Splicing-directed therapy in a new mouse model of human accelerated aging.
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.
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.
Fernando G
FG
Osorio
Claire L
CL
Navarro
Juan
J
Cadiñanos
Isabel C
IC
López-Mejía
Pedro M
PM
Quirós
Catherine
C
Bartoli
José
J
Rivera
Jamal
J
Tazi
Gabriela
G
Guzmán
Ignacio
I
Varela
Danielle
D
Depetris
Félix
F
de Carlos
Juan
J
Cobo
Vicente
V
Andrés
Annachiara
A
De Sandre-Giovannoli
José M P
JM
Freije
Nicolas
N
Lévy
Carlos
C
López-Otín
D000375:Aging / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D006801:Humans; D034904:Lamin Type A / Q000235:genetics; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use; D011371:Progeria / Q000188:drug therapy / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*
D034904:Lamin Type A; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011498:Protein Precursors; C090764:prelamin A