STUDY OF SODIUM PHENYLBUTYRATE IN PEDIATRICS SUBJECTS WITH TYPE II/III SMA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Spinal Muscular Atrophy (SMA) is an autosomal recessive disease characterized by degeneration of spinal cord anterior horn cells resulting in diffuse weakness. Homozygous deletion of the survival motor neuron 1 gene (SMN1) is found in more than 94% of SMA cases regardless of subtype. SMN1 resides in a duplicated inverted region on chromosome 5q. A near identical copy of SMN1, designated SMN2, contains a single nucleotide change which alters splicing and reduces the efficiency by which exon 7 is incorporated, leading to decreased functional protein expression. However, SMN2 transcription produces a small percentage of full length SMN mRNA. An increased number of SMN2 copies, with the resulting increase in functional protein expression, is associated with a less severe human disease and phenotypic rescue in the SMN knockout mouse. Several compounds up-regulate SMN2 expression or alter gene splicing to produce an increased ratio of full length to exon-7-deleted SMN mRNA. Some compounds are available for use in humans and have a proven safety record in treatment of other disorders, such as sodium phenylbutyrate (NaPB) in patients with urea cycle disorders. In fibroblast cultures from SMA patients, NaPB treatment causes an increase in full-length SMN transcripts. In the SMA mouse model, sodium butyrate causes increased SMN expression in spinal cord motor neurons and ameliorates the phenotypic severity. Here we propose to identify the maximum tolerated dose (MTD) of NaPB in pediatric subjects with SMA Type II/III by monitoring dose limiting toxicities (DLTs) associated with administration of NaPB.