title: 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.
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139; cwoo@ranarx.com.
authors.forename: Caroline J
authors.identifier: 0000-0002-2766-3256
authors.initials: CJ
authors.lastname: Woo
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Verena K
authors.initials: VK
authors.lastname: Maier
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Roshni
authors.initials: R
authors.lastname: Davey
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: James
authors.initials: J
authors.lastname: Brennan
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Guangde
authors.initials: G
authors.lastname: Li
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: John
authors.initials: J
authors.lastname: Brothers
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Susana
authors.initials: S
authors.lastname: Gordo
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Anne
authors.initials: A
authors.lastname: Kasper
authors.affiliation: LGC Biosearch Technologies, Petaluma, CA 94954.
authors.forename: Trevor R
authors.initials: TR
authors.lastname: Okamoto
authors.affiliation: LGC Biosearch Technologies, Petaluma, CA 94954.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Johansson
authors.affiliation: Board of Governors-Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.|Induced Pluripotent Stem Cell Core, The David and Janet Polak Stem Cell Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Berhan
authors.initials: B
authors.lastname: Mandefro
authors.affiliation: Board of Governors-Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.|Induced Pluripotent Stem Cell Core, The David and Janet Polak Stem Cell Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Sareen
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Peter
authors.initials: P
authors.lastname: Bialek
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: Balkrishen
authors.initials: B
authors.lastname: Bhat
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: David
authors.initials: D
authors.lastname: Bullough
authors.affiliation: RaNA Therapeutics, Cambridge, MA 02139.
authors.forename: James
authors.initials: J
authors.lastname: Barsoum
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005347:Fibroblasts; D018628:Gene Dosage; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000628:therapy*; D009841:Oligonucleotides / Q000235:genetics*; D017354:Point Mutation; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation
chemical_list: D009841:Oligonucleotides; D062085:RNA, Long Noncoding; C526471:SMN1 protein, human; C526477:SMN2 protein, human; C000597152:SMN2 protein, mouse; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D063151:Polycomb Repressive Complex 2
keywords: PRC2; SMN; lncRNA; spinal muscular atrophy