VEGF-B as a Therapeutic Agent for Neurodegenerative Disease
Description of Invention:
This technology identifies vascular endothelial growth factor-B (VEGF-B) as a potent inhibitor of apoptosis in neuronal and other types of cells, and highlights its ability to rescue these cells from apoptosis in the brain and retina. Members of the VEGF family of proteins are noted for their angiogenic and blood vessel permeabilizing abilities. Some members of this family, such as VEGF-A, may promote neurogenesis; however, the neuroprotective effects are accompanied by inherent angiogenic and vessel permeabilizing activities, which make VEGF-A treatment unsuitable for clinical use as neuroprotective agents. The inventor has recently discovered that unlike the other VEGF family members, the neuroprotective effects of VEGF-B are not associated with undesired angiogenesis or increased blood vessel permeability, but rather through inhibiting apoptosis via suppressing the expression of the apoptotic/cell death related genes (1). This discovery, that the use of VEGF-B can protect endangered neurons from death and avoid the undesirable effects associated with other VEGF family members, makes it a promising candidate for the treatment of neurodegenerative and other diseases that involve neuronal impairment and/or excessive apoptosis, such as muscular dystrophy, stroke, brain injury, myocardial infarction, ischemic renal damage, etc.
In-vivo trials have already demonstrated the efficacy of VEGF-B as a therapeutic agent. VEGF-B has shown efficacy in mouse models suffering from optic nerve crush injury (ONC). ONC induces the apoptotic death of retinal ganglion cells (RGCs) in the retina. However, intravitreal administration of a single dose of the VEGF-B protein significantly restored the number of RGCs by 1.7 fold, demonstrating the potential use of the protein in treating degenerative ocular diseases, such as glaucoma. Similar results were obtained when exogenous administration of VEGF-B to the brain cortex was shown to significantly reduce ischemia-induced stroke volume and to protect neurons from apoptosis in the brain. Further, intracerebroventricular injection of VEGF-B in mutant knockout mice lacking the gene for VEGF-B (VEGFB-KO) has caused a complete reversal of neuronal impairment and restored neurogenesis back to normal levels.
Applications:
VEGF-B as a powerful therapeutic agent for use in a wide range of therapeutic intervention regimes where neuronal repair and inhibition of apoptosis are required.
Yang Li, Fan Zhang, Nobuo Nagai, Zhongshu Tang, Shuihua Zhang, Pierre Scotney, Johan Lennartsson, Chaoyong Zhu, Yi Qu, Changge Fang, Jianyuan Hua, Osamu Matsuo, Guo-Hua Fong, Hao Ding, Yihai Cao, Kevin G. Becker, Andrew Nash, Carl-Henrik Heldin, and Xuri Li. VEGF-B inhibits apoptosis via VEGFR-1–mediated suppression of the expression of BH3-only protein genes in mice and rats. J Clin Invest. 2008 Mar 3;118(3):913-923. Published online 2008 Feb 7, doi 10.1172/JCI33673. [PubMed abs]
Yunjuan Sun, Kunlin Jin, Jocelyn T. Childs, Lin Xie, Xiao Ou Mao, David A. Greenberg. Vascular endothelial growth factor-B (VEGFB) stimulates neurogenesis: Evidence from knockout mice and growth factor administration. Dev Biol. 2006 Jan 15;289(2):329-335. [PubMed abs]
Licensing Status: Available for exclusive or non-exclusive licensing.
Collaborative Research Opportunity:
The National Eye Institute, NIH, Office of Scientific Director, Unit of Retinal Vascular Neurobiology, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize VEGF-B as a therapeutic agent in treating various types of degenerative (neural, vascular, muscular, etc) diseases, and to study the molecular and cellular mechanisms involved. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.
