These authors contributed equally to this paper.
In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy
Article first published online: 18 MAY 2006
Journal of Neurochemistry
Volume 98, Issue 1, pages 193–202, July 2006
How to Cite
Hahnen, E., Eyüpoglu, I. Y., Brichta, L., Haastert, K., Tränkle, C., Siebzehnrübl, F. A., Riessland, M., Hölker, I., Claus, P., Romstöck, J., Buslei, R., Wirth, B. and Blümcke, I. (2006), In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy. Journal of Neurochemistry, 98: 193–202. doi: 10.1111/j.1471-4159.2006.03868.x
- Issue published online: 30 MAY 2006
- Article first published online: 18 MAY 2006
- Received January 19, 2006; revised manuscript received February 9, 2006; accepted February 13, 2006.
- histone deacetylase inhibitor;
- spinal muscular atrophy;
- suberoylanilide hydroxamic acid;
- survival motor neuron gene
Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non-toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an α-motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone-rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), 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 m-Carboxycinnamic acid bis-Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS-275 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 in vivo concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood–brain barrier, oral administration may allow deceleration of progressive α-motoneurone degeneration by epigenetic SMN2 gene activation.