Grant: Project Grant

Fibrodysplasia Ossificans Progressiva (FOP) is a rare and devastating genetic disease characterized by bone formation outside the skeleton. The worldwide prevalence is approximately 1 case in 2 million individuals. The average lifespan of the patients is approximately 40 years of age. There is no effective treatment option available for FOP. Although palovarotene was recently approved only in Canada in 2022, it failed a futility test in a clinical trial and was also placed under a partial clinical hold by the FDA while it probed the safety of the drug. Several reports suggest that deactivation of normal ACVR1 and downstream signaling is harmful to patients, as palovarotene cannot distinguish normal and mutated gene products. We propose to develop a new therapy using small DNA-like molecules (antisense oligonucleotides). We will employ DNA-like molecules proven to be safe and develop a delivery method for them. We designed these molecules to target the mutated gene product only without affecting normal gene function. We already demonstrated that these molecules knocked down most of the mutated gene products while normal (healthy) gene products were minimally affected in patient cells. We aim that these molecules can be injected under the skin or into the vein directly. This is particularly beneficial for FOP patients because virus vector-mediated gene therapy would activate immune responses and cause inflammation, which leads to more bone formation. We will evaluate whether DNA-like molecules are safe and prevent extra bone formation in the patient cells and model mice. This study will facilitate efforts to cure FOP so that patients, particularly children, are provided an opportunity to live without the constraints of disability.