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.