Focal Segmental Glomerulosclerosis

Unmet Medical Need

Focal segmental glomerulosclerosis (FSGS) is a type of chronic kidney disease (CKD). Patients with FSGS exhibit chronic glomerulosclerosis, which is fibrosis and scarring of the renal glomeruli (units of the kidney that perform the function of filtering blood). Glomerulosclerosis can also be caused by diabetic kidney disease (DKD), chronic glomerulonephritis, nephrotic syndrome, or renal hypertension.

FSGS falls into a category of nephrotic diseases, including membranous nephropathy and IgA nephropathy, with abnormality of the filtering apparatus, the glomerular slit diaphragm. The slit diaphragm normally allows small particles to pass through as filtrate that will become urine, but prevents larger molecules, such as albumin, from leaving the blood. A malfunction in the filtering apparatus leads to loss of albumin and other proteins from the blood into the urine (proteinuria). Proteinuria is the most common symptom of FSGS.

As the disease progresses, podocytes (special cells that maintain the slit diaphragm) are lost, the mesangium (glomerular connective tissue) expands, and scarring or fibrosis occurs around the kidney tubules. These changes not only contribute to abnormal filtering by the kidney but to an overall loss of renal function and retention of uremic toxins. If disease progression is not halted with therapy, the net result is CKD, end-stage renal disease (ESRD), cardiovascular disease, and death.

The incidence of primary FSGS has been increasing over the past few decades and is estimated to represent more than 38% of the adult patients with nephrotic proteinuria, and 47% of pediatric patients undergoing a biopsy for nephrotic syndrome, suggesting an overall prevalence of FSGS in the US of 70,000 patients. The estimated prevalence of the nondialysis FSGS population in the US is approximately 50,000 patients. Approximately half of all cases are not responsive to steroid treatment, and severe proteinuria persists.

Role of CTGF in FSGS

Damage to the podocyte appears to be the initiating event in development of FSGS. In an attempt to repair the original insult, TGF-β, VEGF, and endothelin-1 are induced, which are factors known to induce CTGF. Repeated insults lead to disruption of the filtration barrier and massive proteinuria typical of FSGS. Data suggest that CTGF is an active participant in early-stage proteinuria and fibrotic progression of FSGS.

  • Proteinuria: Studies show that increased levels of CTGF expression in podocytes are associated with rapid increases in proteinuria1 and can exacerbate proteinuria and mesangial expansion.2  Various other reports also indicate a key role of CTGF in mediating adhesion of cells,3-6  suggesting CTGF dysregulation may be directly involved in early stages of podocyte detachment and loss. CTGF expression has also been found to be increased in injured podocytes from FSGS patients.7
  • Fibrosis: As FSGS progresses, fibrosis develops in both the glomerulus and tubulointerstitial regions. The participation of CTGF in the pathology of FSGS as well as other renal fibrotic diseases is supported by the increased expression of CTGF in both the glomerulus and in the tubulointerstitial regions.7,8  Further, the cells producing CTGF appear to be myofibroblasts (scar-producing cells), and the number of these cells correlates with the degree of damage.9 The prominent effect that CTGF plays in kidney fibrosis is also demonstrated by multiple studies indicating that inhibiting CTGF blocks kidney fibrosis.9-19
  • Epithelial to Mesenchymal Transition: Kidney tubular cells respond to injury or local chemokine signals by losing their characteristic epithelial cell type and taking on fibroblast-like characteristics of mesenchymal cells – a process termed epithelial to mesenchymal transition, or EMT. EMT permits cells that were previously anchored to migrate and invade the extracellular matrix. CTGF has been shown in cell culture to induce EMT independently of TGF-β,20  and increased expression of CTGF co-localizes with sites of EMT in diabetic kidney tissues21. CTGF plays a key role in cellular adhesion, the dynamics of which represent a key feature of EMT. A large body of evidence from a number of renal diseases indicates that EMT is an important factor in the interstitial fibrosis leading to progressive kidney injury.21,22  Thus, CTGF over-expression may directly contribute to activation of EMT, leading to accumulation and activation of ECM-producing mesenchymal cell types observed in failing kidneys.

