Granulocyte-colony stimulating factor improves outcome in a mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive loss of motoneurons, motor weakness and death within 1-5 years after disease onset. Therapeutic options remain limited despite a substantial number of approaches that have been tested clinically. In particular, various neurotrophic factors have been investigated. Failure in these trials has been largely ascribed to problems of insufficient dosing or inability to cross the blood-brain barrier (BBB). We have recently uncovered the neurotrophic properties of the haematopoietic protein granulocyte-colony stimulating factor (G-CSF). The protein is clinically well tolerated and crosses the intact BBB. This study examined the potential role of G-CSF in motoneuron diseases. We investigated the expression of the G-CSF receptor in motoneurons and studied effects of G-CSF in a motoneuron cell line and in the SOD1(G93A) transgenic mouse model. The neurotrophic growth factor was applied both by continuous subcutaneous delivery and CNS-targeted transgenic overexpression. This study shows that given at the stage of the disease where muscle denervation is already evident, G-CSF leads to significant improvement in motor performance, delays the onset of severe motor impairment and prolongs overall survival of SOD1(G93A)tg mice. The G-CSF receptor is expressed by motoneurons and G-CSF protects cultured motoneuronal cells from apoptosis. In ALS mice, G-CSF increased survival of motoneurons and decreased muscular denervation atrophy. We conclude that G-CSF is a novel neurotrophic factor for motoneurons that is an attractive and feasible drug candidate for the treatment of ALS.
Sygnis Bioscience, Heidelberg, Germany.
Claudia
C
Pitzer
Carola
C
Krüger
Christian
C
Plaas
Friederike
F
Kirsch
Tanjew
T
Dittgen
Ralph
R
Müller
Rico
R
Laage
Stefan
S
Kastner
Stefanie
S
Suess
Robert
R
Spoelgen
Alexandre
A
Henriques
Hannelore
H
Ehrenreich
Wolf-Rüdiger
WR
Schäbitz
Alfred
A
Bach
Armin
A
Schneider
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D055104:Infusions, Subcutaneous; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016896:Treatment Outcome
D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; C000606290:SOD1 protein, human; D016179:Granulocyte Colony-Stimulating Factor; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000069585:Filgrastim