Novosom AG

Halle (Saale), Germany

Novosom AG

Halle (Saale), Germany
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Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-IAPP-2008 | Award Amount: 960.99K | Year: 2009

The past year has been exciting for oligonucleotide-based drug discovery and development. The Nobel Prize was awarded to Mello and Fire for discovering RNA interference. There was also big investment from the Pharmaceutical industry to Biotechnology companies-pioneers in oligonucleotide therapeutics such as Sirna, Alnylam and Isis, all US-based. High expectations were therefore raised but further progress is hampered by the issue of systemic delivery; siRNA oligonucleotides are ineffective in vivo whereas antisense DNA oligonucleotides can be effective for liver-specific targets only. Therefore, delivery systems are a matter of intense investigation with the most recent advances being cationic liposomes with PEGylation or diffusible PEGylation. However, these carriers face tolerability issues, non-specific immune stimulation or limited biodistribution. Novosom has developed a completely novel carrier system based on amphoteric liposomes. This incorporates structural features with unique charge-reversal properties which result into safety and performance advantages over the current best alternative carriers. The aim of this Consortium is to built on Novosoms carrier technology to develop novel improved amphoteric liposomes with targeted delivery modalities to cells of the immune system, and to apply them for therapeutic oligonucleotide delivery to inflammatory diseases. Knowledge transfer between partners will facilitate the design of novel carriers, identification of targets and validation using in vivo models of inflammatory disease. The Consortium stems from two very successful one-to-one collaborations and proposes here a fully integrated program of translational, interdisciplinary research. Knowledge transfer between Novosom, a European leader in oligonucleotide delivery technologies, and two Academic Institutions of international standing in inflammatory disease therapeutics provides the competitiveness needed for a European team in this US-dominated field.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.4.2-1 | Award Amount: 15.32M | Year: 2008

The health of the EC population has never been better. However, serious public health problems remain, which cannot be ignored including high levels of premature death due to cardiovascular diseases. Thus, new preventive, diagnostic and therapeutic strategies against atherosclerotic cardiovascular diseases are needed. The atherosclerotic changes of the vascular wall are central in the development of cardiovascular complications. The traditional view that atherosclerosis is simply a lipid storage disease has recently been challenged by evidence that inflammation plays a central role in all stages of atherosclerosis. However, molecular mechanisms linking inflammation to atherosclerosis development are not fully understood, and this has severely hampered the advance of diagnostic and therapeutic programs. AtheroRemo aims to identify novel inflammatory mechanisms in vascular remodelling by combining the exploration of human biobanks with animal models and established cellular models. This new knowledge will be used to develop new preventive, diagnostic and therapeutic strategies against atherosclerotic cardiovascular disease. AtheroRemo contains several unique strengths: 1) Outstanding expertise on immunity and inflammation. Our expertise facilitates the breakthroughs in the immuno-inflammatory targeted vascular treatments. 2) Finest European cohorts to search for molecular mechanisms behind atherosclerosis development allowing us to combine underlying genetics with lipidomic profiles in multiple cohorts in order to obtain risk factors and biomarker panel related to inflammatory remodelling. 3) Accelerated target validation with novel liposomal-targeted delivery of nucleic acid-based therapeutics in appropriate animal models. Four SME partners able to exploit the new knowledge support AtheroRemo research. Thus, we expect to translate a number of novel findings into potential clinical applications such as new diagnostic tools (biomarkers) and therapeutics.


