These Million Dollar Bike Ride Pilot Grants were made possible by the fundraising efforts of John Emmerich, Lisa Gillooly, Ed Hsiao & Ian Hsiao, Karine Lalonde, the family of Savvy Porter, John Roys, Brendan Scott, Maria Wray and Team Ipsen members Joseph Burns, Seth Fritts, Jeanne McGrath, Curt Mull, the Jacob Reichert family and Tara Valley. We are also grateful for a supportive gift from Ipsen, as well as a generous $30,000 match from the Penn Medicine Orphan Disease Center.
2020 Grant Awardees
Influence of Microbiota on Innate Immune Responses and Heterotopic Ossification in FOP
Principal Investigators: Daniel Perrien, PhD and Ed Hsiao, MD, PhD
Institutions: Emory University and University of California, San Francisco
Country: United States
Award Amount: $40,000
Project Description: FOP is a currently untreatable genetic disease in which skeletal muscle repair is misdirected to endochondral bone formation known as heterotopic ossification (HO). Despite the monogenetic cause of FOP (gain-of-function point mutations in ACVR1/ALK2), disease severity and progression vary widely among patients with the same mutation. This suggests additional factors such as background genetics, environmental or nutritional influences can modify the course of the disease. Based on exciting preliminary data demonstrating that removal of microbiota in FOP mice reduces injury-induced EHO, this project will determine whether introducing specific anti-inflammatory bacteria to the gut microbiota can regulate the severity of injury-induced flares in FOP mice. Unlike commercially available supplements, the probiotics in these studies will include highly potent live bacteria specifically selected for their newly discovered roles in regulating musculoskeletal diseases. If our hypothesis is proven correct, these studies may form the foundation for a clinical trial in FOP patients and multiple applications for National Institutes of Health (NIH) funding.
Role of the GM-CSF Pathway in Heterotopic Ossification Associated with FOP and Novel Therapeutic Strategies to Suppress the Inflammatory Response
Principal Investigators: Eileen Shore, PhD and Nicolas Nicolaides, PhD
Institution/Company: University of Pennsylvania and Navrogen
Country: United States
Award Amount: $40,000
Project Description: FOP is caused by a mutation of the ACVR1 gene, however, poor understanding of the cellular mechanisms that induce heterotopic ossification (HO) has limited new drug development and treatments. It is clinically established that flare-ups precede HO in patients and that inflammatory cells are abundant in FOP lesion biopsies. This proposal will examine whether GM-CSF-responsive cells support the progression of FOP HO lesions and whether neutralizing antibodies targeting GM-CSF prevent HO. Our proposal is based on our findings, generated through a previous MDBR grant, that hyperproliferative cells in HO lesions express high levels of GM-CSF receptor, and that anti-GM-CSF antibodies reduced HO in pilot experiments. Confirmation that the GM-CSF pathway plays a direct or indirect role in HO will better define the specific cellular and inflammatory pathways influencing HO in FOP and offer new strategies to treat and/or manage the disease, including near-term clinical trials using existing anti-GM-CSF monoclonal antibodies that have already been used in human clinical trials.
