Title |
Characterization of Novel PI3Kδ Inhibitors as Potential Therapeutics for SLE and Lupus Nephritis in Pre-Clinical Studies
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Published in |
Frontiers in immunology, May 2014
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DOI | 10.3389/fimmu.2014.00233 |
Pubmed ID | |
Authors |
Philipp Haselmayer, Montserrat Camps, Mathilde Muzerelle, Samer El Bawab, Caroline Waltzinger, Lisa Bruns, Nada Abla, Mark A. Polokoff, Carole Jond-Necand, Marilène Gaudet, Audrey Benoit, Dominique Bertschy Meier, Catherine Martin, Denise Gretener, Maria Stella Lombardi, Roland Grenningloh, Christoph Ladel, Jørgen Søberg Petersen, Pascale Gaillard, Hong Ji |
Abstract |
SLE is a complex autoimmune inflammatory disease characterized by pathogenic autoantibody production as a consequence of uncontrolled T-B cell activity and immune-complex deposition in various organs, including kidney, leading to tissue damage and function loss. There is a high unmet need for better treatment options other than corticosteroids and immunosuppressants. Phosphoinositol-3 kinase δ (PI3Kδ) is a promising target in this respect as it is essential in mediating B- and T-cell function in mouse and human. We report the identification of selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities in human peripheral blood and in primary cell co-cultures (BioMAP(®)) without detecting signs of undesired toxicity. In an IFNα-accelerated mouse SLE model, our PI3Kδ inhibitors blocked nephritis development, whether administered at the onset of autoantibody appearance or the onset of proteinuria. Disease amelioration correlated with normalized immune cell numbers in the spleen, reduced immune-complex deposition as well as reduced inflammation, fibrosis, and tissue damage in the kidney. Improvements were similar to those achieved with a frequently prescribed drug for lupus nephritis, the potent immunosuppressant mycophenolate mofetil. Finally, we established a pharmacodynamics/pharmacokinetic/efficacy model that revealed that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in our disease model. These data demonstrate the therapeutic potential of PI3Kδ inhibitors in SLE and lupus nephritis. |
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United Kingdom | 2 | 50% |
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Demographic breakdown
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Members of the public | 2 | 50% |
Scientists | 1 | 25% |
Science communicators (journalists, bloggers, editors) | 1 | 25% |
Mendeley readers
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Mexico | 1 | 2% |
Unknown | 40 | 98% |
Demographic breakdown
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Researcher | 16 | 39% |
Other | 5 | 12% |
Student > Master | 4 | 10% |
Student > Ph. D. Student | 3 | 7% |
Unspecified | 1 | 2% |
Other | 2 | 5% |
Unknown | 10 | 24% |
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Other | 4 | 10% |
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