In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice
| Autor: | Sean P. Doherty, Chad Krilow, Narisu Narisu, Urraca Tavarez, Luke W. Koblan, Zheng-Mei Xiong, Jonathan D. Brown, Lindsay M. Davison, Yantenew G. Gete, Leslie B. Gordon, Francis S. Collins, Quanhu Sheng, Christine D. Wilson, Michael R. Erdos, Wayne A. Cabral, Kan Cao, Jonathan M. Levy, Charles Y. Lin, David R. Liu, Xiaojing Mao, Gregory A. Newby |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Male congenital hereditary and neonatal diseases and abnormalities Longevity Mice Transgenic Biology medicine.disease_cause LMNA 03 medical and health sciences Mice 0302 clinical medicine Progeria Gene therapy medicine Animals Humans Child Base Pairing Alleles Aorta Gene Editing Mutation Multidisciplinary integumentary system Adenine nutritional and metabolic diseases RNA DNA Fibroblasts Progerin medicine.disease Lamin Type A Molecular biology Research Highlight Alternative Splicing Disease Models Animal 030104 developmental biology RNA editing 030220 oncology & carcinogenesis RNA splicing Genetic engineering Female Mutant Proteins Genetic techniques |
| Zdroj: | Signal Transduction and Targeted Therapy |
| ISSN: | 1476-4687 |
| Popis: | Hutchinson–Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1–4. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87–91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20–60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause. In a mouse model of progeria, an adenine base editor delivered with adeno-associated virus corrects the pathogenic mutation in LMNA, rescues vascular pathology and markedly extends the lifespan of the mice. |
| Databáze: | OpenAIRE |
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