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 inSMN1(Survival Motor Neuron 1). The disease severity inversely correlates with the copy number ofSMN2,a duplicated gene that is nearly identical toSMN1.We have delineated a mechanism of transcriptional regulation in theSMN2locus. A previously uncharacterized long noncoding RNA (lncRNA),SMN-antisense 1(SMN-AS1), repressesSMN2expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction betweenSMN-AS1and PRC2 inhibit the recruitment of PRC2 and increaseSMN2expression 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.