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Brain Advance Access originally published online on October 3, 2008
Brain 2008 131(12):3335-3347; doi:10.1093/brain/awn243
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Claudia Pitzer1, Carola Krüger1, Christian Plaas1, Friederike Kirsch1, Tanjew Dittgen1, Ralph Müller1, Rico Laage1, Stefan Kastner1, Stefanie Suess1, Robert Spoelgen1, Alexandre Henriques1, Hannelore Ehrenreich2, Wolf-Rüdiger Schäbitz3, Alfred Bach1 and Armin Schneider1

1Sygnis Bioscience, Heidelberg, 2Max-Planck Institute of Experimental Medicine, Göttingen and 3Department of Neurology, University of Münster, Münster, Germany

Correspondence to: Dr Armin Schneider, Sygnis Bioscience, Im Neuenheimer Feld 515, 69120 Heidelberg, Germany E-mail: schneider{at}sygnis.de

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.

Key Words: ALS; growth factor; drug candidate; functional outcome; motoneuron survival

Abbreviations: ALS, amyotrophic lateral sclerosis; BBB, blood–brain barrier; CHAT, choline acetyltransferase; G-CSF, granulocyte-colony stimulating factor; SOD1, superoxide dismutase 1

Received March 18, 2008. Revised July 17, 2008. Accepted September 8, 2008.


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