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G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

Duning, T; Schiffbauer, H; Warnecke, T; Mohammadi, S; Floel, A; Kolpatzik, K; Kugel, H; ... Schabitz, WR; + view all (2011) G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial. PLOS ONE , 6 (3) , Article e17770. 10.1371/journal.pone.0017770. Green open access

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Abstract

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 mu g/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.

Type: Article
Title: G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0017770
Publisher version: http://dx.doi.org/10.1371/journal.pone.0017770
Language: English
Additional information: © 2011 Duning et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This investigator-initiated trial was supported by institutional grants (for the randomized filling of G-CSF by the pharmacy of the University of Mainz, Germany) from SYGNIS Bioscience, Heidelberg, Germany. One of the authors (Armin Schneider) is employed by SYGNIS Bioscience, who was involved in the organization of the research project and critical review of the manuscript, and G-CSF was provided by SYGNIS Bioscience. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Armin Schneider is an employee of SYGNIS Bioscience and is an inventor on a patent application claiming the use of G-CSF for the treatment of diseases of the central nervous system. Patent Cooperation Treaty WO04058287, Patent Number: 274597, is licensed to the treatment of amyotrophic lateral sclerosis with G-CSF. All other authors reported no financial disclosure and no conflicts of interest. The mentioned conflicts had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript and this does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Keywords: COLONY-STIMULATING FACTOR, DIFFUSION TENSOR MRI, ALZHEIMERS-DISEASE, COGNITIVE DECLINE, WHOLE-BRAIN, SENSITIVITY, INVOLVEMENT, IMPAIRMENT, ALS
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1301531
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