Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive lossof motoneurons, motor weakness and death within 1^5 years after disease onset. Therapeutic options remainlimited despite a substantial number of approaches that have been tested clinically. In particular, various neuro-trophic factors have been investigated. Failure in these trials has been largely ascribed to problems of insufficientdosing or inability to cross the blood^brain barrier (BBB).We have recently uncovered the neurotrophic propertiesof the haematopoietic protein granulocyte-colony stimulating factor (G-CSF).The protein is clinically well toler-atedandcrossestheintact BBB.Thisstudyexaminedthepotentialrole of G-CSFinmotoneurondiseases.Weinves-tigated the expression of the G-CSF receptor in motoneurons and studied effects of G-CSF in a motoneuron cellline and in the SOD1(G93A) transgenic mouse model.The neurotrophic growth factor was applied both by contin-uous subcutaneous delivery and CNS-targeted transgenic overexpression.This study shows that given at the stageof the disease where muscle denervation is already evident,G-CSF leads to significant improvement in motor per-formance, delays the onset of severe motor impairment and prolongs overall survivalof SOD1(G93A)tg mice.TheG-CSF receptoris expressedby motoneurons and G-CSF protects culturedmotoneuronalcells from apoptosis.InALS mice, G-CSF increased survival of motoneurons and decreased muscular denervation atrophy. Weconclude that G-CSF is a novel neurotrophic factor for motoneurons that is an attractive and feasible drug candi-date for the treatment of ALS.