Splicing-Directed Therapy in a New Mouse Model of Human Accelerated Aging

TLDR

Hutchinson‑Gilford progeria syndrome is caused by a LMNA point mutation that activates a cryptic splice site to produce progerin, a truncated prelamin A also present in normal aging, and although mouse models have enabled therapeutic advances, none have addressed the pathogenic splicing seen in patients due to lack of an appropriate model. We report a genetically modified mouse strain that carries the HGPS mutation. Using this model, we developed an antisense morpholino therapy that blocks pathogenic Lmna splicing, markedly reducing progerin accumulation and its nuclear defects. The mutant mice accumulate progerin, display histological and transcriptional alterations, and recapitulate the main clinical manifestations of HGPS, while morpholino treatment markedly ameliorates the progeroid phenotype and substantially extends lifespan.

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.