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Splicing-directed therapy in a new mouse model of human accelerated aging.

Abstract：

:Hutchinson-Gilford progeria syndrome (HGPS) is caused by a point mutation in the LMNA gene that activates a cryptic donor splice site and yields a truncated form of prelamin A called progerin. Small amounts of progerin are also produced during normal aging. Studies with mouse models of HGPS have allowed the recent development of the first therapeutic approaches for this disease. However, none of these earlier works have addressed the aberrant and pathogenic LMNA splicing observed in HGPS patients because of the lack of an appropriate mouse model. Here, we report a genetically modified mouse strain that carries the HGPS mutation. These mice accumulate progerin, present histological and transcriptional alterations characteristic of progeroid models, and phenocopy the main clinical manifestations of human HGPS, including shortened life span and bone and cardiovascular aberrations. Using this animal model, we have developed an antisense morpholino-based therapy that prevents the pathogenic Lmna splicing, markedly reducing the accumulation of progerin and its associated nuclear defects. Treatment of mutant mice with these morpholinos led to a marked amelioration of their progeroid phenotype and substantially extended their life span, supporting the effectiveness of antisense oligonucleotide-based therapies for treating human diseases of accelerated aging.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Osorio FG,Navarro CL,Cadiñanos J,López-Mejía IC,Quirós PM,Bartoli C,Rivera J,Tazi J,Guzmán G,Varela I,Depetris D,de Carlos F,Cobo J,Andrés V,De Sandre-Giovannoli A,Freije JM,Lévy N,López-Otín C

doi

10.1126/scitranslmed.3002847

subject

Has Abstract

pub_date

2011-10-26 00:00:00

pages

106ra107

issue

106

eissn

1946-6234

issn

1946-6242

pii

3/106/106ra107

journal_volume

3

pub_type

杂志文章

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