Treatment of spinal muscular atrophy by sodium butyrate

Abstract

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. P roximal spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of anterior horn cells of the spinal cord, leading to muscular paralysis with muscular atrophy. Clinical diagnosis of SMA is based on findings of progressive symmetric weakness and atrophy of the proximal muscles. Affected individuals usually are classified into three groups according to the age of onset and progression of the disease. Children with type I SMA are most severely affected and usually have SMA symptoms before the age of 6 months and rarely live beyond 2 years. Type II and type III SMA are milder forms and the age of onset of symptoms varies between 6 months and 17 years. SMA is one of the most common fatal autosomal recessive diseases in children with a carrier rate of 1-2% in the general population and an incidence of 1 in 10,000 newborns (1). No specific treatment is currently available for SMA patients.Two survival motor neuron (SMN) genes (SMN) are typically present on 5q13: SMN1 (also known as SMN T , SMNtel) and SMN2 (also known as SMN C , SMNcen). Loss-of-function mutations of both copies of the telomeric gene, SMN1, are correlated with the development of SMA (2-5). The nearly identical centromeric gene, SMN2, appears to modify disease severity in a dose-dependent manner, as SMN protein levels from this gene are correlated with disease severity (6, 7). However, the expressed amount of intact SMN protein from SMN2 does not provide adequate protection from SMA (8).Although SMN1 and SMN2 encode identical proteins, all three forms of proximal SMA are caused by mutation in the SMN1 gene, but not in the SMN2 gene (2-5). The differences between these highly homologous genes are in their RNA expression patterns (9-12). Most SMN2 transcripts lack exons 3, 5, or most frequently, 7, with only a small amount of full-length mRNA generated. On the other hand, the SMN1 gene...

Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes

“…Recent in vivo studies have shown that treatment with HDAC inhibitors of a wide range of structures provide neuroprotective effects in models of various motor neuron disorders. [44][45][46][47] However, the roles of glia under therapeutic mechanisms of HDAC inhibitors were not investigated. Here we showed that the neurotrophic effects of VPA, a HDAC inhibitor of short-chain fatty acid structure, were associated with Figure 5 VPA is neuroprotective against LPS-induced DA neurodegeneration in rat primary mesencephalic neuronglia cultures.…”

“…Inhibition of HDAC activity was reported to be associated with neuroprotective effects in experimental models of motor neuron disorders by HDAC inhibitors with different chemical structures. [44][45][46][47] Preliminary results from our laboratory suggests that inhibition of HDAC in astroglial cultures is related to the increase in the expression of GDNF and BDNF by VPA treatment (Wu et al, personal communication).…”

Treatment of spinal muscular atrophy cells with drugs that upregulate SMN expression reveals inter- and intra-patient variability

“…11,12 As the differences between SMN1 and SMN2 are related to the complete transcript and the amount of protein, drugs capable of increasing FL-SMN expression and SMN protein may have therapeutic effects for SMA patients. 13 Histone deacetylases inhibitors (HDACi), for example, increase acetylation of histones and other proteins 14 and this hyperacetylation relaxes the tertiary structure of chromatin, facilitating access of the transcriptional machinery to target genes. In vitro experiments with phenylbutyrate (PBA) and valproic acid (VPA) -two well-known HDACi -have shown an increase in SMN mRNA and protein levels in SMA fibroblasts.…”

Epigenetics, fragile X syndrome and transcriptional therapy

“…Some genes may simply require histone hyperacetylation to be turned on or to upregulate their transcriptional output. This the case of the ALDPL1 [Kemp et al, 1998] and SMN2 genes [Chang et al, 2001;Andreassi et al, 2004], involved in adrenoleukodystrophy and spinal muscular atrophy, respectively. Transcriptional activation could partially compensate for disease causing mutations in these two genes.…”