Anna Schubart
Novartis
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Publication
Featured researches published by Anna Schubart.
Journal of the Neurological Sciences | 2008
Veronique E. Miron; Anna Schubart; Jack P. Antel
FTY720, also known as fingolimod, is an orally administered sphingosine-1-phosphate (S1P) analogue that is under investigation as a therapy for both relapsing-remitting (RR) and progressive forms of multiple sclerosis (MS). The demonstrated beneficial effect of FTY720 on disease activity in RR-MS patients and in the animal model experimental autoimmune encephalomyelitis (EAE) is largely attributed to effects on the systemic immune system. In addition, unlike other current systemic immuno-modulators used in MS, the lipophilic nature of FTY720 allows it to cross the blood-brain barrier (BBB). Since S1P receptors are expressed on all cell types, FTY720 has the potential to exert effects directly on the BBB and on resident cells of the CNS. The latter include cells implicated in regulating immune reactivity within the CNS (astrocytes, microglia), those that are targeted by the disease process (oligodendrocytes, neurons), and those involved in repair (oligodendrocyte progenitor cells). In vitro studies document the dose-dependent effects of FTY720 on neural cell survival, differentiation, and cytoskeletal dynamics. Animal model studies, specifically EAE, indicate an overall neuroprotective effect of FTY720 mediated at least in part by its actions within the CNS. Ongoing studies will need to define the direct and indirect (via immune-modulation) effects of FTY720 on the CNS across the broad clinical spectrum of MS.
Journal of Medicinal Chemistry | 2014
Sven Weiler; Nadine Braendlin; Christian Beerli; Christian Bergsdorf; Anna Schubart; Honnappa Srinivas; Berndt Oberhauser; Andreas Billich
Sphingosine 1-phosphate (S1P) lyase has recently been implicated as a therapeutic target for the treatment of multiple sclerosis (MS), based on studies in a genetic mouse model. Potent active site directed inhibitors of the enzyme are not known so far. Here we describe the discovery of (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitrile 5 in a high-throughput screen using a biochemical assay, and its further optimization. This class of compounds was found to inhibit catalytic activity of S1PL by binding to the active site of the enzyme, as seen in the cocrystal structure of derivative 31 with the homodimeric human S1P lyase. 31 induces profound reduction of peripheral T cell numbers after oral dosage and confers pronounced protection in a rat model of multiple sclerosis. In conclusion, this novel class of direct S1P lyase inhibitors provides excellent tools to further explore the therapeutic potential of T cell-targeted therapies in multiple sclerosis and other autoimmune and inflammatory diseases.
Journal of Neuroinflammation | 2016
Catherine O’Sullivan; Anna Schubart; Anis Khusro Mir; Kumlesh K. Dev
BackgroundBAF312 (Siponimod) is a dual agonist at the sphingosine-1 phosphate receptors, S1PR1 and S1PR5. This drug is currently undergoing clinical trials for the treatment of secondary progressive multiple sclerosis (MS). Here, we investigated the effects of BAF312 on isolated astrocyte and microglia cultures as well as in slice culture models of demyelination.MethodsMouse and human astrocytes were treated with S1PR modulators and changes in the levels of pERK, pAkt, and calcium signalling as well as S1PR1 internalization and cytokine levels was investigated using Western blotting, immunochemistry, ELISA and confocal microscopy. Organotypic slice cultures were prepared from the cerebellum of 10-day-old mice and treated with lysophosphatidylcholine (LPC), psychosine and/or S1PR modulators, and changes in myelination states were measured by fluorescence of myelin basic protein and neurofilament H.ResultsBAF312 treatment of human and mouse astrocytes activated pERK, pAKT and Ca2+ signalling as well as inducing S1PR1 internalization. Notably, activation of S1PR1 increased pERK and pAKT in mouse astrocytes while both S1PR1 and S1PR3 equally increased pERK and pAKT in human astrocytes, suggesting that the coupling of S1PR1 and S1PR3 to pERK and pAKT differ in mouse and human astrocytes. We also observed that BAF312 moderately attenuated lipopolysaccharide (LPS)- or TNFα/IL17-induced levels of IL6 in both astrocyte and microglia cell cultures. In organotypic slice cultures, BAF312 reduced LPC-induced levels of IL6 and attenuated LPC-mediated demyelination. We have shown previously that the toxic lipid metabolite psychosine induces demyelination in organotypic slice cultures, without altering the levels of cytokines, such as IL6. Importantly, psychosine-induced demyelination was also attenuated by BAF312.ConclusionsOverall, this study suggests that BAF312 can modulate glial cell function and attenuate demyelination, highlighting this drug as a further potential therapy in demyelinating disorders, beyond MS.
Toxicologic Pathology | 2015
Jens Schümann; Armelle Grevot; David Ledieu; Armin Wolf; Anna Schubart; Alessandro Piaia; Esther Sutter; Serge Côté; Christian Beerli; Francois Pognan; Andreas Billich; Pierre Moulin; Ursula Junker Walker
Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity of the enzyme in animal models of inflammation. Since S1P lyase deficiency in mice causes a severe, lethal phenotype, it was of interest to investigate any pathological alterations associated with only partially reduced activity of S1P lyase as may be encountered upon pharmacological inhibition. Both genetic reduction of S1P lyase activity in mice and inhibition of S1P lyase with a low-molecular-weight compound in rats consistently resulted in podocyte-based kidney toxicity, which is the most severe finding. In addition, skin irritation and platelet activation were observed in both instances. The similarity of the findings in both the genetic model and the pharmacological study supports the value of analyzing inducible partially target-deficient mice for safety assessment. If the findings described in rodents translate to humans, target-related toxicity, particularly podocyte dysfunction, may limit chronic systemic treatment of autoimmune diseases with S1P lyase inhibitors. Furthermore, partial deficiency or inhibition of S1P lyase appears to provide an in vivo rodent model to enable studies on the mechanism of podocyte dysfunction.
Journal of Neuroinflammation | 2016
Antonietta Gentile; Alessandra Musella; Silvia Bullitta; Diego Fresegna; Francesca De Vito; Roberta Fantozzi; Eleonora Piras; Francesca Gargano; Giovanna Borsellino; Luca Battistini; Anna Schubart; Georgia Mandolesi; Diego Centonze
Archive | 2008
Yves-Alain Barde; Graeme Bilbe; Ruben Deogracias; Rainer Kuhn; Tomoya Matsumoto; Anis Khusro Mir; Anna Schubart
Neurology | 2016
Antonietta Gentile; Alessandra Musella; Silvia Bullitta; Diego Fresegna; Francesca De Vito; Eleonora Piras; Francesca Gargano; Giovanna Borsellino; Luca Battistini; Georgia Mandolesi; Anna Schubart; Diego Centonze
Neurology | 2018
Anna Schubart; Gaelle Elain; Cindy Schmid; Julien Perdoux; Catherine Huck; David Leppert; Anis Khusro Mir; Gisbert Weckbecker
Molecular Immunology | 2018
Anna Schubart; Sarah Gonschorek; Joerg Eder
Neurology | 2016
Seema K. Tiwari-Woodruff; Hana Yamate-Morgan; Maria Sekyi; Kelli Lauderdale; Jonathan Hasselmann; Anna Schubart