Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS

• Published in: Nature neuroscience Vol. 8; no. 1; pp. 85 - 92
• Main Authors: Carmeliet, Peter, Storkebaum, Erik, Lambrechts, Diether, Dewerchin, Mieke, Moreno-Murciano, Maria-Paz, Appelmans, Saskia, Oh, Hideyasu, Van Damme, Philip, Rutten, Bart, Man, Wing Yan, De Mol, Maria, Wyns, Sabine, Manka, David, Vermeulen, Kristel, Van Den Bosch, Ludo, Mertens, Nico, Schmitz, Christoph, Robberecht, Wim, Conway, Edward M, Collen, Désiré, Moons, Lieve
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.01.2005
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Axonal Transport; Cell Survival - drug effects; Diagnosis; Disease Models, Animal; Humans; Injections, Intraventricular; Motor neurons; Motor Neurons - drug effects; Nerve Degeneration - physiopathology; Neuromuscular Junction - drug effects; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - pharmacology; Physiological aspects; Rats; Rats, Sprague-Dawley; Rats, Wistar; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Risk factors; Superoxide Dismutase - genetics; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - administration & dosage; Vascular Endothelial Growth Factor A - pharmacokinetics; Vascular Endothelial Growth Factor A - pharmacology; Belgium
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn1360

Neurotrophin 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.