G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis

TY - JOUR

T1 - G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis

T2 - a pilot trial

AU - Duning, Thomas

AU - Schiffbauer, Hagen

AU - Warnecke, Tobias

AU - Mohammadi, Siawoosh

AU - Floel, Agnes

AU - Kolpatzik, Katja

AU - Kugel, Harald

AU - Schneider, Armin

AU - Knecht, Stefan

AU - Deppe, Michael

AU - Schäbitz, Wolf Rüdiger

PY - 2011/1/1

Y1 - 2011/1/1

N2 - BACKGROUND: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.METHODS: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 µg/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.RESULTS: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.CONCLUSIONS: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors.TRIAL REGISTRATION: ClinicalTrials.gov NCT00298597.

AB - BACKGROUND: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and -regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.METHODS: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 µg/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.RESULTS: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.CONCLUSIONS: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors.TRIAL REGISTRATION: ClinicalTrials.gov NCT00298597.

KW - Aged

KW - Amyotrophic Lateral Sclerosis

KW - Demography

KW - Diffusion Tensor Imaging

KW - Disease Progression

KW - Endpoint Determination

KW - Female

KW - Granulocyte Colony-Stimulating Factor

KW - Humans

KW - Male

KW - Middle Aged

KW - Neuropsychological Tests

KW - Pilot Projects

KW - Recombinant Proteins

U2 - 10.1371/journal.pone.0017770

DO - 10.1371/journal.pone.0017770

M3 - SCORING: Journal article

C2 - 21423758

VL - 6

SP - e17770

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 3

ER -