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Therapeutics for Rare and Neglected Diseases

Bone Morphogenetic Protein Inhibitors to Treat Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare, fatal disease marked by inappropriate growth of bone fragments within the muscles, ligaments and other connective tissues, causing pain and progressive immobility. There are no disease-modifying therapies approved by the Food and Drug Administration (FDA). This bone formation is initiated by inappropriate activation of the bone morphogenetic protein (BMP) pathway. The lead collaborator has identified a compound that inhibits this spurious activation of the BMP pathway. The purpose of this project is to develop this early-stage inhibitor compound into a drug that may be taken orally and to perform the studies needed for testing in FOP patients.

Scientific Synopsis

Heterotopic ossification (HO), the formation of ectopic bone in skeletal muscle and other connective tissues, is an important cause of morbidity from joint immobility and pain. FOP, a rare form of HO, is inherited as an autosomal dominant trait and is typically associated with activating mutations in Acvr1, the gene encoding the BMP type I receptor, ALK2. Individuals with FOP only have minimal skeletal abnormalities at birth, but extensive HO affecting nearly all skeletal muscles, ligaments and fascia is triggered after birth by traumatic injury or inflammation. No effective treatments currently exist for FOP patients, and disease progression results in severe restriction of joint function and premature mortality.

In 2008, the principal collaborators identified the first small molecule inhibitor of BMP signaling. The compound, dorsomorphin, blocks BMP signaling by inhibiting BMP type I receptors. Dorsomorphin derivatives were developed through initial medicinal chemistry optimization. The overall objective of this research is to advance the development of a dorsomorphin derivative in preparation for clinical testing in patients with FOP.

Lead Collaborator

Brigham and Women’s Hospital, Boston

Paul Yu, M.D., Ph.D.

Public Health Impact

No effective treatments currently exist for FOP patients, and disease progression results in severe debilitation, restriction of joint function and premature mortality.

Outcomes

The TRND researchers determined that the initial lead molecule was unsuitable for further pre-clinical development. As such, TRND scientists are performing further medicinal chemistry optimization to identify a compound suitable for formal pre-clinical development.

Last updated: 09-06-2017
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