Frey O.,Universitatsklinikum Jena | Reichel A.,Universitatsklinikum Jena | Bonhagen K.,Universitatsklinikum Jena | Morawietz L.,Charité - Medical University of Berlin | And 2 more authors.
Annals of the Rheumatic Diseases | Year: 2010

Objectives: Glucose-6-phosphate isomerase (G6PI)-induced arthritis is a spontaneously remitting experimental arthritis model. It was hypothesised that regulatory T cells (Tregs) are involved in remission and their role in G6PI-induced arthritis was investigated. Methods: Tregs were depleted by injection of anti-CD25 before immunisation of DBA/1 mice with G6PI. The severity of arthritis was assessed clinically and histologically and the number and function of G6PI-specific T helper (Th) cells were determined by flow cytometry. Th cells and monocytes/macrophages were depleted using anti-CD4 or clodronate-containing liposomes. Results: Injection of anti-CD25 depleted Tregs transiently. Normal numbers of Tregs were restored 5 weeks after G6PI immunisation. Whereas arthritis started to resolve in control mice 3 weeks after immunisation with G6PI, severe arthritis was still present in the anti-CD25-treated mice 12 weeks after immunisation. The most striking ex vivo correlate of non-remitting arthritis was a strong increase in G6PI-specific Th cells 3 days after G6PI immunisation. This difference between treated and control mice declined at later time points. Depletion of CD4 cells ameliorated arthritis in controls but not in anti-CD25-treated mice. In contrast, clodronate-containing liposomes were an effective treatment in both groups. Conclusions: Tregs control the transition from acute self-limiting to non-remitting destructive G6PI-induced arthritis already in the preclinical disease stage. Once established, non-remitting destructive arthritis is not controlled by restoration of normal Treg numbers. These findings question the rationale of therapeutic approaches augmenting Treg number or function in established arthritis.


Klasczyk B.,Max Planck Institute of Colloids and Interfaces | Panzner S.,Novosom AG | Lipowsky R.,Max Planck Institute of Colloids and Interfaces | Knecht V.,Max Planck Institute of Colloids and Interfaces
Journal of Physical Chemistry B | Year: 2010

Cholesterol hemisuccinate (CHEMS) is a protonable lipid that is frequently used for the construction of pH-responsive delivery systems. Such systems have a stable, lamellar phase at pH 7, but can form a fusogenic, hexagonal phase at pH 5. This behavior can be explained by binding or release of counterions from the solvent and the related variations of the effective size of the polar lipid part. Here, we use MD simulations to study the ion recruitment to neutral or anionic bilayers of CHEMS in water. For deprotonated (anionic) CHEMS, we observed an almost complete decoration of the bilayer with sodium, potassium, or argininium cations, which challenges the previous hypothesis that the stability of bilayers from anionic CHEMS results from the electrostatic repulsion between the charged head groups. Protonated (neutral) bilayers of CHEMS did not bind sodium or potassium, but did adsorb argininium cations. Whereas the headgroup of protonated CHEMS is bent and strongly tilted away from the bilayer normal, the headgroup of the deprotonated CHEMS is found to become outstretched and significantly less tilted arising from the adsorption of the counterions. The tilt reduction is most pronounced upon adsorption of arginine which also leads to an increase in the otherwise constant area per lipid. In general, the cation binding to the deprotonated CHEMS acts to increase the effective headgroup volume. This change in the lipid shape may be one possible fact explaining the hexagonal-lamellar phase transitions for CHEMS known from experiments. © 2010 American Chemical Society.


Anderson R.,University Hospital Jena | Anderson R.,University of Barcelona | Franch A.,University of Barcelona | Castell M.,University of Barcelona | And 10 more authors.
Arthritis Research and Therapy | Year: 2010

