Quantitative Systems Pharmacology Model for Alzheimer Disease Indicates Targeting Sphingolipid Dysregulation as Potential Treatment Option
Alzheimer disease (AD) is a devastating neurodegenerative disorder with high unmet medical need. Drug development is hampered by limited understanding of the disease and its driving factors. Quantitative Systems Pharmacology (QSP) modeling provides a comprehensive quantitative framework to evaluate...
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| Veröffentlicht in: | CPT: pharmacometrics and systems pharmacology 2018-11, Vol.7 (11), p.759-770 |
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| container_title | CPT: pharmacometrics and systems pharmacology |
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| creator | Clausznitzer, Diana Pichardo‐Almarza, Cesar Relo, Ana Lucia Bergeijk, Jeroen Kam, Elizabeth Laplanche, Loic Benson, Neil Nijsen, Marjoleen |
| description | Alzheimer disease (AD) is a devastating neurodegenerative disorder with high unmet medical need. Drug development is hampered by limited understanding of the disease and its driving factors. Quantitative Systems Pharmacology (QSP) modeling provides a comprehensive quantitative framework to evaluate the relevance of biological mechanisms in the context of disease and to predict the efficacy of novel treatments. Here, we report a QSP model for AD with a particular focus on investigating the relevance of dysregulation of cholesterol and sphingolipids. We show that our model captures the modulation of several biomarkers in subjects with AD, as well as the response to pharmacological interventions. We evaluate the impact of targeting the sphingosine‐1‐phosphate 5 receptor (S1PR5) as a potential novel treatment option for AD, and model predictions increase our confidence in this novel disease pathway. Future applications for the QSP model are in validation of further targets and identification of potential treatment response biomarkers. |
| doi_str_mv | 10.1002/psp4.12351 |
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Drug development is hampered by limited understanding of the disease and its driving factors. Quantitative Systems Pharmacology (QSP) modeling provides a comprehensive quantitative framework to evaluate the relevance of biological mechanisms in the context of disease and to predict the efficacy of novel treatments. Here, we report a QSP model for AD with a particular focus on investigating the relevance of dysregulation of cholesterol and sphingolipids. We show that our model captures the modulation of several biomarkers in subjects with AD, as well as the response to pharmacological interventions. We evaluate the impact of targeting the sphingosine‐1‐phosphate 5 receptor (S1PR5) as a potential novel treatment option for AD, and model predictions increase our confidence in this novel disease pathway. 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This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). 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Future applications for the QSP model are in validation of further targets and identification of potential treatment response biomarkers.</description><subject>Biology</subject><subject>Brain research</subject><subject>Cholesterol</subject><subject>Drug development</subject><subject>Employees</subject><subject>Lipids</subject><subject>Metabolism</subject><subject>Parameter estimation</subject><subject>Pharmacology</subject><issn>2163-8306</issn><issn>2163-8306</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNp9kcFu1DAQhiMEolXphQdAlrigSls8jpM4F6SqpVCpqIt2OVuTZJJ15cTBToq2j8BT42VLVTjgiz2aT5_H_pPkNfBT4Fy8H8MoT0GkGTxLDgXk6UKlPH_-5HyQHIdwy-MqJIeSv0wOUi5iIcrD5OfXGYfJTDiZO2KrbZioD2y5Qd9j7azrtuyLa8iy1nl2Zu83ZHry7MIEwkDsamhMjRMFtkbf0WSGjq3GTdycNaNp2MU2eOpmG_1uYBjVbqJ4IVq29oRTHwt2M-66r5IXLdpAxw_7UfLt8uP6_PPi-ubT1fnZ9aKWUsECFQmVFsCRZFZACqos21rVss5AVaUgkLJoZQUoeFmVWUMqa0RRNqBQAVXpUfJh7x3nqqemjhN4tHr0pke_1Q6N_rszmI3u3J3ORZ7muYiCdw8C777PFCbdm1CTtTiQm4MWwEUZvx9URN_-g9662Q_xeVqI6FIxCB6pkz1Vexfif7WPwwDXu5T1LmX9O-UIv3k6_iP6J9MIwB74YSxt_6PSy9VS7qW_AEyOtII</recordid><startdate>201811</startdate><enddate>201811</enddate><creator>Clausznitzer, Diana</creator><creator>Pichardo‐Almarza, Cesar</creator><creator>Relo, Ana Lucia</creator><creator>Bergeijk, Jeroen</creator><creator>Kam, Elizabeth</creator><creator>Laplanche, Loic</creator><creator>Benson, Neil</creator><creator>Nijsen, Marjoleen</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201811</creationdate><title>Quantitative Systems Pharmacology Model for Alzheimer Disease Indicates Targeting Sphingolipid Dysregulation as Potential Treatment Option</title><author>Clausznitzer, Diana ; 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| subjects | Biology Brain research Cholesterol Drug development Employees Lipids Metabolism Parameter estimation Pharmacology |
| title | Quantitative Systems Pharmacology Model for Alzheimer Disease Indicates Targeting Sphingolipid Dysregulation as Potential Treatment Option |
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