Novel Activin A Antagonists for Treatment of Osteoporosis

DESCRIPTION provided by applicant Bone loss and fragility from osteoporosis afflict more than million people worldwide including at least million Americans Current osteoporosis treatments are significantly deficient most fail to reverse bone loss and or have adverse effects that prohibit their long term use New therapeutic approaches are urgently needed Recently the TGF family ligand Activin A emerged as an important target in bone loss treatment Activin A is highly expressed in bone and inhibits bone formation More importantly inhibition of Activin A greatly increases bone mass in animal models demonstrating considerable potential as bone forming therapy However off target effects of current Activin A inhibitors make their therapeutic
use impractical for this indication To overcome this obstacle an ideal Activin A inhibitor would retain its bone forming capabilities while minimizing off target effects We recently discovered a novel Activin A inhibitor the extracellular protein `Crypticandapos We found that a `Crypticandapos human Igg Ffucsion protein Cryptic Fc binds Activin A with picomolar affinity and potently inhibits Activin A signaling Strikingly Cryptic Fc showed greater target specificity than current Activin inhibitors suggesting that Cryptic Fc has the desired antagonistic properties The goal of this phase I proposal is to demonstrate that Cryptic derived polypeptides can promote bone formation in vivo with limited off target effects Successful proof of concept studies will pave th way for pre clinical development of a Cryptic derived polypeptide as therapeutic for osteoporosis

PUBLIC HEALTH RELEVANCE Osteoporosis affects over million people in this country and results in frail bones that can break easily We are developing a new drug that will help regrow bone in patients with osteoporosis