Fibrogen / CTGF
(from website - fibrogen.com)
"...FibroGen's corporate collaborations include a partnership with Taisho Pharmaceutical Co., Ltd of Japan to develop a human monoclonal antibody that inhibits CTGF to be used in treating renal fibrosis and chronic transplant rejection. Taisho has rights in the Pacific Rim.
Sankyo Pharmaceutical Co. and FibroGen are collaborating to discover and develop small molecule inhibitors of signal transduction pathways as anti-fibrotic therapeutics against diabetic nephropathy, retinopathy, and other forms of renal fibrosis, as well as pulmonary fibrosis, organ transplant rejection, liver fibrosis, and atherosclerosis. All other indications will be the property of FibroGen.
Aventis Pasteur SA and FibroGen have a collaboration agreement to develop novel synthetic gelatins that will confer optimal stabilization and activity attenuation specific for select Aventis Pasteur vaccines.
Additionally, FibroGen has a large number of Feasibility Assessment Agreements with leading pharmaceutical and medical device manufacturers for the evaluation of its collagens and gelatins in their current and future products...
CTGF References
The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Brigstock DR. Endocr Rev. 1999 Apr; 20(2):189-206.
Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Grotendorst GR. Cytokine Growth Factor Rev. 1997 Sep; 8(3):171-9.
CTGF in Fibroproliferative Disorders
Significant correlation between CTGF gene expression and skin sclerosis in tissue sections from patients with systemic sclerosis. A. Igarashi, G. Grotendorst, K. Takahara et al. (Tokyo Univ.), J. Invest. Dermatol. 1995.
Regulation of connective tissue synthesis in systemic sclerosis. J. Varga, R.I. Bashey (TJU), Int. Rev. Immunol. 1995.
Human CTGF is expressed in advanced atherosclerotic lesions. B.S. Oemar, et al. (Univ. Hospital, Switzerland), Circulation 1997.
Growth regulation in scleroderma fibroblasts: increased response to TGFBeta1. K. Kikuchi, T. Kadono, H. Ihn, A. Igarashi, H. Nakagawa, K. Tamaki, K. Takehara (Univ. of Tokyo). J. Invest. Dermatol. 1995.
CTGF in Kidney Fibrosis
CTGF as a determinant of ECM deposition in diabetic glomerulosclerosis. B.L. Riser, M. DeNichilio et. Al. (Henry Ford Hospital/FibroGen), J. Am. Soc. Nephr. 1998.
Novel gene transcripts preferentially expressed in human IgA nephropathy revealed by quantitative hybridization of a high density cDNA array. N. Yano et al. (Brown Univ./Tokai Univ.), Am. Soc. Nephr. Mtg. October 1998.
CTGF in hypertensive nephrosclerosis of shr-unx. Y. Ito et al. (Univ. Amsterdam), Am. Soc. Nephr. Mtg. October 1998.
CTGF expression in human mesangial cells exposed to high glucose. M. Murphy et. al. (Mater Misericordiae Hospital), Am. Soc. Nephr. Mtg. October 1998.
High glucose induces the expression of CTGF in human mesangial cells. R. Mason et al. (Imperial College, London), Pathophysiology of Renal Disease: Diabetes Mellitus-Basic.
CTGF in Pulmonary Fibrosis
Connective tissue growth factor in fibrotic lung disease. S.W. Xu, D.J. Abraham, G.R. Martin, C.M. Black (Royal Free Hospital UK), Arthritis & Rheumatism 1998.
CTGF mRNA is upregulated in bleomycin induced lung fibrosis. Laskey, Am. J. Physiol. 275 365-371 (1998)
TGFBeta and lung allograft fibrosis. El-Gamel et al., Eur. J. Cardiothoracic Surg. 13: 424-430 (1995)
Pulmonary and cardiac late effects of injuring radiation alone or with chemotherapy. Gerinsky Cancer Radiotherapy, 735-743 (1997)
Cytokines in human lung fibrosis. Martinet. Arch Toxicol. 18, 127-239 (1996)
What is Prolyl Hydroxylase? Prolyl hydroxylase is an intracellular enzyme required for the synthesis and formation of all 21 known types of collagen. Prolyl hydroxylase works by modifying the individual polypeptide alpha chains of procollagen to allow them to form stable, triple helical structures. The triple helical structure gives the collagen molecule its stiffness, strength and insolubility.
Why is Prolyl Hydroxylase an Important Target? Prolyl hydroxylase catalyzes the hydroxylation of proline residues during the post-translational processing of collagen. The formation of genetically non-coded hydroxyproline enables the collagen molecule to form its stable, triple helical conformation common to all types of collagen. Effective inhibitors of this enzyme generate unstable collagen that is degraded inside the cell and is not secreted.
R&D Activities: FibroGen has established a recombinant expression system to produce large quantities of human prolyl hydroxylase. Additionally, FibroGen has identified compounds that effectively inhibit prolyl hydroxylase enzyme activity.
