{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:50:39Z","timestamp":1792273839619,"version":"4.4.0"},"reference-count":31,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T00:00:00Z","timestamp":1543449600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004337","name":"Roche","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004337","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2018,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Spinal muscular atrophy (<jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content>) is a rare, inherited neuromuscular disease caused by deletion and\/or mutation of the Survival of Motor Neuron 1 (<jats:italic><jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content>1)<\/jats:italic> gene. A second gene, <jats:italic><jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content>2<\/jats:italic>, produces low levels of functional <jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content> protein that are insufficient to fully compensate for the lack of <jats:italic><jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content>1<\/jats:italic>. Risdiplam (<jats:styled-content style=\"fixed-case\">RG<\/jats:styled-content>7916; <jats:styled-content style=\"fixed-case\">RO<\/jats:styled-content>7034067) is an orally administered, small\u2010molecule <jats:italic><jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content>2<\/jats:italic> pre\u2010<jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> splicing modifier that distributes into the central nervous system (<jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>) and peripheral tissues. To further explore risdiplam distribution, we assessed in\u00a0vitro characteristics and in\u00a0vivo drug levels and effect of risdiplam on <jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content> protein expression in different tissues in animal models. Total drug levels were similar in plasma, muscle, and brain of mice (n\u00a0=\u00a090), rats (n\u00a0=\u00a0148), and monkeys (n\u00a0=\u00a024). As expected mechanistically based on its high passive permeability and not being a human multidrug resistance protein 1 substrate, risdiplam <jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content> levels reflected free compound concentration in plasma in monkeys. Tissue distribution remained unchanged when monkeys received risdiplam once daily for 39\u00a0weeks. A parallel dose\u2010dependent increase in <jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content> protein levels was seen in <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content> and peripheral tissues in two <jats:styled-content style=\"fixed-case\">SMA<\/jats:styled-content> mouse models dosed with risdiplam. These in\u00a0vitro and in\u00a0vivo preclinical data strongly suggest that functional <jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content> protein increases seen in patients\u2019 blood following risdiplam treatment should reflect similar increases in functional <jats:styled-content style=\"fixed-case\">SMN<\/jats:styled-content> protein in the <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content>, muscle, and other peripheral tissues.<\/jats:p>","DOI":"10.1002\/prp2.447","type":"journal-article","created":{"date-parts":[[2018,11,29]],"date-time":"2018-11-29T11:56:22Z","timestamp":1543492582000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":163,"title":["Risdiplam distributes and increases <scp>SMN<\/scp> protein in both the central nervous system and peripheral 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