Effective Valproic Acid Treatment in Motor Function Is Caused by Possible Mechanism of Elevated Survival Motor Neuron Protein Related With Splicing Factor Gene Expression in Spinal Muscular Atrophy

Abstract

Background: Spinal muscular atrophy (SMA) is a lower motor neuron disease caused by SMN1. Several clinical trials have indicated that valproic acid (VPA) benefits a limited number of SMA patients. To clarify the difference in VPA responsiveness and elucidate the mechanism, we analyzed gene expression changes by VPA treatment in Japanese pediatric patients using data from clinical trials. Methods: To identify VPA responders, we correlated the changes in motor function and survival motor neuron (SMN) protein levels. To determine the effects of VPA on gene expression profiles, a microarray analysis was performed. The Gene Ontology (GO) analysis evaluated statistically overexpressed GO terms within a group of genes. Results: The group with significant improvement showed elevated SMN protein levels following VPA administration, whereas that with the highest SMN levels at baseline did not improve immediately. GO analysis suggested that specific factors contributed to the correlation between changes in motor function and the SMN protein levels, including splicing factors HNRNPC and SNRNP70. Conclusions: This is the first study to indicate that the time for VPA effectiveness varies among individuals and is associated with SMN protein levels at baseline and expression changes in splicing factor genes. Clinical Trials Registry of the Center for Clinical Trials, Japan Medical Association, a registry of the Japan Primary Registries Network certified by the World Health Organization as a primary registry (registration numbers: SMART01 trial, JMA-II A00190; SMART02 trial, JMA-II A00231; SMART03 trial, JMA-II A00259).

Keywords

• spinal muscular atrophy
• valproic acid
• motor function
• smn protein
• splicing