Treatment of spinal muscular atrophy by sodium butyrate.
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular paralysis with muscular atrophy. No effective treatment of this disorder is presently available. Studies of the correlation between disease severity and the amount of survival motor neuron (SMN) protein have shown an inverse relationship. We report that sodium butyrate effectively increases the amount of exon 7-containing SMN protein in SMA lymphoid cell lines by changing the alternative splicing pattern of exon 7 in the SMN2 gene. In vivo, sodium butyrate treatment of SMA-like mice resulted in increased expression of SMN protein in motor neurons of the spinal cord and resulted in significant improvement of SMA clinical symptoms. Oral administration of sodium butyrate to intercrosses of heterozygous pregnant knockout-transgenic SMA-like mice decreased the birth rate of severe types of SMA-like mice, and SMA symptoms were ameliorated for all three types of SMA-like mice. These results suggest that sodium butyrate may be an effective drug for the treatment of human SMA patients.
Chang
J G
JG
Department of Medical Research, China Medical College Hospital, Taiwan.
Hsieh-Li
H M
HM
Jong
Y J
YJ
Wang
N M
NM
Tsai
C H
CH
Li
H
H
D000015:Abnormalities, Multiple / Q000235:genetics; D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D002087:Butyrates / Q000627:therapeutic use*; D002461:Cell Line, Transformed / Q000187:drug effects; D003433:Crosses, Genetic; D017362:Cyclic AMP Response Element-Binding Protein; D004353:Drug Evaluation, Preclinical; D004742:Enhancer Elements, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D005260:Female; D005315:Fetal Diseases / Q000188:drug therapy; D005419:Flavonoids / Q000494:pharmacology; D005865:Gestational Age; D006197:Hair / Q000002:abnormalities; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008431:Maternal-Fetal Exchange; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D019319:Okadaic Acid / Q000494:pharmacology; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D055540:Survival of Motor Neuron 2 Protein; D013623:Tail / Q000002:abnormalities
D002087:Butyrates; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one