Protein Deficiency Linked to Lou Gehrig's Disease, MDA Researchers Find

Muscular Dystrophy Association
Sunday, 6 July 2003

A European study supported by the Muscular Dystrophy Association shows that genetic deficiencies of a growth factor protein increase the risk of developing the deadly neuromuscular disease amyotrophic lateral sclerosis, and that the same protein might be used to treat it.

ALS, also known as Lou Gehrig's disease, attacks muscle-controlling nerve cells in the spinal cord, typically leading to paralysis and death within three to five years of diagnosis. About 10 percent of ALS cases have a family history — with 2 percent caused by mutations in the SOD1 gene and 8 percent caused by mutations in unknown genes. The remaining 90 percent are sporadic, with no clear cause.

Analyzing some 2,000 people from Belgium, Sweden and the United Kingdom, a team of researchers led by MDA grantee Peter Carmeliet of the University of Leuven in Belgium found that certain variations in the gene for vascular endothelial growth factor (VEGF) almost double a person's risk of developing ALS.

The scientists also found that more cases of ALS are caused by the VEGF defect than by the SOD1 defect — 6 percent compared to 2 percent, said Carmeliet, adjunct director for the Center for Transgene Technology & Gene Therapy at the Flanders Interuniversity Institute for Biotechnology in Leuven.

The results were published online today by Nature Genetics.

Carmeliet, whose primary expertise is in cardiovascular research, began the study two years ago, after serendipitously finding that a subtle deletion in the VEGF gene, causing low VEGF levels, produced an ALS-like disease in mice. VEGF, which promotes the growth and permeability of blood vessels, is thought to protect the brain from low oxygen conditions (such as stroke), and might have direct effects on nerve cells.

Carmeliet scanned the VEGF gene of ALS patients for single nucleotide polymorphisms (SNPs) — single-letter changes in the DNA code that are usually harmless — and found three that stood out. All three appear to reduce the production of VEGF, and combinations of the SNPs causing the lowest VEGF levels were significantly more common in people with ALS.

"These results fit nicely with a long-held theory that a genetic predisposition sets people up for sporadic ALS, and then a ‘hit' from the environment provides the final trigger," MDA Director of Research Development Sharon Hesterlee said. "They also suggest that VEGF supplementation might be an effective treatment."

To further investigate the role of VEGF in ALS, Carmeliet bred mice carrying the VEGF gene deletion to SOD1 mutant mice. The double-mutant mice developed more severe ALS symptoms and died earlier than either parent strain.

A final experiment on normal mice probed VEGF's therapeutic potential against ALS. By clamping off blood vessels to the spinal cord during short periods, Carmeliet gave the mice a stroke that caused them to become paralyzed, but mice injected with the VEGF protein largely recovered from the procedure.

"These data provide hope that VEGF might also be used for ALS," he said. "We're currently assessing the therapeutic potential of VEGF in SOD1 mice and rats and expect to have final results in the very near future."

MDA is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services, and far-reaching professional and public health education. The Association's programs are funded almost entirely by individual private contributors.

For more information, or to contact Muscular Dystrophy Association, see their website at: www.mdausa.org