Bruce L Riser
Henry Ford Hospital, USA
Title: CCN3-based therapy: A first-in-class preventative and treatment to block and reverse renal and other organ fibrosis complicating diabetes
Biography
Biography: Bruce L Riser
Abstract
We first demonstrated a role for the matricellular protein CCN2 (formerly CTGF) as a critical downstream pro-fibrotic element in renal fibrosis. Then, in 2009 we published the first work identifying a role for CCN3 (NOV), another family member, as a co-regulating molecule working in a yin/yang manner to block mesangial cell transformation to a fibroblast phenotype and the over-production of collagen. Recently, we conducted pharmacokinetic and proof-of-principle efficacy studies in the BT/BR ob/ob mouse as a best rodent model of human diabetic nephropathy (DN). We showed that IV and IP dosing resulted in primary drug targeting to the kidney and a suitable half-life. A 3x/week treatment for 8 weeks, beginning in established DN, completely blocked and returned to normal the overexpression of key pro-fibrosis genes. Further, it completely blocked and reversed podocyte cell loss, glomerular fibrosis, reduction of kidney function and albuminuria. We therefore elucidated mechanisms operating at multiple therapeutic levels or pathways; both upstream (protecting against cell injury) and downstream (regulating CCN2 activity and ECM metabolism/accumulation. The unexpected protection from podocyte injury and glomerular hypertrophy is extremely important, since it is a key early marker of DN and thought to be critical to the development of proteinuria and glomerular / interstitial fibrosis. Most recently, we have identified key regions on the CCN3 protein, and created small peptide mimetics to specifically replicate the anti-fibrotic activity of CCN3 without additional unrelated functions. We have similarly tested these therapeutics in the BT/BR ob/ob mouse and other models of fibrosis with very positive results. BLR Bio is currently developing this as a platform for the treatment of renal disease.