SYGNIS Bioscience

Heidelberg, Germany

SYGNIS Bioscience

Heidelberg, Germany
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Henriques A.,SYGNIS Bioscience | Henriques A.,French Institute of Health and Medical Research | Henriques A.,University of Strasbourg | Pitzer C.,SYGNIS Bioscience | And 5 more authors.
Molecular Therapy | Year: 2011

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons. We have recently uncovered a new neurotrophic growth factor, granulocyte-colony stimulating factor (G-CSF), which protects α-motoneurons, improves functional outcome, and increases life expectancy of SOD-1 (G93A) mice when delivered subcutaneously. However, chronic systemic delivery of G-CSF is complicated by elevation of neutrophilic granulocytes. Here, we used adeno-associated virus (AAV) to directly target and confine G-CSF expression to the spinal cord. Whereas intramuscular injection of AAV failed to transduce motoneurons retrogradely, and caused a high systemic load of G-CSF, intraspinal delivery led to a highly specific enrichment of G-CSF in the spinal cord with moderate peripheral effects. Intraspinal delivery improved motor functions, delayed disease progression, and increased survival by 10%, longer than after systemic delivery. Mechanistically, we could show that G-CSF in addition to rescuing motoneurons improved neuromuscular junction (NMJ) integrity and enhanced motor axon regeneration after nerve crush injury. Collectively, our results show that intraspinal delivery improves efficacy of G-CSF treatment in an ALS mouse model while minimizing the systemic load of G-CSF, suggesting a new therapeutic option for ALS treatment. © The American Society of Gene & Cell Therapy.

Henriques A.,SYGNIS Bioscience | Henriques A.,French Institute of Health and Medical Research | Henriques A.,University of Strasbourg | Pitzer C.,SYGNIS Bioscience | Schneider A.,SYGNIS Bioscience
PLoS ONE | Year: 2010

Amyotrophic Lateral Sclerosis (ALS) is a fatal motoneuron disease, characterized by progressive weakness, muscle wasting and death ensuing 3-5 years after diagnosis. The etiology of ALS is complex and therapeutic approaches rely mostly on transgenic animal models with SOD-1 mutations. Most frequently employed is a mouse line transgenic for SOD-1 (SOD-1 Tg) that contains a point mutation at amino acid position 93 (G-.A), present in patients suffering from a familial form of amyotrophic lateral sclerosis. Here we report on a SOD-1 (G93A) Tg mouse line with abnormally delayed onset of disease and prolonged survival. This phenotype arose spontaneously in our colony of the classic SOD-1 (G93A) line. We found that the copy number of the SOD-1 transgene was drastically decreased. We established a new breeding colony, the SOD-1 (G93A)PS line (PS for prolonged survival) where the phenotype is stably inherited for 4 generations now. The mice develop symptoms at an age of approximately 12 months and die at 15 months of age. The delayed development of disease may more closely mimic human pathophysiology, and studying drug effects in this model may yield added confidence for potential efficacy of ALS drug candidates. © 2010 Henriques et al.

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; 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.

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.

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: NCT00298597. © 2011 Duning et al.

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.

Spoelgen R.,Sygnis Bioscience | Meyer A.,Sygnis Bioscience | Moraru A.,Sygnis Bioscience | Kirsch F.,Sygnis Bioscience | And 4 more authors.
Journal of Neurochemistry | Year: 2011

The stimulation of neurogenesis is an exciting novel therapeutic option for diseases of the central nervous system, ranging from depression to neurodegeneration. One major bottleneck in screening approaches for neurogenesis-inducing compounds is the very demanding in vivo quantification of newborn neurons based on stereological techniques. To effectively develop compounds in this area, novel fast and reliable techniques for quantification of in vivo neurogenesis are needed. In this study, we introduce a flow cytometry-based method for quantifying newly generated neurons in the brain based on the counting of cell nuclei from dissected brain regions. Important steps involve density sedimentation of the cell nuclei, and staining for the proliferation marker bromodeoxy uridine and nuclear cell type markers such as NeuN. We demonstrate the ability of the technique to detect increased neurogenesis in the hippocampus of animals which underwent physical exercise and received fluoxetine treatment. © 2011 International Society for Neurochemistry.

Dittgen T.,SYGNIS Bioscience | Pitzer C.,SYGNIS Bioscience | Plaas C.,SYGNIS Bioscience | Kirsch F.,SYGNIS Bioscience | And 3 more authors.
PLoS ONE | Year: 2012

Granulocyte-colony stimulating factor (G-CSF) improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. Previously we have employed the mouse hemisection SCI model and studied motor function after subcutaneous or transgenic delivery of the protein. To further broaden confidence in animal efficacy data we sought to determine efficacy in a different model and a different species. Here we investigated the effects of G-CSF in Wistar rats using the New York University Impactor. In this model, corroborating our previous data, rats treated subcutaneously with G-CSF over 2 weeks show significant improvement of motor function. © 2012 Dittgen 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.

Vogt G.,SYGNIS Bioscience | Laage R.,SYGNIS Bioscience | Shuaib A.,University of Alberta | Schneider A.,SYGNIS Bioscience
Stroke | Year: 2012

Background and Purpose-Age and National Institutes of Health Stroke Scale early after stroke onset have been identified as important determinants of final stroke outcome. We analyzed the Virtual International Stroke Trials Archive (VISTA) database to define the influence of infarct or hemorrhagic volume on clinical outcome after stroke. Methods-All patients were extracted from VISTA where infarct or hemorrhage volume information was available (n=2538; most images obtained by CT within 72 hours after stroke onset with a subset of MRI data included, volumes calculated by the ABC/2 approximation method). We used multivariate regression models to study the influence of age, National Institutes of Health Stroke Scale at baseline, and initial infarct/hemorrhage volume on clinical outcome (modified Rankin Scale, National Institutes of Health Stroke Scale, mortality) at day 90. Results-We find that in a large cohort of >1800 patients with ischemic stroke, initial lesion size is a strong and independent predictor of stroke outcome in a statistical regression model that also accounts for age and National Institutes of Health Stroke Scale at baseline (P<0.0001). The use of infarct/hemorrhage volume as an additional predictive factor further reduces the fraction of unexplained variance in outcome by approximately 15% (R of 0.41 versus 0.26 in a model without lesion volume). The predictive strength of initial lesion size is only marginally influenced by image modality or time point of image acquisition within the first 72 hours. The model was equally valid for both ischemic and hemorrhagic strokes. Conclusions-Infarct/hemorrhage volume at baseline together with age and National Institutes of Health Stroke Scale at baseline should be used in the effect analysis of future therapeutic stroke trials to improve power. © 2012 American Heart Association, Inc.

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