Novel Small Molecule Multi-targeted Ligands as Therapeutics for the Treatment of

DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SMA), a common autosomal recessive motor neuron disorder is the leading genetic cause of infant mortality. SMA is caused by the loss of the survival motor neuron1 (SMN1) gene. SMN2, a nearly identical paralog, is present in all SMA patients but differs by a critical nucleotide that alters exon 7 splicing efficiency. This results in low SMN levels which are not enough to sustain motor neurons and a varying clinical presentation that inversely correlates with SMN2 copy number. Currently, no approved therapy for SMA is available. However, since all patients carry at least one functional SMN2 gene, numerous approaches aimed at identifying small molecule therapeutics that increase or stabilize SMN protein by some means are currently being investigated. Two small molecule pharmacologic approaches, modification of RNA cap metabolism (by DcpS enzyme) and class-I histone deacetylase (HDAC) inhibition, can both increase SMN protein levels in SMA patient