Avtor/Urednik		Rogalska, Malgorzata Ewa; Tajnik, Mojca; Licastro, Danilo; Bussani, Erica; Camparini, Luca; Mattioli, Chiara; Pagani, Franco
Naslov		Therapeutic activity of modified U1 core spliceosomal particles
Tip		članek
Vol. in št.		, št. Vol. 7
Leto izdaje		2016
Obseg		str. 1-13
ISSN		2041-1723 - Nature communications
Jezik		eng
Abstrakt		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.
Proste vsebinske oznake		therapeutic activity spinal muscular atrophy RNA mutant mutations U1A protein terapevtska dejavnost spinalna mišična atrofija RNA mutant mutacije beljakovine U1A