Kidney Week

Abstract: TH-PO1063

GFB-887, a Small Molecule Inhibitor of TRPC5, Attenuates Proteinuria in Animal Models of FSGS, Minimal Change Disease, and Diabetic Nephropathy

Session Information

• Glomerular Diseases: Podocyte Biology - I
  November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1204 Podocyte Biology

Authors

• Reilly, John F., Goldfinch Bio, Inc., Cambridge, Massachusetts, United States

John F. Reilly,

• Coeffet-LeGal, Marie F.y, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States

Marie F.y Coeffet-LeGal,

• Pan-Zhou, Xin-Ru, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States

Xin-Ru Pan-Zhou,

• Joly, Kristin M., Plato BioPharma, Inc., Westminster, Colorado, United States

Kristin M. Joly,

• Richards, Toni L., Plato BioPharma, Inc., Westminster, Colorado, United States

Toni L. Richards,

• Walsh, Liron, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States

Liron Walsh,

• Harmange, Jean-Christophe, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States

Jean-Christophe Harmange,

• Plato, Craig F., Plato BioPharma, Inc., Westminster, Colorado, United States

Craig F. Plato,

• Mundel, Peter H., Goldfinch Bio, Inc., Cambridge, Massachusetts, United States

Peter H. Mundel,

Background

Focal segmental glomerulosclerosis (FSGS) is a podocytopathy with proteinuria and a high likelihood of progression to end stage renal disease (ESRD). Minimal change disease (MCD) is a podocytopathy resulting in nephrotic syndrome and is frequently refractory to current therapies. Diabetic nephropathy (DN), the most common cause of ESRD worldwide, is also characterized by proteinuria and podocyte loss. The Ca²⁺-permeable transient receptor potential canonical 5 (TRPC5) channel is a critical mediator of proteinuria. Activation of the TRPC5 pathway in podocytes culminates in activation of Rac1, which is the primary driver of proteinuria in many forms of proteinuric kidney disease. Inhibition of TRPC5 channel activity with tool compounds has been shown to protect against proteinuria and podocyte loss in AT1R transgenic and Dahl salt-sensitive rats.

Methods

We evaluated GFB-887, a potent, subtype-selective TRPC5 inhibitor, in two models of FSGS, the unilaterally nephrectomized (UNx) deoxycorticosterone acetate (DOCA)-salt rat model and the AT1R transgenic rat model with the phenotype accelerated by UNx and continuous administration of angiotensin II at a sub-pressor dose. GFB-887 efficacy was also assessed in the low-dose puromycin aminonucleoside nephrosis (PAN) rat model of MCD and the ZDSD rat model of DN.

Results

Inhibition of TRPC5 by GFB-887 attenuated albuminuria in hypertension-induced FSGS in DOCA-salt rat model without altering blood pressure, and also in the non-hypertensive AT1R rats. In both FSGS models, GFB-887 demonstrated efficacy in a therapeutic context by reducing established albuminuria. GFB-887 also reduced albuminuria in the PAN model of MCD and in the ZDSD model of DN.

Conclusion

GFB-887, a subtype-selective small molecule inhibitor of TRPC5, demonstrated efficacy in reducing proteinuria in animal models of FSGS, MCD and DN.

Funding

• Commercial Support –