July 14, 2003
New data implicates abnormalities in VEGF gene as a risk factor for ALS
A new study by a group of European researchers has produced data that strongly implicates the VEGF gene as a risk factor in ALS. The study, in the current issue of Nature Genetics, reports that VEGF (vascular endothelial growth factor) may be a modifier gene associated with motor neuron degeneration. This finding could be significant for sporadic ALS, which accounts for 90 percent of ALS cases and for which a specific contributing factor has not been identified. However, it is not clear whether these variations themselves or other genetic contributors or other factors in combination with these variations are the important link to the disease. Further work needs to be done to establish this question.
Among the findings in the study: individuals carrying any one of three variations in the VEGF gene had a 1.8 times greater risk (than the general population) of developing ALS. Associated with these variations was a lower level of plasma VEGF.
"The finding that VEGF may be a risk factor for sporadic ALS is an extremely exciting one and may provide a potential new target for therapy. Important follow up studies are now underway," comments Dr. Lucie Bruijn, science director and vice president of The ALS Association (ALSA).
About the study
The European study, involving more than 30 investigators, was very thorough and included detailed follow-up to verify the validity of the associations with ALS. Some 1900 individuals in Sweden, Belgium and England were studied patients with familial ALS without the SOD1 mutation, sporadic ALS, along with healthy individuals of similar age, geography and ethnicity as control groups.
The investigators also generated these variations in a cell system and showed that introducing these variations resulted in low VEGF levels. Further evidence of the role of abnormal VEGF in ALS came from their mouse studies -- cross breeding mice with low levels of VEGF with SOD1G93A mutant mice. The disease progressed more rapidly in mice with mutant SOD1 and lower levels of VEGF than in mice with the mutant SOD1 gene alone. Individuals with ALS (those that the investigators were able to study in the Swedish population) had lower plasma levels of VEGF providing strong support for a possible involvement of VEGF in the disease. Again, the caution is that altered levels of VEGF and the variations in the gene may be associated with other more important gene changes. VEGF may be a modifier of ALS whose influence may depend on genetic background, the presence of additional modifiers, environment or lifestyle. This is highlighted by the fact that a subpopulation in England showed no association with these mutations.
It is important for other groups to replicate the data and to look for similar or other mutations in VEGF in the U.S. population, according to the researchers. Laboratory examinations of existing blood/tissue samples are now underway in the United States to determine whether a similar increased risk can be identified in the U.S. population
Researchers are using both mouse models and cell culture studies to identify the role of VEGF in motor neurons in Dr. Wim Robberechtıs current ALSA-funded study, performed in collaboration with Dr. Peter Carmelietıs research group. "Our results suggest that VEGF has direct trophic effects on motor neurons, but more studies are needed to establish the mechanism through which VEGF may form a risk factor to develop ALS," said Dr. Robberecht.
The serendipity of scientific research
VEGF is best known for its role in development and maintenance of the vascular system (blood vessels) and response to oxygen deficiency. Dr. Peter Carmeliet of Belgium was conducting studies associated with the vascular system. He engineered a mouse model such that it could not up-regulate (turn on or raise) VEGF levels during hypoxia. Quite unexpectedly, this mouse model showed motor neuron degeneration and became paralyzed. This was the first indication that VEGF might play an important role in motor neurons. Dr. Carmeliet turned to investigators involved in motor neuron degeneration research and the new study was launched.
"Our ongoing studies using additional transgenic and pharmacological models further underscore the role of VEGF in motor neuron degeneration," said Dr. Carmeliet. "We are therefore now intensively studying whether VEGF has any therapeutic potential to delay or slow down ALS in animal models, using various protein delivery, gene transfer and cellular transplantation methodologies, and expect to have conclusive answers very soon. Moreover, we are pursuing additional studies to better understand the molecular and cellular mechanisms whereby VEGF affects motor neuron survival in stressed conditions. Such insights should be helpful to design future therapeutic strategies."
Questions & Answers
1. Is there a test to see if I have abnormalities in the VEGF gene?
The European study suggests that VEGF abnormalities may be a risk factor. It is important for other researchers to replicate the data and to look for similar or other variations in the VEGF gene in the U.S. population. It is too soon to consider any testing until we can, at the very least, repeat the results. Also, as the study described above indicates, the variations in VEGF may be a risk factor -- variations in the VEGF gene may need to be in combination with other gene changes, or may be dependent on environment and lifestyle. The technique used in the research study is neither available nor indicated for ALS at this time.
2. Is VEGF available as a treatment?
No. VEGF is a protein that is rapidly degraded and present normally in the body (like BDNF and GDNF). Delivery is a challenge as it is for GDNF and IGF-1 so, it would likely be a good candidate for gene therapy, where it would be delivered with a viral vector. Also, we do not have enough evidence that VEGF levels alone are indeed a factor in ALS. Studies to confirm the European research teamıs findings are needed.
3. Since VEGF is best known for its role in the development of blood vessels and response to oxygen deficiency, does this mean blood supply to the nerves and low oxygen levels have a role in ALS?
It is not clear that there is any association with the blood supply to the nerves and low oxygen levels leading to ALS. VEGF may play a very different role in motor neurons. In fact, in the European study, there were no variations in the region of the gene that is responsive to oxygen levels. More research is needed to determine what role VEGF may have in ALS and what therapies might be developed.
