FDF and UPenn ODC Award Four FD/MAS Research Grants

The Fibrous Dysplasia Foundation and University of Pennsylvania Orphan Disease Center are pleased to announce the winners of the 2018 Million Dollar Bike Ride research grants. These important seed grants pave the way for new, innovative research proposals to investigate fibrous dysplasia and McCune-Albright syndrome (FD/MAS).

Thanks to Team Captain Cindi Brandt Levin and eleven other enormously successful community campaigners, this year the FD/MAS community raised over $272,000 to support cutting edge research. “Each year Team FD gains more supporters and more momentum towards finding a cure. I am thrilled that we’ve been able to award more grants this year than ever before,” said Brandt Levin. “Every researcher we give a grant to is another opportunity for the FD/MAS community to move closer towards the promise of a better future with clearer answers to our most important medical questions.”

This year’s awardees are:

• Identification and Characterization of Novel Cell-Permeable, Small Molecule Adenylyl Cyclase Inhibitors for Future Development as Drugs to Treat FD/MAS, Dr. Charles Hoffman, Boston College
• Single Cell Transcriptome Analysis of Skeletal Stem Cells Derived from FD/MAS Patients, Dr. Fernando Fierro, University of California Davis.
• Elucidating the Role of GNAS Mosaicism in Fibrous Dysplastic Lesions, Dr. Kelly Wentworth, University of California, San Francisco
• Anti-resorptive drugs in fibrous dysplasia of bone: Studies on the effects of a RANKL inhibitor and Zoledronic Acid in a murine model of the disease by radiography, histology, and genome-wide expression analysis (NanoString), Dr. Mara Riminucci, Sapienza University of Rome

Each of the study proposals are unique, and will examine key questions.

Dr. Charles Hoffman’s proposal will focus on identifying and testing new compounds for future FD/MAS drug development. Fibrous dysplasia of bone is associated with excess levels of a signaling molecule called cyclic AMP (cAMP). It might be possible to correct cAMP levels in humans by inhibiting a type of enzyme called adenylyl cyclase. Dr. Hoffman’s lab has already narrowed down their search from 125,000 possible compounds to 47 top candidates, and will use the MDBR funding to carefully examine 47 adenylyl cyclase inhibitors, an inhibitor that should lower the amount of cAMP in the body, to see if they seem likely to be effective in human cells. “These funds will allow us to purchase a collection of 47 candidate adenylyl cyclase inhibitors and support a PhD student who will validate their activity and determine their specificity,” said Dr. Hoffman. “Along with determining which compounds directly target these cyclases, we will be examining their potential as lead compounds for drug development in a collaboration with the National Center for Advancing Translational Sciences (NCATS) who will carry out pharmacokinetic studies of the validated compounds.” NCATS is one of the institutes at the National Institutes of Health.

Two of the funded projects of the 2018 grant cycle will investigate the roles of specific cell-types involved in the development of fibrous dysplasia bone lesions. These studies will answer central factual questions about the biology of FD/MAS that will help us develop new ideas about how to treat or cure FD/MAS. Dr. Fernando Fierro will use funding to isolate skeletal stem cells (SSC) from FD/MAS patients and to learn how they differ from SSC derived from healthy donors. “Our findings should lead to the development of potential treatments to restore bone metabolism in FD/MAS patients,” said Fernando Fierro. “For example, the identification of specific markers on mutated SSC (proteins expressed in ill-functioning cells, but not in healthy SSC), could lead to therapeutic approaches to direct the immune system against the malfunctioning cells, while not affecting healthy SSC.” This type of study is quite cutting-edge, explained Dr. Fierro: “Until only very recently, SSC in health and disease have been understudied, because we had no specific tools to isolate the cells. For the past two years, my laboratory has been working on an isolation protocol, and have now succeeded.”