Introduction: The objective of this study was to evaluate the efficacy of intravenous (i.v.) injection of liposomally encapsulated dexamethasone phosphate (DxM-P) in comparison to free DxM-P in rats with established adjuvant arthritis (AA). This study focused on polyethylene glycol (PEG)-free liposomes, to minimize known allergic reactions caused by neutral PEG-modified (PEG-ylated) liposomes.Methods: Efficacy was assessed clinically and histologically using standard scores. Non-specific and specific immune parameters were monitored. Activation of peritoneal macrophages was analyzed via cytokine profiling. Pharmacokinetics/biodistribution of DxM in plasma, synovial membrane, spleen and liver were assessed via mass spectrometry.Results: Liposomal DxM-P (3 × 1 mg/kg body weight; administered intravenously (i.v.) on Days 14, 15 and 16 of AA) suppressed established AA, including histological signs, erythrocyte sedimentation rate, white blood cell count, circulating anti-mycobacterial IgG, and production of interleukin-1beta (IL-1β) and IL-6 by peritoneal macrophages. The suppression was strong and long-lasting. The clinical effects of liposomal DxM-P were dose-dependent for dosages between 0.01 and 1.0 mg/kg. Single administration of 1 mg/kg liposomal DxM-P and 3 × 1 mg/kg of free DxM-P showed comparable effects consisting of a partial and transient suppression. Moreover, the effects of medium-dose liposomal DxM-P (3 × 0.1 mg/kg) were equal (in the short term) or superior (in the long term) to those of high-dose free DxM-P (3 × 1 mg/kg), suggesting a potential dose reduction by a factor between 3 and 10 by liposomal encapsulation. For at least 48 hours after the last injection, the liposomal drug achieved significantly higher levels in plasma, synovial membrane, spleen and liver than the free drug.Conclusions: This new PEG-free formulation of macrophage-targeting liposomal DxM-P considerably reduces the dose and/or frequency required to treat AA, with a potential to enhance or prolong therapeutic efficacy and limit side-effects also in the therapy of rheumatoid arthritis. Depot and/or recirculation effects in plasma, inflamed joint, liver, and spleen may contribute to this superiority of liposomally encapsulated DxM-P. © 2010 Anderson et al.; licensee BioMed Central Ltd.


Patent
ProNAi Therapeutics and Novosom AG | Date: 2014-12-12

The invention relates to compositions and methods to inhibit gene expression. In particular, the invention provides DNAi oligonucleotides sequestered by amphoteric liposomes for the treatment of cancer.


Patent
Novosom AG and ProNAi Therapeutics | Date: 2013-01-28

The invention relates to compositions and methods to inhibit gene expression. In particular, the invention provides DNAi oligonucleotides sequestered by amphoteric liposomes for the treatment of cancer.


Siepi E.,Novosom AG | Lutz S.,Novosom AG | Meyer S.,Fraunhofer Center For Silizium Photovoltaik | Panzner S.,Novosom AG
Biophysical Journal | Year: 2011

Here we identify the recruitment of solvent ions to lipid membranes as the dominant regulator of lipid phase behavior. Our data demonstrate that binding of counterions to charged lipids promotes the formation of lamellar membranes, whereas their absence can induce fusion. The mechanism applies to anionic and cationic liposomes, as well as the recently introduced amphoteric liposomes. In the latter, an additional pH-dependent lipid salt formation between anionic and cationic lipids must occur, as indicated by the depletion of membrane-bound ions in a zone around pH 5. Amphoteric liposomes fuse under these conditions but form lamellar structures at both lower and higher pH values. The integration of these observations into the classic lipid shape theory yielded a quantitative link between lipid and solvent composition and the physical state of the lipid assembly. The key parameter of the new model, κ(pH), describes the membrane phase behavior of charged membranes in response to their ion loading in a quantitative way. © 2011 by the Biophysical Society.


Patent
Novosom Ag | Date: 2010-08-09

Amphoteric liposomes are proposed, which comprise positive and negative membrane-based or membrane-forming charge carriers as well as the use of these liposomes.


Patent
novosom AG | Date: 2010-01-13

This invention provides pH-responsive zwitterionic nucleotides and nucleic acids comprising said nucleotides, wherein said zwitterions are constituted from one or more anionic internucleoside linkages and one or more cationic moieties and said zwitterionic nucleotides further comprise either one or more hydrophobic moieties or one or more TEEs with the general structure (I) Hydrophobic element - pH-responsive hydrophilic elements (I).

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