In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy.
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 alpha-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 alpha-motoneurone degeneration by epigenetic SMN2 gene activation.
Hahnen
Eric
E
Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. eric.hahnen@uk-koeln.de
Eyüpoglu
Ilker Y
IY
Brichta
Lars
L
Haastert
Kirsten
K
Tränkle
Christian
C
Siebzehnrübl
Florian A
FA
Riessland
Markus
M
Hölker
Irmgard
I
Claus
Peter
P
Romstöck
Johann
J
Buslei
Rolf
R
Wirth
Brunhilde
B
Blümcke
Ingmar
I
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005069:Evaluation Studies as Topic; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D056572:Histone Deacetylase Inhibitors; D066298:In Vitro Techniques; D009046:Motor Neurons / Q000187:drug effects; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D055532:SMN Complex Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; C526473:Smn1 protein, rat; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein