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This technology has the potential to increase the Spinal Muscular Atrophy protein levels in patients with Spinal Muscular Atrophy. The innovation is a blocking antisense oligonucleotide and its target site located in a deep intronic sequence of the SMN2 gene. The blocking of the SMN2 target sequence corrects the defective splicing of the gene.

Humans possess two nearly identical copies of survival motor neuron (SMN) gene: SMN1 and SMN2. Loss of SMN1 coupled with the inability of SMN2 to compensate for loss of SMN1 causes spinal muscular atrophy (SMA), one of the leading genetic causes of infant mortality. SMN2 produces a truncated non-functional SMN protein (SMNΔ7) due to skipping of exon 7. It is generally believed that strategies aimed at correction of SMN2 exon 7 splicing hold great promise to cure SMA. By constructing and testing a series of overlapping deletions, Iowa State University researchers identified intronic positions 290 to 295 (LDI Site-1 or LS-1) as being involved in a long-distance inhibitory interaction. By carrying out an anti-sense micro walk the researchers observed that anti-sense oligonucleotides targeting LS-1 stimulate SMN2 exon 7 splicing in SMA patient cells. This is the first finding in which anti-sense oligonucleotide blocking of a deep intronic sequence has been found to correct the defective splicing of SMA gene.

• Low cost of synthesis due to small size

• High target specificity and low off-target effect

• Effective at very low dose

• Amenable to modifications for transport across blood brain barrier

• Unique mechanism of splicing regulation through modulation of catalytic core of spliceosome

Development of drugs for the treatment of spinal muscular atrophy

1. Singh, N. N., Lawler, M. N., Ottesen, E. W., Upreti, D., Kaczynski, J. R., & Singh, R. N. (2013). An intronic structure enabled by a long-distance interaction serves as a novel target for splicing correction in spinal muscular atrophy. Nucleic Acids Research, 41(17), 8144–8165.

2. Deep Intronic Target For Splicing Correction On Spinal Muscular Atrophy Gene, US patent application number 20150315582