Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by progressive motor neuron loss and caused by mutations in SMN1 (Survival Motor Neuron 1). The disease severity inversely correlates with the copy number of SMN2, a duplicated gene that is nearly identical to SMN1. We have delineated a mechanism of transcriptional regulation in the SMN2 locus. A previously uncharacterized long noncoding RNA (lncRNA), SMN-antisense 1 (SMN-AS1), represses SMN2 expression by recruiting the Polycomb Repressive Complex 2 (PRC2) to its locus. Chemically modified oligonucleotides that disrupt the interaction between SMN-AS1 and PRC2 inhibit the recruitment of PRC2 and increase SMN2 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.spinal muscular atrophy | lncRNA | PRC2 | SMN S pinal muscular atrophy is the leading genetic cause of infant mortality and is caused by deletions or mutation of Survival Motor Neuron 1 (SMN1) (1). Unique to humans, SMN1 is duplicated in the genome as SMN2, which is nearly identical in sequence. However, a C-to-T point mutation in exon 7 of SMN2 results in preferential skipping of this exon during pre-mRNA splicing and production of a truncated and unstable protein. A small fraction (10-20%) of pre-mRNA transcribed from SMN2 is spliced correctly to include exon 7 and produces a full-length SMN (SMN-FL, inclusive of exon 7) that is identical to the SMN1 gene product (2-4).Spinal motor neurons are highly sensitive to SMN1 deficiency, and their premature death causes motor function deficit in SMA patients (5, 6). The SMN2-derived SMN protein can extend spinal motor neuron survival, yet insufficient levels of SMN eventually lead to cell death. Overall, SMA patients with higher SMN2 genomic copy number have a less severe disease phenotype (7, 8). Type 0 or I patients, carrying one or two copies of SMN2, show onset of SMA within a few months of life with a life expectancy of less than 2. In contrast, type III and IV patients, carrying three or more copies, respectively, show juvenile or adult onset and slower disease progression (9). As further genetic evidence, SMA mouse models have been produced in which smn1 −/− mice, which would otherwise be embryonic lethal (10), can be rescued in the presence of high copy numbers of the human SMN transgene (11-13). Similar to the human disease spectrum, increased copy number of a human SMN transgene is inversely associated with decreased disease severity and mortality. We reasoned that increasing SMN2 transcription could phenocopy the beneficiary effect of SMN2 gene amplification and compensate for SMN1 deficiency. In addition, SMN1 heterozygotes are asymptomatic, whereas affected homozygotes have 10-20% of normal SMN levels. Therefore, we predict that modest SMN2 up-regulation will provide significant therapeutic benefit. H...