Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy

Abstract

Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analogue (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs—glyceryl tributyrate (BA3G) and VX563—on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favourable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling.

The effect of the DcpS inhibitor D156844 on the protective action of follistatin in mice with spinal muscular atrophy

“…In addition to regulating its promoter, other approaches showing in vivo efficacy for increasing SMN2 expression include modulation of the splicing of its pre-mRNA so that a greater proportion of SMN2 mRNAs contain exon 7—with compounds like LDN-76070 [29] and SMN-C3 [30]—and translational read-through of SMNΔ7 mRNAs to help stabilize its protein—with compounds like geneticin [31] and TC007 [32–34]. Aside from increasing SMN2 expression, other compounds like 4-phenylbutyrate ([35;36] manuscript in preparation ) and the Rho kinase inhibitor Y-27632 [37] ameliorate the phenotypes of SMA mouse models independent of SMN. Combination therapeutics will be viable strategies for treating SMA especially if these combination treatments increase SMN2 expression at different levels of gene regulation and/or protect vulnerable motor neurons.…”

Effect of the Butyrate Prodrug Pivaloyloxymethyl Butyrate (AN9) on a Mouse Model for Spinal Muscular Atrophy

“…Tissue levels of butyrate were measured in neonatal mice receiving a single dose of AN9 or vehicle by high-performance liquid chromatography (HPLC) as described previously [7]. …”

“…Continuous administration of BA via the water supply to SMA mice ( SMN2;mSmn Δ7/ Δ7 ) results in a moderately increase in survival of these mice [6]. However, oral administration of BA directly to SMNΔ7 SMA neonates via modified gavage does not improve survival [7]. SMNΔ7 SMA mice treated with the BA analogue 4-phenylbutyrate (4PBA) or one of two BA prodrugs—glyceryl tributyrate (BA3G) or VX563—show marked improvement in survival and motor function [7].…”

“…However, oral administration of BA directly to SMNΔ7 SMA neonates via modified gavage does not improve survival [7]. SMNΔ7 SMA mice treated with the BA analogue 4-phenylbutyrate (4PBA) or one of two BA prodrugs—glyceryl tributyrate (BA3G) or VX563—show marked improvement in survival and motor function [7]. BA is present in the forebrains of neonatal mice treated with BA3G or VX563 but not with BA [7].…”

“…SMNΔ7 SMA mice treated with the BA analogue 4-phenylbutyrate (4PBA) or one of two BA prodrugs—glyceryl tributyrate (BA3G) or VX563—show marked improvement in survival and motor function [7]. BA is present in the forebrains of neonatal mice treated with BA3G or VX563 but not with BA [7]. The lack of efficacy of BA in SMNΔ7 SMA mice is most likely due to the poor plasma pharmacokinetics of this compound in rodents [8].…”