TIMP2 Loop 6 peptide: an endogenous angiogenesis inhibitor
Inventors: Marsha Moses, Cecilia Fernandez
Invention Types: Therapeutics
Research Areas: Oncology/Hematology, Ophthalmology
Keywords: Anti-angiogenesis, Composition of Matter, PeptideFor More Information Contact: Wong, Adrienne
In many pathophysiological states, the growth of new blood vessels, or angiogenesis, is concomitant with disease progression. For example, in arthritis, new capillary blood vessels invade the joint and destroy cartilage. In cancer, unregulated angiogenesis, which serves to supply nutrients to cancer cells, is an essential factor in tumor growth and metastasis. In 'wet' macular degeneration and diabetic retinopathy, ''neovascularization'' in the eye leads to an increased chance of blindness. Effective treatment of these diseases will include new agents that inhibit angiogenesis.
Children's Hospital investigators have recently identified a novel, potent, small molecular weight inhibitor of angiogenesis. The Moses laboratory has been investigating the mechanism of action of a family of endogenous angiogenesis inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Through a series of structure-function studies, the investigators have demonstrated that the C-terminal end of TIMP2 is a potent inhibitor of both embryonic and mitogen-stimulated angiogenesis in vivo. This activity maps to a 24 amino acid loop structure of TIMP2, referred to as Loop6. Loop6 significantly inhibits both embryonic, unstimulated angiogenesis in vivo in the chick chorioallantoic membrane (CAM) assay, as well as mitogen-stimulated neovascularization in a second and more complex in vivo system, the mouse corneal pocket assay. Interestingly, Loop 6 inhibits in vitro and in vivo angiogenesis at doses comparable to those of intact TIMP2. Thus, the 24 amino acid loop6 of TIMP-2 is a novel angiogenesis inhibitor that is a promising new therapeutic for the treatment of diseases involving neovascularization.
Anti-angiogenesis |Oncology |Wet macular degeneration
As an endogenous angiogenesis inhibitor, TIMP2 Loop 6 is expected to have a good safety profile. As a short peptide, the 24 amino acid TIMP2 Loop6 would not be associated with the manufacturing issues that can accompany larger protein therapeutics.
Exclusive License for Therapeutics/ Non-Exclusive for Research
Key Publications: Fernandez CA, Roy R, Lee S, Yang J, Panigrahy D, Van Vliet KJ, Moses MA. The anti-angiogenic peptide, Loop 6, binds insulin-like growth factor-1 receptor. J. Biol. Chem. 2010 Dec 31
Fernandez CA, Butterfield C, Jackson G, Moses MA. Structural and functional uncoupling of the enzymatic and angiogenic inhibitory activities of TIMP-2: Loop 6 is a novel angiogenesis inhibitor''.
J. Biol. Chem. 2003 Aug
Related Publications: US Issued patent: 7,371,812