FibroGen has collected a significant amount of data on its small molecules that inhibit prolyl hydroxylase and has demonstrated proof of concept in several preclinical models, including dermal scarring, tendon adhesion formation, lung fibrosis, kidney fibrosis, and spinal cord regeneration after traumatic injury.
At the 1999 and 2000 Annual Meetings of the American Heart Association, scientists at the University of Illinois at Chicago collaborating with FibroGen, reported on studies that demonstrated that treatment with a prolyl hydroxylase inhibitor blocked the reactive fibrosis occurring in the heart after myocardial infarction. Blocking the reactive fibrosis preserved heart function and improved survival rates in these studies.
Selected small molecule inhibitors of prolyl hydroxylase have been tested for oral and topical administration, and the compounds have been found to be active and effective via both forms of delivery.
FibroGen is evaluating several potential clinical indications for prolyl hydroxylase inhibitors, such as hypertrophic scars (burns), keloids and scleroderma. Further preclinical testing for specific cardiovascular indications is being rapidly advanced.
What is C-Proteinase? C-proteinase, also known as bone morphogenic protein-1 (BMP-1), is an extracellular enzyme required for the processing of procollagen molecules, particularly procollagen types I, II and III. In addition, C-proteinase activates the enzyme lysyl oxidase, whose activity results in covalent cross-links between collagen chains that promote its stability and resistance to degradation.
Why is C-Proteinase an Important Target? C-proteinase is required for the conversion of procollagens to fibrillar collagens by removing the carboxyl terminal globular domain, thereby enabling the spontaneous self-assembly of collagen monomers into larger collagen fibrils.
By inhibiting the action of C-proteinase, procollagens can not assemble into collagen fibrils and the deposition of collagen in tissues is blocked.
R&D Activities: FibroGen has established recombinant expression systems to produce human C-proteinase and its related isoenzymes (mTolloid, mTolloid-like1 and mTolloid-like2). FibroGen scientists are evaluating candidate small molecule inhibitors of C-proteinase. In preclinical studies, FibroGen's lead compounds have shown efficacy in animal models of wound healing and post-surgical abdominal adhesions. The prevention of dermal scarring and the formation of post-surgical adhesions are two potential clinical indications for C-proteinase inhibitors being evaluated by FibroGen.
What is CTGF? Connective tissue growth factor is a fibrogenic cytokine, a growth factor that is required for the fibrotic response mechanism in tissues. CTGF is key to the maintenance of persistent fibrosis and scarring and is an important target in FibroGen's anti-fibrotic drug discovery efforts.
CTGF functions as an autocrine growth factor, which means that it acts on the same cells that produce it, causing the cells (fibroblasts) to proliferate, differentiate and produce more collagen. CTGF was discovered in the laboratory of Dr. Gary Grotendorst, a FibroGen collaborator, while at the University of South Florida.
FibroGen is developing monoclonal antibodies and small molecules that block the activity of the intact CTGF molecule, as well as its fragments, at critical steps during the fibrotic cascade, including:
* CTGF signaling
* CTGF receptor activation
* TGF-beta stimulation of CTGF gene induction
* Proteolytic processing of CTGF
Why is CTGF an Important Target? CTGF is a cytokine produced by connective tissue cells after activation by another growth factor, TGF-beta (transforming growth factor beta).
TGF-beta is a pluripotent growth factor, which means that it has numerous functions in many different types of cells in the body. TGF-beta is important in wound healing and the pathogenesis of fibrosis, but it is involved in other critical biological activities including suppression of autoimmune diseases and the suppression of cancer. Because of its multifaceted role, inhibiting TGF-beta would be expected to impact numerous other important functions, many in an adverse way.
Due to CTGF's specific role in maintaining persistent fibrosis and scarring, FibroGen is focusing on the development of therapeutics to block this key fibrogenic cytokine.
Overexpression of CTGF Reported in Numerous Fibrotic Disorders
Skin Lesions
- Scleroderma (Morphea, Generalized Morphea, Linear Scleroderma)
- Keloids
- Hypertrophic Scar
- Nodular Fasciitis
- Eosinophilic Fasciitis
- Dupuytren's Contracture
Internal Organs
- Kidney Fibrosis
- Pulmonary Fibrosis
- Chemotherapy / Radiation Induced Lung Fibrosis
- Atherosclerotic Plaques
- Inflammatory Bowel Disease
- Crohn's Disease
- Arthritic Joints
Cancer
- Invasive Breast Carcinoma Desmosplasis
- Dermatofibromas
- Endothelial Cell Expression
- Angiolipoma
- Angioleiomyoma
R&D Activities: FibroGen scientists have successfully demonstrated that by inhibiting CTGF, excessive scarring and fibrosis can be prevented without interfering with normal body maintenance.
FibroGen has generated human monoclonal antibodies that neutralize the activity of CTGF and has demonstrated proof of concept in several preclinical models, including kidney fibrosis and lung fibrosis. FibroGen scientists have also identified small molecules that act to inhibit TGF-beta induced CTGF release from fibroblasts, thus blocking collagen accumulation. Proof of concept has been demonstrated in cell-based models of fibrosis. |
