for FOP and related common disorders of heterotopic ossification.
This research was supported in part by the International Fibrodysplasia Ossificans Progressiva Association, the Center for Research in FOP and Related Disorders, the Ian Cali Endowment for FOP Research, the Whitney Weldon Endowment for FOP Research, the Cali-Weldon FOP Pre-Clinical Drug Testing Program, the Brinkman Family, the Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine, the Cali-Weldon Research Professorship in FOP, the Ian Cali Clinical and Research Scholarship, the Rita Allen Foundation, the Roemex Fellowship for FOP Research, the McGuire Fund for FOP Research, the Ashley Martucci Fund for FOP Research, the Penn Center for Musculoskeletal Disorders, and the National Institutes of Health (NIH R01-AR41916).
In early, 2006, I
heard the words through the telephone, “Megan, they have discovered the gene.”
It was a phone call from the then president of the board for the IFOPA, Amanda
Cali, telling me that the FOP lab had discovered that the ACVR1 gene is the
cause of FOP.I can’t tell you the emotions
that ran through me.I was so ecstatic;
all I could do was cry.
The lead researcher
at the FOP Lab at U of Penn, Dr.Frederick Kaplan, had been in Germany for work.
He received a call from Meiqui Xu who was part of the research team at U of
Penn. Meiqui told Dr. Kaplan that she was certain she had found the gene that
caused FOP. Cautiously the team began
the process of double and triple checking their findings until they were
certain that the ACVR1gene was in fact the one, which causes FOP.
On April 23, 2006, ten years ago today, Penn Medicine held a press conference to announce the findings.I was honored to be able to be in Pennsylvania to share the joy and celebrate
with Jeannie Peeper, the founder of the IFOPA, Dr. Kaplan and Dr. Shore, along
with the researchers from the FOP Lab and of course many of the families from
the FOP community.
In honor of that important announcement, April 23rd became International FOP Awareness Day.
Post Press Conference with other FOP Moms - from left to right Hillary Weldon, Amanda Cali, Jennifer Snow and Jerry Licht.
After Hayden was
diagnosed in 2002, I started researching about FOP and rare diseases. I
learned words like “orphan drugs”, “mouse model”, “humanitarian exception”, “BNP
Receptors”, “Noggin Gene”and “heterotopic” to name a few. Of all
the words that were new to me one word kept me going, “HOPE”.
Of the 7,000 rare
diseases listed in the NORD directory, only 4% have a cure or therapy. Today, the IFOPA is in drug
trials with Clementia Pharmaceuticals with a drug that shows strong hope of
bringing a therapy for our FOP Community.Recently the Journal of Bone and Mineral Research published online a non-Clementia sponsored study
describing palovarotene’s novel, beneficial effects on spontaneous heterotopic
ossification, mobility, and skeletal growth in mouse models of fibrodysplasia
So much has happened since
Hayden’s diagnosis. It is truly amazing. What a journey it has been. Thank you
all for your support.
It seems fitting that today the 40th and last participant has enrolled into the Clementia Phase 2 clinical trail that is investigating palovartene for the treatment of FOP.
When Hayden was diagnosed September 11, 2002, hope seemed to very, very far away. However the following pretty much sums up the FOP Community. "Alone we are rare. Together we are strong." Nothing demonstrates this more that the determination of our families who fundraise, our board members who guide us along our mission and the researchers who are continually on a quest to discover a cure. World Rare Disease Day is an annual observance held on the last day of February to raise awareness for rare diseases and improve access to treatments and medical representaiotn for individuals with rare diseases and their families.
In 2015 the IFOPA launched the Competitive Research Grant Program, to encourage collaborative research on many venues to further advance our search for a cure to FOP.
The 2016, the IFOPA gave out three research grants. Below are the winners.
Allosteric inhibitors of ALK2 for FOP therapy
Principal Investigator: Alex Bullock, PhD Co-investigators: Paul Brennan, PhD and Frank von Delft, PhD Institution: Oxford University, United Kingdom Award Amount: $26,421 This grant is funded in partnership with FOP Friends® UK.
Project Description: The University of Oxford FOP Research Team plans to develop a second generation ALK2/ACVR1 inhibitor for FOP therapy by targeting novel allosteric sites that allow for exquisite target selectivity and further improved drug safety. The team will screen a drug fragment library using X-ray crystallography and solve hundreds of 3D structures of the ALK2/ACVR1 protein to identify drug fragments that bind outside the ATP pocket and lock the kinase domain in an inactive state. Further chemistry will then be used to optimize these fragments into potent inhibitors that can block heterotopic ossification (HO) in FOP.
Development of antisense oligonucleotide therapy for FOP
Principal Investigator: Oana Caluseriu, MD and Toshifumi Yokota, PhD Co-applicant: Rika Maruyama, PhD Institution: University of Alberta, Canada Award Amount: $35,070 This grant is funded in partnership with the FOP Canadian Network.
Project Description: The University of Alberta team will develop a new therapy for FOP using small DNA-like molecules. These molecules can reduce the gene product that induces abnormal bone formation in FOP patients. The team will evaluate the efficacy and safety of these molecules in an FOP mouse model. This research will identify new drug candidates for FOP.
Experimental therapy to prevent secondary heterotopic ossification following surgical intervention in FOP
Principal Investigators: Paul B. Yu, MD, PhD and Dong-Dong Xia, MD Institution: Brigham and Women’s Hospital and Harvard Medical School, United States Award Amount: $46,446
Project Description: In advanced stages of FOP, progressive disease affects nearly all joints, with very limited mobility and high risk for traumatic injury. Surgical excision of heterotopic bone from muscle and soft tissues has been attempted, but almost always leads to rapid recurrence of heterotopic bone and recurrent loss of function. Current options for elective surgery in FOP are extremely limited, due to the lack of effective measures to prevent secondary bone formation following surgical trauma. We hypothesize that dysregulated ACVR1 ALK2 activity, in addition to driving primary heterotopic ossification (HO) in FOP, is responsible for the formation of secondary HO following surgical injury. We propose that pharmacologic inhibition of ALK2 kinase activity for a limited period following surgical intervention will prevent recurrent bone formation while permitting normal wound healing. We will test the efficacy and tolerability of this approach in an animal model of FOP expressing the ACVR1R206H mutant allele. It is hoped these experiments will provide a rationale for initiating clinical trials investigating the efficacy of this strategy in patients with advanced FOP.