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

被引：68

作者：

Woo, Caroline J. ^{[1
]}

Maier, Verena K. ^{[1
]}

Davey, Roshni ^{[1
]}

Brennan, James ^{[1
]}

Li, Guangde ^{[1
]}

Brothers, John, II ^{[1
]}

Schwartz, Brian ^{[1
]}

Gordo, Susana ^{[1
]}

Kasper, Anne ^{[1
]}

Okamoto, Trevor R. ^{[2
]}

Johansson, Hans E. ^{[2
]}

Mandefro, Berhan ^{[3
,4
]}

Sareen, Dhruv ^{[3
,4
,5
]}

Bialek, Peter ^{[1
]}

Chau, B. Nelson ^{[1
]}

Bhat, Balkrishen ^{[1
]}

Bullough, David ^{[1
]}

Barsoum, James ^{[1
]}

机构：

[1] RaNA Therapeut, Cambridge, MA 02139 USA

[2] LGC Biosearch Technol, Petaluma, CA 94954 USA

[3] Cedars Sinai Med Ctr, Board Governors Regenerat Med Inst, Los Angeles, CA 90048 USA

[4] Cedars Sinai Med Ctr, David & Janet Polak Stem Cell Lab, Induced Pluripotent Stem Cell Core, Los Angeles, CA 90048 USA

[5] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 08期

关键词：

spinal muscular atrophy; lncRNA; PRC2; SMN; MOTOR-NEURON GENE; NONCODING RNAS; SINGLE NUCLEOTIDE; MOUSE MODEL; CHROMATIN; PROTEIN; EXPRESSION; CELLS; IDENTIFICATION; SEVERITY;

D O I：

10.1073/pnas.1616521114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 oligo-nucleotides 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.

引用

页码：E1509 / E1518

页数：10

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