By Sharon Kingman
BioWorld International Correspondent
LONDON ¿ An investigation into the cellular role of a growth factor involved in blood vessel development has reaped unexpected insights into the neurodegenerative disease known as amyotrophic lateral sclerosis (ALS).
The genetically manipulated mice developed for the study will now provide an animal model for ALS, helping pharmacologists to design and evaluate new drugs for the disease using novel approaches suggested by the new research. For those investigating a strategy of inhibiting the same growth factor as a treatment for cancer, however, the research sounds a warning note that such a therapy could have harmful side effects on the nervous system.
ALS is the disease made famous by the British scientist Stephen Hawking, who suffers from it, and the American baseball player Lou Gehrig, who died from it. It affects about five in every 100,000 people, usually in the second half of life and usually causing death within five years of diagnosis. Its hallmark is progressive deterioration of motor neurons, although the rate of progression is highly variable, even within affected families.
In 2 percent of patients with ALS, there is a metabolic abnormality involving a protein called superoxide dismutase 1 (SOD1), which becomes toxic to cells although it is not known exactly how this happens. In the remaining 98 percent of patients, the cause of the disease remains unknown, and no treatments are available for patients in either group.
These questions were not, however, at the forefront of the mind of Peter Carmeliet, professor of medicine at Flanders Interuniversity Institute for Biotechnology in Leuven, Belgium, when he embarked on a study to find out what would happen when he interfered with the cellular response to low cellular oxygen levels, which normally leads to upregulation of vascular endothelial growth factor (VEGF).
He, together with colleagues at The Centre for Transgene Technology and Gene Therapy in Leuven and elsewhere, had already shown that VEGF and one of its receptors, VEGF receptor 2, are needed for the development of new blood vessels (angiogenesis) during normal development and in many pathological processes such as angiogenesis in tumors. Other researchers had also shown that VEGF is produced in large amounts when cellular oxygen levels fall.
Together with an observation that production of abnormal amounts of VEGF may play a role in development of ischemic heart disease, these findings led Carmeliet to investigate what happens when VEGF is not produced during hypoxia. Working with an international team of researchers, he developed mice that lacked the gene sequence to which certain molecules normally bind in order to stimulate VEGF production following a fall in oxygen levels.
These experimental mice produced much smaller amounts of VEGF than normal in response to low oxygen levels. The surprise to the researchers, however, was that the experimental mice developed a syndrome very similar to ALS.
Carmeliet and his colleagues report their results in a paper in Nature Genetics titled ¿Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration.¿ The first author is Bert Oosthuyse.
Carmeliet told BioWorld International: ¿We had not anticipated this ALS-like phenotype, but that is precisely what makes this study so exciting and novel. This mouse model has the typical histological and clinical features of motor neuron degeneration and therefore may provide novel insights into the disease as well as novel treatment possibilities.¿
The team has patented the use of VEGF to treat ALS and would welcome approaches from companies prepared to enter a partnership to help develop the findings. Carmeliet said, ¿We are planning to develop strategies to treat motor neuron disease in humans using VEGF and VEGF mimetics and would welcome industrial support for this development.¿
Commenting on the paper in the same issue of Nature Genetics, J.H. Pate Skene, of Duke University Medical Center in Durham, N.C., and Don W. Cleveland, of the Ludwig Institute for Cancer Research in La Jolla, Calif., write that the paper is likely to stimulate a search for abnormalities in the metabolic pathways that respond when oxygen is low, in patients with both familial and sporadic ALS, as well as a trawl for mutations in the genes encoding the molecules concerned.
Carmeliet already has embarked on some of the predicted studies. ¿We are in the process of screening large databases of ALS patients for possible mutations in VEGF or its receptors as well as related molecules,¿ he said. ¿We also need to examine whether VEGF is abnormally expressed in ALS patients and whether VEGF can be considered for chronic treatment.¿
The group is currently using its new animal model to test the VEGF protein as a treatment for ALS but will soon embark on gene therapy, too.
Carmeliet predicted that the findings might also have implications for current clinical trials evaluating the use of anti-VEGF therapy to suppress pathological angiogenesis in cancer, arthritis and diabetic retinopathy. ¿Caution is warranted,¿ he said, ¿because it remains to be determined whether small molecules that pass the blood-brain barrier may, when chronically administered systemically, as would be needed for anti-angiogenic treatment, induce unwanted neurological side effects.¿