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Therapeutic activity of modified U1 core spliceosomal particles.

ABSTRACT: Modified U1 snRNAs bound to intronic sequences downstream of the 5' splice site correct exon skipping caused by different types of mutations. Here we evaluate the therapeutic activity and structural requirements of these exon-specific U1 snRNA (ExSpeU1) particles. In a severe spinal muscular atrophy, mouse model, ExSpeU1, introduced by germline transgenesis, increases SMN2 exon 7 inclusion, SMN protein production and extends life span. In vitro, RNA mutant analysis and silencing experiments show that while U1A protein is dispensable, the 70K and stem loop IV elements mediate most of the splicing rescue activity through improvement of exon and intron definition. Our findings indicate that precise engineering of the U1 core spliceosomal RNA particle has therapeutic potential in pathologies associated with exon-skipping mutations.

SUBMITTER: Rogalska ME

PROVIDER: S-EPMC4822034 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Therapeutic activity of modified U1 core spliceosomal particles.

Rogalska Malgorzata Ewa ME Tajnik Mojca M Licastro Danilo D Bussani Erica E Camparini Luca L Mattioli Chiara C Pagani Franco F

Nature communications 20160404

Modified U1 snRNAs bound to intronic sequences downstream of the 5' splice site correct exon skipping caused by different types of mutations. Here we evaluate the therapeutic activity and structural requirements of these exon-specific U1 snRNA (ExSpeU1) particles. In a severe spinal muscular atrophy, mouse model, ExSpeU1, introduced by germline transgenesis, increases SMN2 exon 7 inclusion, SMN protein production and extends life span. In vitro, RNA mutant analysis and silencing experiments show ...[more]

PMID: 27041075

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