title: CNS-targeted viral delivery of G-CSF in an animal model for ALS: improved efficacy and preservation of the neuromuscular unit.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons. We have recently uncovered a new neurotrophic growth factor, granulocyte-colony stimulating factor (G-CSF), which protects α-motoneurons, improves functional outcome, and increases life expectancy of SOD-1 (G93A) mice when delivered subcutaneously. However, chronic systemic delivery of G-CSF is complicated by elevation of neutrophilic granulocytes. Here, we used adeno-associated virus (AAV) to directly target and confine G-CSF expression to the spinal cord. Whereas intramuscular injection of AAV failed to transduce motoneurons retrogradely, and caused a high systemic load of G-CSF, intraspinal delivery led to a highly specific enrichment of G-CSF in the spinal cord with moderate peripheral effects. Intraspinal delivery improved motor functions, delayed disease progression, and increased survival by 10%, longer than after systemic delivery. Mechanistically, we could show that G-CSF in addition to rescuing motoneurons improved neuromuscular junction (NMJ) integrity and enhanced motor axon regeneration after nerve crush injury. Collectively, our results show that intraspinal delivery improves efficacy of G-CSF treatment in an ALS mouse model while minimizing the systemic load of G-CSF, suggesting a new therapeutic option for ALS treatment.
authors.affiliation: Department of Molecular Neurology, SYGNIS Bioscience, Heidelberg, Germany.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Henriques
authors.forename: Claudia
authors.initials: C
authors.lastname: Pitzer
authors.forename: Tanjew
authors.initials: T
authors.lastname: Dittgen
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Luc
authors.initials: L
authors.lastname: Dupuis
authors.forename: Armin
authors.initials: A
authors.lastname: Schneider
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000628:therapy*; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D007278:Injections, Spinal; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries
chemical_list: D016179:Granulocyte Colony-Stimulating Factor