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Bone Morphongenetic Protein Inhibitors to Treat FOP
The purpose of this project is to develop this early stage inhibitor compound into a drug that may be taken orally, and perform the studies needed for testing in FOP patients.
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 FDA-approved disease modifying therapies. 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 perform the studies needed for testing in FOP patients.
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. A rare form of HO, fibrodysplasia ossificans progressiva (FOP), is inherited as an autosomal dominant trait and is typically associated with activating mutations in Acvr1, the gene encoding the bone morphogenetic protein (BMP) type I receptor, ALK2. While individuals with FOP have only minimal skeletal abnormalities at birth, extensive HO affecting nearly all skeletal muscles, ligaments, and fascia is triggered after birth with 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.
Recently, the principal investigators identified the first small molecule inhibitor of BMP signaling. The compound, dorsomorphin, blocks BMP signaling by inhibiting BMP type I receptors. Through medicinal chemistry optimization, dorsomorphin derivatives were developed. The overall objective of this research proposal is to advance the development of a dorsomorphin derivative in preparation for clinical testing in patients with FOP. The resources and expertise of the TRND program are sought to complete: scaled-up synthesis; development of an optimal oral formulation; pharmacokinetic, ADME, and toxicology studies; product development planning and preparation for IND submission; and possibly, Phase I tolerability studies.
Massachusetts General Hospital, Boston, Mass.
Kenneth Bloch, M.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.
TRND is currently performing the animal toxicology studies necessary to demonstrate safety and determine the feasibility of carrying the lead compound forward in development. TRND also is performing medicinal chemistry optimization to produce additional compounds in case the current lead compound proves insufficient for pre-clinical development.