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SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone\u2010rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (<jats:italic>SMN2<\/jats:italic>), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment. In contrast to SAHA, the compounds <jats:italic>m<\/jats:italic>\u2010Carboxycinnamic acid bis\u2010Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS\u2010275 failed to increase SMN levels. Clinical trials have revealed that SAHA, which is under investigation for cancer treatment, has a good oral bioavailability and is well tolerated, allowing <jats:italic>in vivo<\/jats:italic> concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood\u2013brain barrier, oral administration may allow deceleration of progressive \u03b1\u2010motoneurone degeneration by epigenetic <jats:italic>SMN2<\/jats:italic> gene activation.<\/jats:p>","DOI":"10.1111\/j.1471-4159.2006.03868.x","type":"journal-article","created":{"date-parts":[[2006,5,18]],"date-time":"2006-05-18T09:51:23Z","timestamp":1147945883000},"page":"193-202","source":"Crossref","is-referenced-by-count":128,"title":["<i>In vitro<\/i> and <i>ex vivo<\/i> evaluation of second\u2010generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy"],"prefix":"10.1111","volume":"98","author":[{"given":"Eric","family":"Hahnen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilker Y.","family":"Ey\u00fcpoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Brichta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Haastert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Tr\u00e4nkle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian A.","family":"Siebzehnr\u00fcbl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Riessland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irmgard","family":"H\u00f6lker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Claus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Romst\u00f6ck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Buslei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brunhilde","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingmar","family":"Bl\u00fcmcke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,5,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201102"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.11.1961"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.2001.00647.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.171105098"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M303740200"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03098.x"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(01)00758-2"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.24.6969"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2004.09.003"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1006\/abio.2001.5542"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm0497592"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0437870100"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.055541"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm991091h"},{"key":"e_1_2_7_16_1","first-page":"3578","article-title":"Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously","volume":"9","author":"Kelly W. 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