Author/Editor		Rogalska, Malgorzata Ewa; Tajnik, Mojca; Licastro, Danilo; Bussani, Erica; Camparini, Luca; Mattioli, Chiara; Pagani, Franco
Title		Therapeutic activity of modified U1 core spliceosomal particles
Type		članek
Vol. and No.		, št. Vol. 7
Publication year		2016
Volume		str. 1-13
ISSN		2041-1723 - Nature communications
Language		eng
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.
Keywords		therapeutic activity spinal muscular atrophy RNA mutant mutations U1A protein terapevtska dejavnost spinalna mišična atrofija RNA mutant mutacije beljakovine U1A