Novel Treatment for Angiogenesis-dependent Diseases
Inventors: Donald Ingber, Abigail Bracha, Kaustabh Ghosh, Akiko Mammoto, Arvind Ravi, Benjamin Matthews, Charles Thodeti
Invention Types: Therapeutics
Research Areas: Oncology/Hematology, Ophthalmology
Keywords: Anti-angiogenesis, Ion ChannelsFor More Information Contact: Wong, Adrienne
TRP calcium channels respond to a number of small molecules, such as archanoids and capsaicin, and physical stimuli, for example heat and mechanical stress, by inducing appropriate cell signalling. Recent work indicates that angiogenesis and vascular remodeling can be stimulated and spatially directed by mechanical forces applied to tissue matrix. Drs. Ingber and Thodeti have identified transient receptor potential vanilloid 4 (TRPV4) as a stretch-activated channel responsible for beta1 integrin activation in response to mechanical strain application to microvascular cells. They further show that TRPV4 siRNA suppressed strain-induced reorientation and migration of normal capillary endothelial cells, and inhibited angiogenesis in vitro.
The discovery by Drs. Ingber and Thodeti indicate that TRPV4 may be a novel target for therapies of angiogenesis-dependent diseases, such as cancer, arthritis and macular degeneration. TRPV4 inhibitors would inhibit angiogenesis, whereas activators might increase capillary growth.
Any of the angiogenesis-dependent diseases represent unmet medical needs. Members of the TRP ion channel family and TRPV4 in particular are actively being pursued as drug targets, especially for pain and inflammation indications. The work by Drs. Ingber and Thodeti suggest pursuing TRPV4 as targets for angiogenesis modulation, both alone and in combination in the future.
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Key Publications: Adapala RK, et al. Activation of mechanosensitive ion channel TRPV4 normalizes of tumor vasculature and improves cancer therapy. Oncogene. 2016 Jan 21;35(3)
Thodeti CK, et al. TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. Circ Res. 2009 May 8;104(9)
Related Publications: Matthews BD, et al. Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface beta1 integrins. Integr Biol (Camb). 2010 Sep;2(9)
US 8,304,779 B2