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Heidelberg, Germany

Duning T.,University Hospital Muenster | Schiffbauer H.,University Hospital Muenster | Warnecke T.,University Hospital Muenster | Mohammadi S.,University Hospital Muenster | And 7 more authors.
PLoS ONE | Year: 2011

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. © 2011 Duning et al.


Conzelmann N.,SYGNIS Bioscience | Schneider A.,SYGNIS Bioscience
BMC Research Notes | Year: 2011

Background: Granulocyte-colony stimulating factor (G-CSF) is one of the most important pharmacologically used proteins. Potential uses beyond the stimulation of neutrophilic granulocytes are the treatment of CNS disorders. Disadvantages of the G-CSF protein as a drug are its moderate plasma half-life time and considerable production costs. We therefore conducted a screen for peptide agonists derived from the sequence of human G-CSF. Findings. Despite of the high sensitivity of our screening system we could not detect any positive hits in a single peptide approach. In a multiplex approach using a permutation of any combination of 10 different peptides we could also not detect a positive block. Conclusions: We conclude that larger coherent parts of the protein or dimerising peptides may be needed to achieve activation of the receptor. © 2011 Schneider et al; licensee BioMed Central Ltd.


Schneider A.,SYGNIS Bioscience | Huentelman M.J.,The Translational Genomics Research Institute | Kremerskothen J.,University of Munster | Duning K.,University of Munster | And 2 more authors.
Frontiers in Aging Neuroscience | Year: 2010

The genetic locus encoding KIBRA, a member of the WWC family of proteins, has recently been shown to be associated with human memory performance through genome-wide single nucleotide polymorphism screening. Gene expression analysis and a variety of functional studies have further indicated that such a role is biologically plausible for KIBRA. Here, we review the existing literature, illustrate connections between the different lines of evidence, and derive models based on KIBRA's function(s) in the brain that can be further tested experimentally. © 2010 Schneider, Huentelman, Kremerskothen, Duning, Spoelgen and Nikolich.


Seib D.R.M.,German Cancer Research Center | Corsini N.S.,German Cancer Research Center | Ellwanger K.,German Cancer Research Center | Plaas C.,SYGNIS Bioscience | And 5 more authors.
Cell Stem Cell | Year: 2013

Memory impairment has been associated with age-related decline in adult hippocampal neurogenesis. Although Notch, bone morphogenetic protein, and Wnt signaling pathways are known to regulate multiple aspects of adult neural stem cell function, the molecular basis of declining neurogenesis in the aging hippocampus remains unknown. Here, we show that expression of the Wnt antagonist Dickkopf-1 (Dkk1) increases with age and that its loss enhances neurogenesis in the hippocampus. Neural progenitors with inducible loss of Dkk1 increase their Wnt activity, which leads to enhanced self-renewal and increased generation of immature neurons. This Wnt-expanded progeny subsequently matures into glutamatergic granule neurons with increased dendritic complexity. As a result, mice deficient in Dkk1 exhibit enhanced spatial working memory and memory consolidation and also show improvements in affective behavior. Taken together, our findings show that upregulating Wnt signaling by reducing Dkk1 expression can counteract age-related decrease in neurogenesis and its associated cognitive decline. © 2013 Elsevier Inc.


Schabitz W.R.,University of Munster | Laage R.,SYGNIS Bioscience | Vogt G.,SYGNIS Bioscience | Koch W.,HaaPACS GmbH | And 11 more authors.
Stroke | Year: 2010

Background and Purpose: Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data. Methods: Four intravenous dose regimens (total cumulative doses of 30-180 μg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch. Results: Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions >14-17 cm. Conclusions: We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points. © 2010 American Heart Association, Inc.

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