Direct Brain Delivery of Trophic Factor Prolongs Survival in Rat Model of ALS
January 10, 2005
[QUICK SUMMARY: VEGF given directly into the brain provided a striking increase in survival in mutant SOD1 rats, researchers report.]
Belgian researchers published in the January issue of Nature Neuroscience that direct delivery of the trophic factor, vascular endothelial growth factor (VEGF), increased survival in a rat model of amyotrophic lateral sclerosis (ALS).
Led by Peter Carmeliet M.D., Ph.D., the team of investigators showed that infusion of VEGF into the fluid surrounding the brain and spinal cord of the brain can rescue neurons and extend survival in mutant SOD1 rats (click here for more information). Carmeliet’s team was working on the vascular properties of VEGF when they noticed that a mouse with blunted expression of the VEGF gene develops some features similar to ALS.
“Only three years have elapsed since the serendipitous discovery, yet VEGF is poised as a clinical candidate in ALS research,” commented the science director and vice president for The ALS Association (ALSA), Lucie Bruijn, Ph.D.
Many different trophic factors can prolong survival in models of the disease, but clinical trials in ALS patients have so far failed to replicate the animal findings. Researchers speculate that the agents have trouble reaching the crucial target tissues, namely, the spinal cord and brain. To clarify the issue, the Belgian investigators administered VEGF directly into the ventricles, the fluid filled space inside the brain.
They found that ventricular delivery of VEGF delayed the onset of paralysis by 17 days in the ALS rats. The treatment also improved motor performance and prolonged survival by 22 days. The effect, the investigators write, represents “the largest effects in animal models of ALS achieved by protein delivery.”
Peter Carmeliet and colleagues wrote that the direct delivery to the brain seemed to be particularly effective in rats at protecting cervical motor neurons. This was due to the fact that higher levels of VEGF were present in the cervical than in the lumbar spinal cord after delivery of VEGF into the brain.
Delivery of the trophic factor inside the spaces of the brain produced effects in the cell bodies of distant neurons, supporting the notion that VEGF is taken up by nerve endings and transported back along the axons to the cell bodies. The trophic factor also preserved neuromuscular junctions in the SOD1 (G93A) mutant rats.
“Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general,” the researchers concluded. Discussions are underway to develop VEGF as an ALS therapeutic, to be delivered by a gene therapy approach. For additional information click here.
