VEGF-B as a Therapeutic Agent for Neurodenerative Disease

Background:
The National Institutes of Health's National Eye Institute is seeking statements of capability or interest from parties to form a collaborative research alliance to further develop VEGF-B as a Therapeutic Agent for Neurodegenerative Disease.

Technology:
The biological functions of vascular endothelial growth factor-B (VEGF-B) remain poorly understood. Dr. Xuri Li and her colleagues at the National Eye Institute have recently discovered that the protein is a potent inhibitor of apoptosis, and unlike other VEGF proteins, is not associated with undesired angiogenesis. The neuroprotective effects of VEGF-B have potential applications in the treatment and prevention of debilitating diseases including glaucoma, Alzheimer's and Parkinson's diseases, retinitis pigmentosa, stroke, and brain injury. It is estimated that glaucoma and RP strike, respectively, 2.2 million and 100,000 people each year in the United States.

Pre-clinical, In-vivo trials using a variety of mouse models have validated the potential of VEGF-B as a therapeutic agent. In an optic nerve crush (ONC) mouse model, an ocular disease that induces apoptotic death of retinal ganglion cells (RGCs), administration of VEGF-B was able to restore the number of RGCs by 1.7-fold while intravitreal treatment with VEGF-B neutralizing antibody decreased the number of the viable RGCs by about 33%. These results indicate that VEGF-B is critical to RGC survival in the injured retina. Similarly, VEGF-B was able to inhibit excitotoxin-induced apoptosis in the retina in an NMDA injury mouse model.

Using a cerebral ischemic stroke model, it was shown that VEGF-B expression is highly upregulated in the brain after stroke. VEGF-B deficiency led to about 50% larger brain damage volume as compared with that in wild-type mice. Despite upregulation of the protein in wildtype mice, VEGF-B treatment still decreased the stroke volume by about 32% and was able to protect neurons from apoptosis.

Further R&D Needed:

• Test the neuroprotective effect of VEGF-B in other animal models, including, but not limited to, intraocular hypertension-induced glaucoma, retinitis pigmentosa, Alzheimer's disease, Parkinson's disease, etc.
• Test whether VEGF-B affects blood vessel morphology and function in the neural system
• Examine VEGF-B gene and cell therapy using different viral and non-viral vectors

R&D Status:
In vivo studies using VEGF-B as a therapeutic agent for several diseases involving neural impairment have been conducted.

IP Status:
U.S. Provisional Application No. 60/972,780 filed 15 Sep 2007

Value Proposition:

• Potential to develop powerful therapeutic agents that can be used to treat a variety of neurodegenerative diseases and ocular degenerative diseases
• Ability to protect endangered neurons from death and avoid the undesirable angiogenesis and increased blood vessel permeability

Related Publication(s):
Li, Y., Zhang, F., Nagai, N., Tang, Z., Zhang, S., Scotney, P., et al. (2008). VEGF-B inhibits apoptosis via VEGFR-1-mediated suppression of the expression of BH3-only protein genes in mice and rats. Journal of Clinical Investigation, 118(3), 913-923.

Contact Information:
Alan Hubbs, Ph.D., NCI Technology Transfer Center
Phone: 301-594-4263
E-mail: hubbsa@mail.nih.gov

Reference:  #636 AH

Updated 04/21/2008