title: Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS.
abstract: 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.
authors.affiliation: The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KU Leuven, Leuven B-3000, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Storkebaum
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Moreno-Murciano
authors.forename: Saskia
authors.initials: S
authors.lastname: Appelmans
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Oh
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Bart
authors.initials: B
authors.lastname: Rutten
authors.forename: Wing Yan
authors.initials: WY
authors.lastname: Man
authors.forename: Maria
authors.initials: M
authors.lastname: De Mol
authors.forename: Sabine
authors.initials: S
authors.lastname: Wyns
authors.forename: David
authors.initials: D
authors.lastname: Manka
authors.forename: Kristel
authors.initials: K
authors.lastname: Vermeulen
authors.forename: Ludo
authors.initials: L
authors.lastname: Van Den Bosch
authors.forename: Nico
authors.initials: N
authors.lastname: Mertens
authors.forename: Christoph
authors.initials: C
authors.lastname: Schmitz
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D001370:Axonal Transport; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007276:Injections, Intraventricular; D009046:Motor Neurons / Q000187:drug effects*; D009410:Nerve Degeneration / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase