Research Project
8782058
DESCRIPTION (provided by applicant): Novel Targeted Cytokine for Chronic Kidney Disease End stage renal disease (ESRD) affects >485,000 Americans, including over 341,000 hemodialysis patients with an estimated 90,000 new cases per year. The annual cost of treating Americans suffering from some form of kidney failure is about $23 billion. Progression of kidney disease is characterized by a persistent inflammatory response that causes irreversible renal glomerulosclerosis and tubulointerstitial fibrosis eventually leading to ESRD (reviewed in Kanamaru, 2008). Bone morphogenetic protein 7 (BMP7) plays an important role in kidney homeostasis through its interaction with activin-like-kinase receptors 2,3, 6 (alk2, alk3, alk6) an BMPR2. Treatment with or ectopic expression of BMP7 in chronic kidney disease (CKD) blocks apoptosis, reduces inflammation, reverses the epithelial to mesenchymal transition (EMT) and fibrosis, inducing kidney regeneration [1] [2]. Recombinant BMP7 (rBMP7) would be a promising therapeutic candidate for CKD except that it exerts biological effects on numerous cell and tissue types. Even more problematic is that in some cases BMP7 may promote cancer progression, such as in gastric cancer [3], although it does appear to inhibit early tumor formation by antagonizing TGF-beta in other cell types [4]. To address these serious concerns, we propose to construct bifunctional fusion proteins that target attenuated BMP7 to the kidney through an antibody domain that specifically binds kidney epithelial cells. The attenuated BMP7 has reduced binding affinity for its receptors, but retains biological activity. Localization by th Ab domain will raise the local concentration at the target cell surface enough to compensate for the reduced intrinsic affinity. We utilize a novel proprietary protein heterodimerization strategy polyprotein heterodimerization (PPH) for facile assembly and expression. Our targeted renal BMP7 will reduce or eliminate potential unwanted effects to make BMP7 therapeutics practical. We expect that this new renal therapy will help minimize kidney damage, restore kidney function in CKD and halt progression of ESRD.
