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ABSTRACT: In Vivo Adenine Base Editing Corrects Hutchinson - Gilford Progeria Syndrome

PROVIDER: PRJNA627465 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11591200.fastq.gz	Fastqsanger.gz
	SRR11591300.fastq.gz	Fastqsanger.gz
	SRR11599900.fastq.gz	Fastqsanger.gz
	SRR11591201.fastq.gz	Fastqsanger.gz
	SRR11591301.fastq.gz	Fastqsanger.gz

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Project description:Background: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by rapid premature aging. Without treatment, accelerated atherosclerosis results in death from heart attack or stroke in the early teens. Recent echocardiographic study has also demonstrated a progressive cardiomyopathy in HGPS patients, characterized by diastolic dysfunction with preserved ejection fraction. We sought to define the cardiovascular phenotype and molecular mechanisms underlying progeria-associated cardiomyopathy in a humanized mouse model, and to determine whether these abnormalities can be corrected by in vivo adenine base editing. Methods: Cardiovascular phenotypes were extensively characterized in LMNAG608G/G608G progeria mice using echocardiography, vascular biomechanical testing, histopathology, transmission electron microscopy, snRNA-seq, RNA in situ hybridization, and plasma biomarker analyses. The effects of in vivo adenine base editing on pathological cardiac remodeling were subsequently evaluated. Results: LMNAG608G/G608G mice developed progressive left ventricular diastolic dysfunction with normal ejection fraction, accompanied by severe central arterial stiffening, impaired vasoreactivity, and reduced vascular distensibility. Histological and ultrastructural analyses of the heart revealed cardiomyocyte nuclear abnormalities, sarcomere disruption, mitochondrial defects, and increased myocardial collagen deposition. Transcriptomic profiling identified a signature of pathological myocardial remodeling, characterized by activation of proteostatic stress responses, suppression of contractile and calcium signaling pathways, enhanced extracellular matrix remodeling and inflammatory signaling, and reactivation of the fetal heart failure gene program. Robust upregulation of Nppa and Nppb, two established heart failure markers, was validated by RNA in situ hybridization and accompanied by significantly elevated circulating NT-proBNP levels. In vivo delivery of an AAV9-encapsulated adenine base editor achieved partial correction of the progeria mutation in the heart and partially reversed cardiomyocyte transcriptional alterations, pathological myocardial remodeling, fibrosis, and heart failure marker expression. Conclusions: A humanized mouse model of HGPS is associated with progressive atherosclerosis, as well as a progressive cardiomyopathy characterized by diastolic dysfunction, pathological myocardial remodeling, and activation of a heart failure transcriptional program. Partial reversal of these abnormalities following in vivo adenine base editing demonstrates that progeria cardiomyopathy is therapeutically modifiable. Future human trials of gene-editing therapies for HGPS should target both the arterial tree and the myocardium.

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