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 SOD1G93A 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 SOD1G93A mice. On i.c.v. delivery, Vegf is anterogradely transported and preserves neuromuscular junctions in SOD1G93A rats. Our findings in preclinical rodent models of ALS may have implications for treatment of neurodegenerative disease in general.
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We thank Y. Laroche for advice and A. Bouche, P. Chevron, S. Plaisance, E. Demarsin, D. Dejaegere, B. Hermans, S. Jansen, L. Kieckens, A. Manderveld, K. Maris, S. Meynen, M. Nijs, S. Terclavers, M. Vandewalle and B. Vanwetswinkel for their contribution. E.S. and D.L. are sponsored by the Fund for Scientific Research-Flanders (FWO). This work is supported, in part, by grants from the Muscular Dystrophy Association (3751), the FWO (G.0113.02), the European Union (QLK6-CT-2000-0053) and the Concerted Research Activities, Belgium (GOA2001/09), and by an unrestricted grant from Bristol-Myers-Squibb.
P.C. and D.C. are named as inventors on a patent application regarding the use of VEGF to treat amyotrophic lateral sclerosis. The Flanders Interuniversity Institute for Biotechnology (VIB) is one of the joint owners of this patent application, and the said patent application has been licensed to an outside company. Neither VIB nor any of the authors have equity stakes in the company. However, VIB and some of the authors stand to eventually receive royalties.
Effect of ICV delivery of Vegf on exploring activity, righting activity and grip strength in ALS rat models. (GIF 24 kb)
Effect of ICV delivery of Vegf on body weight loss, disease onset, motor performance and survival in SOD1G93A/HWr rats. (GIF 41 kb)
Axonal transport of VEGF. (JPG 57 kb)
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Storkebaum, E., Lambrechts, D., Dewerchin, M. et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 8, 85–92 (2005). https://doi.org/10.1038/nn1360
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