Investigators at the Weill Medical College of Cornell University have made the surprising finding that a protein called “brain-derived neurotrophic factor,”  which is usually considered important only for cells in the nervous system, actually plays a critical role in the growth and maintenance of blood vessels. 

 

            Cancer and vascular disease, the two leading killers of Americans under 85, are in some ways mirror images of one another.  One way that tumors grow is by hijacking the body’s blood supply system, making new arteries and blood vessels for themselves in a process called “angiogenesis.”  In several forms of heart disease, the blood supply to the heart is inadequate and the heart needs to  generate new blood vessels.

           

            The traditional responses by doctors to such heart diseases have been invasive catheter-based and open-heart surgeries.  But cardiologists have hoped to find ways to use drugs to grow new arteries and blood vessels so that these invasive procedures can be avoided, along with the painful period of healing they require.   Doctors working with those who suffer from peripheral vascular disease have also looked for such drugs.

 

            Doctors who treat cancer also are interested in angiogenesis, only from the opposite point of view – they seek ways to prevent tumors from getting an adequate blood supply, thus starving them to death.

 

            Most attention on angiogenesis in academia, as well as in the pharmaceutical and biotech industries, has focused on regulating a protein called vascular endothelial growth factor (VEGF). 

 

            Proving the adage that it is easier to destroy than to build, work to create cancer drugs that block VEGF has progressed quickly, with at least two cancer-starving drugs already on the market, while companies have struggled to develop drugs that can promote angiogenesis and feed the heart and other muscles.  The initial approach to promote angiogenesis, has been to administer VEGF directly, either as a gene or a protein.  While this approach has been shown to lead to the formation of new vessels, the vessels can be leaky and disorganized.

 

            In 1999, a research team led by Dr. Barbara Hempstead, an MD/PhD who is Co-Chief of the Weill Medial College’s Division of Hematology & Oncology, discovered that mice lacking the gene for BDNF were not viable – they died around the time of birth.  While the blood vessels in their  hearts began to form and develop normally, at a certain point they just fell apart and the mice died.  “It became clear at that time that VEGF may kick off the angiogenic process, but that BDNF may be required to stabilize and maintain the vasculature,” says Dr. Hempstead.  “We see that with levels of gene expression as well – VEGF starts out being expressed at a high level during development and tapers off in adulthood, while BDNF starts out low, rises, and remains elevated in the adult.”

 

            In a  paper earlier this year published in the Journal of Clinical Investigation, Dr. Hempstead teamed with a large group of Weill Medical College researchers including Dr. Ronald Crystal, Chair of Department of Genetic Medicine, and Dr. Shahin Rafii, the Director of the Ansary Center for Stem Cell Research, to explore the more difficult question of the role played by BDNF in adult angiogenesis, again using mice as a model for humans.   They found that administration of BDNF either via gene therapy or in protein form was as powerful as VEGF in promoting angiogenesis, and that the new vasculature was well organized.  They hypothesize that local, chronic delivery of low doses of BDNF may be the most effective therapeutic approach.

 

            Surprisingly, the Cornell team found that the BDNF had profound effects on “hematopoietic stem cells” -  immature cells that reside in the bone marrow, and leave the bone marrow to form new blood cells, blood vessels, and other tissues.  Working both on cells and on living mice, they found that BDNF caused the stem cells to leave the bone marrow at a higher rate than normal, and to home to areas of ischemia.

 

            “We found that BDNF was able to stimulate the hematopoietic stem cells as much as VEGF did,” said Dr. Kermani, the lead author.   “This means that BDNF may stimulate angiogenesis not only by causing existing blood vessels to sprout, but by mobilizing and attracting stem cells to the site of need, where they implant and mature,” said Dr. Shahin Rafii, a VEGF expert.

 

            The team published further evidence connecting BDNF, stem cells, and angiogenesis this year in a paper in Circulation, which showed that when certain populations of stem cells are cultured in BDNF, they mature into cardiomyocytes. 

 

            This research provides the foundation for further work to explore the role of BDNF in therapeutic angiogenesis.  Experiments are planned to administer BDNF to pigs to promote angiogenesis; pigs are much better models for the human cardiovascular system than mice, albeit much more expensive to work with.  If those experiments are successful and a pharma or biotech partner is found, clinical trials in humans could follow.

 

            Since angiogenesis is fundamental to both cardiovascular disease and cancer (not enough angiogenesis in vascular disease; too much in cancer), one would expect there to be a role for BDNF in cancer as well - albeit a pathological one.  Dr. Hempstead, together with Dr. Roger Pearse, another Weill Medical College researcher  published a paper in the journal Blood earlier this month entitled, “A Neurotrophin Axis in Myeloma:  TrkB and BDNF Promote Tumor Cell Survival.”   This paper demonstrates that in myeloma, a devastating cancer in which a subset of blood cells proliferates and crowds out healthy blood cells, the cancerous cells are able to use BDNF signaling to promote their own survival.

 

            Cornell has patent applications pending to protect the use of BDNF in angiogenesis, as well as the prevention of angiogenesis by interfering with BDNF signaling.   This technology has been widely marketed to big pharma and biotech companies, who currently view it as too early stage.  While therapeutic angiogenesis using other proteins has been demonstrated in vivo, this research has been funded by the NIH, and has been directed to obtaining basic scientific proof-of-concept data for the role of BDNF in angiogensis using models and delivery modes that are not of the highest commercial interest.   More recently, Cornell has been in discussions with angel investors to obtain funding to conduct experiments in which BDNF protein will be delivered to an animal model of cardiac myopathy, to demonstrate more convincingly the commercial potential of the technology in cardiovascular therapy.