Nature Neuroscience
8, 85 - 92 (2004)
Published online: 28 November 2004; | doi:10.1038/nn1360
Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALSErik Storkebaum1, 5, Diether Lambrechts1, 5, Mieke Dewerchin1, Maria-Paz Moreno-Murciano1, Saskia Appelmans1, Hideyasu Oh1, Philip Van Damme2, Bart Rutten3, Wing Yan Man1, Maria De Mol1, Sabine Wyns1, David Manka1, Kristel Vermeulen1, Ludo Van Den Bosch2, Nico Mertens4, Christoph Schmitz3, Wim Robberecht2, Edward M Conway1, Désiré Collen1, Lieve Moons1
& Peter Carmeliet11
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KU Leuven, Leuven B-3000, Belgium. 2
Department of Neurology, Faculty of Medicine, KU Leuven, Leuven B-3000, Belgium. 3
Department of Psychiatry and Neuropsychology, Division of Cellular Neuroscience, Maastricht University, and European Graduate School of Neuroscience (EURON), Maastricht N-6200 MD, The Netherlands. 4
Department of Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology, University of Ghent, Ghent B-9052, Belgium. 5
These authors contributed equally to this work.
Correspondence should be addressed to Peter Carmeliet peter.carmeliet@med.kuleuven.ac.beNeurotrophin treatment has so far failed to prolong the survival of individuals affected with amyotrophic lateral sclerosis (ALS), an incurable motoneuron degenerative disorder. Here we show that intracerebroventricular (i.c.v.) delivery of recombinant vascular endothelial growth factor (Vegf) in a SOD1
G93A rat model of ALS delays onset of paralysis by 17 d, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery. By protecting cervical motoneurons, i.c.v. delivery of Vegf is particularly effective in rats with the most severe form of ALS with forelimb onset. Vegf has direct neuroprotective effects on motoneurons in vivo, because neuronal expression of a transgene expressing the Vegf receptor prolongs the survival of SOD1
G93A mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1
G93A rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.
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