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, Carmeliet Peter
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology (VIB), KU Leuven, Leuven B-3000, Belgium.
Nat Neurosci. 2005 Jan;8(1):85-92. doi: 10.1038/nn1360. Epub 2004 Nov 28.
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.
迄今为止,神经营养因子治疗未能延长肌萎缩侧索硬化症(ALS)患者的生存期,ALS是一种无法治愈的运动神经元退行性疾病。在此我们表明,在ALS的SOD1(G93A)大鼠模型中,经脑室内(i.c.v.)递送重组血管内皮生长因子(Vegf)可将瘫痪发作延迟17天,改善运动能力,并将生存期延长22天,这是通过蛋白质递送在ALS动物模型中取得的最大效果。通过保护颈段运动神经元,i.c.v.递送Vegf对最严重形式的前肢起病的ALS大鼠特别有效。Vegf在体内对运动神经元具有直接的神经保护作用,因为表达Vegf受体的转基因的神经元表达可延长SOD1(G93A)小鼠的生存期。经i.c.v.递送后,Vegf可被顺行运输,并保留SOD1(G93A)大鼠的神经肌肉接头。我们在ALS临床前啮齿动物模型中的发现可能对一般神经退行性疾病的治疗具有启示意义。