BioWorld International Correspondent

LONDON - A molecule that stimulates the growth of new blood vessels may provide a treatment for a neurodegenerative disease of humans called amyotrophic lateral sclerosis (ALS).

Researchers in Belgium said they already have shown that the molecule, vascular endothelial growth factor (VEGF), can protect animals against death of motor neurons caused by ischemia.

Peter Carmeliet, professor of medicine at Flanders Interuniversity Institute for Biotechnology in Leuven, Belgium, told BioWorld International: "We are now in the process of testing whether VEGF is a useful treatment for chronic ALS in mice and rats, and we expect to have conclusive data in the very near future. Once that is available, then we can go into the clinic."

Carmeliet and his colleagues report their findings in a paper in Nature Genetics, published online July 6, 2003, and titled "VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death." 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 their findings.

ALS affects about five in every 100,000 people, usually in their 50s or 60s. It causes progressive deterioration of motor neurons, and usually results in death within three to five years. Famous sufferers include the British scientist Stephen Hawking, who is still alive years after diagnosis; the American baseball player Lou Gehrig, who died; the Chinese leader Mao Tse-tung; the Russian composer Dmitri Shostakovitch; and the first Belgian to die by euthanasia.

About 2 percent of cases are known to be due to mutations in a gene called SOD1, but the cause of the remaining 98 percent remains elusive. There is no treatment.

Two years ago, Carmeliet's group described how, in mice, knocking out the gene sequence to which certain molecules normally bind in order to stimulate the production of VEGF following a fall in oxygen levels gave rise to animals that manufactured very low levels of VEGF. The team, however, was surprised to find that the experimental mice also developed a syndrome very similar to ALS.

As BioWorld International reported on June 13, 2001, the researchers planned to screen large groups of patients with ALS for possible mutations in the gene for VEGF or related molecules in the same pathway.

Their latest paper describes some of these findings.

"The motor neuron degeneration so reminiscent of ALS that was exhibited by the mice was so surprising that it was critical for us to confirm that VEGF also plays a role in human ALS patients," Carmeliet said. "Our latest study shows that VEGF levels are indeed reduced in ALS patients. We have also identified a genetic haplotype that lowers levels of VEGF expression, and which is more commonly found in ALS patients."

Further experiments confirmed the importance of VEGF in modifying the course of ALS. The researchers crossed their mutant mice that lacked VEGF with a mouse model for ALS. They were able to show that ALS mice with very low VEGF levels had much more severe motor neuron degeneration and died sooner than would have been expected.

Their next test involved inducing acute ischemia in the ALS mouse model that has very low VEGF levels. Clamping several major blood vessels for eight minutes normally causes only transient paralysis in wild-type mice, but all six of the ALS mice - which had low levels of VEGF - were severely paralyzed for three days, and did not recover.

So the group set out to discover whether giving VEGF to wild-type mice might salvage motor neurons that are at risk of irreversible damage. They therefore prolonged the clamping of the blood vessels to 12 minutes - a treatment that normally would lead to severe paralysis with only partial recovery after three days. When those mice were given daily intraperitoneal VEGF, however, they made a rapid and extensive recovery.

"It seems that if you don't have enough VEGF, then perfusion of neurons in the spinal cord is impaired and this leads to ischemia. In addition, VEGF has a direct neurotrophic effect on neurons. Without sufficient levels of VEGF, you don't have sufficient protection against ischemia, and since the motor neurons are very sensitive to that, they die," Carmeliet said.

He and his colleagues are now evaluating treatment with VEGF, either by direct delivery into the cerebrospinal fluid or via gene therapy with several genetically modified viral vectors, in the ALS mouse model. This is an established model for the chronic motor neuron degeneration seen in human ALS.

Carmeliet said VEGF may turn out to have roles in other neurodegenerative diseases that affect humans. He and his colleagues are looking for mutations in relevant genes in populations affected by, for example, Alzheimer's disease, multiple sclerosis and motor neuron disease. They already have crossed their VEGF mutant mice with mouse models of Alzheimer's disease, for example, to see what effect changes in VEGF expression have on the disease.