Like Dr. Fierro’s project, the goal of Dr. Kelly Wentworth’s proposal is to learn more about the specific cell types that carry the GNAS mutation in human FD bone. While FD/MAS researchers have long known that FD bone lesions only develop when there is a mix of healthy and mutant cells (or “mosaicism”), they didn’t have the tools to find out which specific combination of healthy and mutant cells of different cell types result in the development of FD bone lesions. Dr. Wentworth will use advanced, modern “single cell sequencing” technologies to finally answer this fundamental question. “This funding makes it possible to perform detailed analyses at the individual cell level to better understand how cells with and without the GNAS mutation interact in human FD bone lesions,” explained Dr. Wentworth. This isn’t the first time that Dr. Wentworth has applied state-of-the-art technology to stubborn questions about the biology of FD/MAS. In 2017, Dr. Wentworth won the Young Investigator Award at the Orthopedic Research Society’s Sun Valley Workshop for her work applying CRISPR/cas9 to create a stem cell model of FD/MAS.

Dr. Mara Riminucci will continue her work on the development of therapies for FD/MAS through experimentation on mouse models. This is Dr. Riminucci’s fourth consecutive year winning a Million Dollar Bike Ride grant. “Without this funding, we would not be able to perform the proposed studies,” explained Dr. Riminucci. Her 2018 project will focus on refining the approach she tested in a previous grant cycle, where she administered an anti-RANKL antibody to mouse models of FD/MAS. In prior years, Dr. Riminucci has reported that while undergoing this anti-RANKL antibody treatment, mice with simulated FD showed an increase of bone mass, increase of bone formation, blocked resorption, and no development of new lesions or bone deformities. However, after going off the treatment, the results were not permanent. The mice would relapse. Dr. Riminucci now proposes combining the antibody treatment with a course of the bisphosphonates Zoledronic Acid, a drug that inhibits bone resorption by inhibiting the activity of bone resorbing cells. She anticipates that this combination will provide the same therapeutic effect as the anti-RANKL treatment did, while also preventing the relapse of the disease. She plans to use the results of this study to inform additional studies in the future. “Besides testing the combined treatment mentioned above, we will continue to investigate the mechanisms through which bone resorbing cells (osteoclasts) are involved in the development of FD,” said Mara Riminucci. “We hope that by understanding these mechanisms we will be able to identify new potential molecular therapeutic targets to be tested in future studies.”

These proposals were among many study proposals considered by the Scientific Advisory Council for these highly anticipated and competitive awards. Members of the Fibrous Dysplasia Foundation Scientific Advisory Council reviewed each proposal for scientific merit and potential to serve the FD/MAS community, and helped identify the most promising proposals.

The FD/MAS community should take great pride in funding these impressive projects. “There are currently no FDA-approved treatments for FD or MAS, and the best way we can fight to change that is to continue to fund and encourage research. While many researchers brought forward high-quality proposals for consideration, we were only able to fund four. Yet again, their were truly excellent proposals that we were unable to fund. We fundraise as much as we can every year to be able to say yes to more researchers so that no important questions go unexplored,” said Deanna Portero, FDF’s Executive Director. “Funding this kind of medical research is a lot like a relay race where patients and families are the only people willing to fund the first leg. Key people and institutions that can help us run the second leg are beginning to take note of all the work this community has put in to supporting research through the FD/MAS Patient Registry, international research collaborations, and of course these grants.”

These four projects were mainly funded through small donations to crowdfunded community fundraisers. We are grateful to the amazing people, supporters and donors behind Cycle for Carly, Rylan’s Rhythms, Coos for a Cure, Jack’s Journey, FD Warriors, Bike to Best FD, Hope for Harper, Team FUFD, A Cure for Jonathan, Wahoo Riders, and Adam’s Friends and Fans for your hard work and dedication to funding FD/MAS research. These research projects are only possible because of the hundreds of donations their campaigns received. The Million Dollar Bike Ride is a program of the University of Pennsylvania Orphan Disease Center, which provided $50,000 in matching funds for 2018’s FD/MAS grants. The Hertrich Family of Auto Dealerships provided an additional $10,000 in matching funds. 100% of each and every dollar donated to the Million Dollar Bike Ride fundraiser goes directly to FD/MAS research grants.

You can act today to support tomorrow’s promising ideas from scientific researchers. Donations to the Fibrous Dysplasia Foundation support important research programs, including the Million Dollar Bike Ride. Click here to donate to the Fibrous Dysplasia Foundation.