Novel Treatment for Ocular Neovascularizing Diseases
Inventors: Donald Ingber, Akiko Mammoto, Kip Connor, Tadanori Mammoto, Christopher Aderman, Gustavo Mostoslavsky, Lois Smith
Invention Types: Therapeutics
Research Areas: Ophthalmology, Surgery/Wound Healing
Keywords: Animal Model (mouse), Anti-angiogenesisFor More Information Contact: Ives, Catherine L.
The vascular endothelial growth factor (VEGF) family of growth factors controls pathological angiogenesis in important eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). In addition to VEGF, other microenvironmental signals, such as mechanical forces conveyed by the extracellular matrix, control blood vessel formation. Drs. Ingber and Mammoto have identified a new mechanosensitive signaling pathway that modulates angiogenesis. They have shown, using siRNA and overexpression studies in human microvascular endothelial cells in vitro and in an in vivo neonatal mouse retina assay, that p190RhoGAP controls VEGF receptor 2 expression by altering the balance of two antagonistic transcription factors, TFII-I and GATA2.
The discovery by Drs. Ingber and Mammoto indicate that p190RhoGAP, TFII-I and GATA2 may be novel therapeutic targets for angiogenesis-dependent diseases, especially AMD and DR. Both of these diseases are leading causes of vision loss and blindness in both developed and developing nations. There are approximately 2 million AMD patients in the US, and up to 45 percent of adults diagnosed with diabetes in the US have some degree of diabetic retinopathy. The development of siRNA silencing for this pathway by Drs. Ingber and Mammoto could lead to new therapeutic strategies. Moreover, this pathway could also be employed to induce angiogenesis and treat any ischemic conditions in the body, as well as promote wound healing and vascularization of tissue engineering constructs or in reconstructive surgery.
Current FDA-approved angiogenesis inhibitors solely target VEGF. p190RhoGAP, TFII-I and GATA2 modifiers could be developed into novel therapeutics for ocular neovascularizing diseases. The only treatment options for DR are surgical interventions, and there is no cure for AMD. Presently approved anti-angiogenic therapies for ophthalmic conditions are biologic agents that inhibit VEGF directly: an anti-VEGF aptamer (Macugen); and a Fab fragment of a monoclonal antibody directed against VEGF-A (Lucentis). The work by Drs. Ingber and Mammoto suggest a method to modulate angiogenesis and potentially treat AMD and DR through targets that are sensitive to mechanical forces.
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Key Publications: Mammoto A, et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature. 2009 Feb 26;457(7233):1103-8.
Related Publications: Pat. US 8,722,638 B2