Anti-CTGF therapy for treating FSGS

FibroGen believes that effective blockade of CTGF could be essential in preserving renal function, decreasing the level of proteinuria and delaying or preventing progression to ESRD. FibroGen expects the therapeutic benefit of anti-CTGF therapy in FSGS would significantly delay the time to dialysis or kidney transplant, by reducing early-stage pathology related to proteinuria and structural changes in the glomerulus, and by preventing the development of interstitial fibrosis and chronic scarring.

References

  1. Roestenberg,P. et al. Temporal expression profile and distribution pattern indicate a role of connective tissue growth factor (CTGF/CCN-2) in diabetic nephropathy in mice. AJP - Renal Physiology 290, F1344-F1354 (2006).
  2. Yokoi,H. et al. Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. Kidney Int 73, 446-455 (2008).
  3. Babic,A.M., Chen,C.C. & Lau,L.F. Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 19, 2958-2966 (1999).
  4. Gao,R. & Brigstock,D.R. Low density lipoprotein receptor-related protein (LRP) is a heparin-dependent adhesion receptor for connective tissue growth factor (CTGF) in rat activated hepatic stellate cells. Hepatol. Res 27, 214-220 (2003).
  5. Ball,D.K., Rachfal,A.W., Kemper,S.A. & Brigstock,D.R. The heparin-binding 10 kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion. J Endocrinol. 176, R1-R7 (2003).
  6. Chen,C.C., Chen,N. & Lau,L.F. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J Biol Chem 276, 10443-10452 (2001).
  7. Ito,Y. et al. Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 53, 853-861 (1998).
  8. Suzuki,D. et al. Glomerular expression of connective tissue growth factor mRNA in various renal diseases. Nephrology (Carlton. ) 8, 92-97 (2003).
  9. Chunn,J.L. et al. Partially adenosine deaminase-deficient mice develop pulmonary fibrosis in association with adenosine elevations. Am J Physiol Lung Cell Mol Physiol 290, L579-L587 (2006).
  10. Zhang,C., Meng,X., Zhu,Z., Yang,X. & Deng,A. Role of connective tissue growth factor in renal tubular epithelial-myofibroblast transdifferentiation and extracellular matrix accumulation in vitro. Life Sci 75, 367-379 (2004).
  11. Zhang,C., Meng,X., Zhu,Z., Liu,J. & Deng,A. Connective tissue growth factor regulates the key events in tubular epithelial to myofibroblast transition in vitro. Cell Biol Int 28, 863-873 (2004).
  12. Wahab,N.A. et al. Role of connective tissue growth factor in the pathogenesis of diabetic nephropathy. Biochem J 359, 77-87 (2001).
  13. Ruperez,M. et al. Angiotensin II increases connective tissue growth factor in the kidney. Am J Pathol 163, 1937-1947 (2003).
  14. Yokoi,H. et al. Reduction in connective tissue growth factor by antisense treatment ameliorates renal tubulointerstitial fibrosis. J Am Soc Nephrol 15, 1430-1440 (2004).
  15. Ruperez,M. et al. Connective tissue growth factor is a mediator of angiotensin II-induced fibrosis. Circulation 108, 1499-1505 (2003).
  16. Garrett,Q. et al. Involvement of CTGF in TGF-beta1-Stimulation of Myofibroblast Differentiation and Collagen Matrix Contraction in the Presence of Mechanical Stress. Invest Ophthalmol Vis. Sci 45, 1109-1116 (2004).
  17. Okada,H. et al. Dexamethasone induces connective tissue growth factor expression in renal tubular epithelial cells in a mouse strain-specific manner. Am J Pathol 168, 737-747 (2006).
  18. Hishikawa,K., Oemar,B.S. & Nakaki,T. Static pressure regulates connective tissue growth factor expression in human mesangial cells. J Biol Chem 276, 16797-16803 (2001).
  19. Lam,S. et al. Connective tissue growth factor and IGF-I are produced by human renal fibroblasts and cooperate
  20. Burns,W.C. et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol 17, 2484-2494 (2006).
  21. Lee,D.B., Huang,E. & Ward,H.J. Tight junction biology and kidney dysfunction. AJP - Renal Physiology 290, F20-F34 (2006).
   

 
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