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

Abstract

Spinal muscular atrophy (SMA) is an early-onset motor neuron disease that leads to loss of muscle function. Butyrate (BA)-based compounds markedly improve the survival and motor phenotype of SMA mice. In this study, we examine the protective effects of the BA prodrug pivaloyloxymethyl butyrate (AN9) on the survival of SMNΔ7 SMA mice. Oral administration of AN9 beginning at PND04 almost doubled the average lifespan of SMNΔ7 SMA mice. AN9 treatment also increased the growth rate of SMNΔ7 SMA mice when compared to vehicle-treated SMNΔ7 SMA mice. In conclusion, BA prodrugs like AN9 have ameliorative effects on SMNΔ7 SMA mice.

Keywords: AN9; Motor neuron disease; neonatal mouse; preclinical drug trial; spinal muscular atrophy.

Figure 1. The effect of AN9 on survival of SMNΔ7 SMA mice

SMNΔ7 SMA mice were treated daily with AN9 (200 mg/kg/d, b.i.d.) or vehicle (4% ethanol in Intralipid-20) starting at PND04 and monitored for change in lifespan (A) and onset of loss of body mass (B). AN9 increased the average lifespan of SMNΔ7 SMA mice by 85% (A; p = 0.039) and delayed the onset of body mass loss by 95% (B; p = 0.031).

Figure 2. The effect of AN9 on the growth of SMNΔ7 SMA mice

(A) Body mass curves of SMNΔ7 SMA mice (solid shapes) or non-SMA littermates (either carrier or normal; open shapes) treated daily with either AN9 (circles) or vehicle (triangles). (B) Growth rates—measured as changes in body mass between PND11 and PND04—of SMNΔ7 SMA mice and non-SMA littermates treated with either AN9 or vehicle. The statistical significances for pairs of experimental groups are provided below the bar graph.