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 fibroblast cells. DcpS and HDAC inhibitors also show improved survival in SMA mouse models. This raises an important scientific question, can a single small molecule that simultaneously impacts these pathways, i.e. a multi-targeted ligand (MTL), provide a synergistic response and increase the level of efficacy and/or the margin of safety in patient treatment. Here, we provide in-vitro and in-vivo data for co-administration of reported small molecule inhibitors for these two enzyme classes showing a superior profile vs. individual compound treatment, thus supporting the development of single molecules with MTL activity profiles. We also present in-vitro profile evidence for brain permeability and in-vivo evaluation in SMA mice showing improved survival with a prototype MTL analog. We propose to diversify our initial (two) small molecules with POC data, to optimize and identify novel, patentable MTLs with improved brain permeability. The optimized compounds possessing desired drug-like attributes (CNS-MPO scores) shall be evaluated in patient derived fibroblast cells for SMN mRNA and/ protein increases. For promising MTLs, in-vitro ADME and pharmacokinetic analysis to determine brain(B)/plasma(P) ratio (brain penetration assessment) and brain and plasma levels in wt. mice will be performed. For the best 1-2 MTL analogs, in-vivo evaluation versus vehicle control, in severe and intermediate SMA mouse models to demonstrate enhancement of survival and other phenotypic changes will be carried out. This program is anticipated to provide a novel patentable best-in-class MTL lead series for SMA. The collated in-vitro/in-vivo data will be used to file a provisional patent application at the end of his grant period. Subsequently, we intend to seek SBIR Phase-II grant funding for further optimization studies, leading to identification of a clinical development candidate, initiate compound scale-up, pre-clinical safety studies for IND track data generation and seeking a clinical development partner.
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