In vitro and ex vivo evaluation of second‐generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy

• Published in: Journal of neurochemistry 2006-07, Vol.98 (1), p.193-202
• Main Authors: Hahnen, Eric, Eyüpoglu, Ilker Y., Brichta, Lars, Haastert, Kirsten, Tränkle, Christian, Siebzehnrübl, Florian A., Riessland, Markus, Hölker, Irmgard, Claus, Peter, Romstöck, Johann, Buslei, Rolf, Wirth, Brunhilde, Blümcke, Ingmar
• Format: Article
• Language: English
• Subjects: Acids; Analysis of Variance; Animals; Animals, Newborn; Biological and medical sciences; Blotting, Western - methods; Cell Survival - drug effects; Cells, Cultured; Cyclic AMP Response Element-Binding Protein - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Diseases of striated muscles. Neuromuscular diseases; Dose-Response Relationship, Drug; Drug therapy; Enzyme Activation - drug effects; Enzyme Inhibitors - therapeutic use; Enzymes; Evaluation Studies as Topic; Gene Expression - drug effects; Hippocampus - drug effects; Hippocampus - pathology; histone deacetylase inhibitor; Histone Deacetylase Inhibitors; In Vitro Techniques; Medical sciences; Motor Neurons - drug effects; Muscular Atrophy, Spinal - drug therapy; Muscular system; Nerve Tissue Proteins - metabolism; Neurology; Neurons; Proteins; Rats; RNA-Binding Proteins - metabolism; SMN Complex Proteins; Spinal cord injuries; spinal muscular atrophy; suberoylanilide hydroxamic acid; survival motor neuron gene; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03868.x

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.