In vivo base editing rescues Hutchinson–Gilford progeria syndrome in mice

Luke W. Koblan, Michael R. Erdos, Christopher Wilson, Wayne A. Cabral, Jonathan M. Levy, Zheng-Mei Xiong, Urraca L. Tavarez, Lindsay M. Davison, Yantenew G. Gete, Xiaojing Mao, Gregory A. Newby, Sean P. Doherty, Narisu Narisu, Quanhu Sheng, Chad Krilow, Charles Y. Lin, Leslie B. Gordon, Kan Cao, Francis S. Collins (), Jonathan D. Brown () and David R. Liu ()
Additional contact information
Luke W. Koblan: Broad Institute of Harvard and MIT
Michael R. Erdos: National Institutes of Health
Christopher Wilson: Broad Institute of Harvard and MIT
Wayne A. Cabral: National Institutes of Health
Jonathan M. Levy: Broad Institute of Harvard and MIT
Zheng-Mei Xiong: National Institutes of Health
Urraca L. Tavarez: National Institutes of Health
Lindsay M. Davison: Vanderbilt University Medical Center
Yantenew G. Gete: University of Maryland
Xiaojing Mao: University of Maryland
Gregory A. Newby: Broad Institute of Harvard and MIT
Sean P. Doherty: Vanderbilt University Medical Center
Narisu Narisu: National Institutes of Health
Quanhu Sheng: Vanderbilt University Medical Center
Chad Krilow: National Institutes of Health
Charles Y. Lin: Baylor College of Medicine
Leslie B. Gordon: Alpert Medical School of Brown University
Kan Cao: University of Maryland
Francis S. Collins: National Institutes of Health
Jonathan D. Brown: Vanderbilt University Medical Center
David R. Liu: Broad Institute of Harvard and MIT

Nature, 2021, vol. 589, issue 7843, 608-614

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-020-03086-7

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