Gene activation of SMN by selective disruption of lncRNA-mediated recruitment of PRC2 for the treatment of spinal muscular atrophy.

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in <i>SMN1</i> (<i>Survival Motor Neuron 1</i>). The disease severity inversely correlates with the copy number of <i>SMN2,</i> a duplicated gene that is nearly identical to <i>SMN1.</i> We have delineated a mechanism of transcriptional regulation in the <i>SMN2</i> locus. A previously uncharacterized long noncoding RNA (lncRNA), <i>SMN-antisense 1</i> (<i>SMN-AS1</i>), represses <i>SMN2</i> expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction between <i>SMN-AS1</i> and PRC2 inhibit the recruitment of PRC2 and increase <i>SMN2</i> expression in primary neuronal cultures. Our approach comprises a gene-up-regulation technology that leverages interactions between lncRNA and PRC2. Our data provide proof-of-concept that this technology can be used to treat disease caused by epigenetic silencing of specific loci.