Disruption of the nuclear localization signal in RBM20 is causative in dilated cardiomyopathy DOI Creative Commons
Yanghai Zhang, Zachery R. Gregorich, Yujuan Wang

et al.

JCI Insight, Journal Year: 2023, Volume and Issue: 8(13)

Published: May 23, 2023

Human patients carrying genetic mutations in RNA binding motif 20 (RBM20) develop a clinically aggressive dilated cardiomyopathy (DCM). Genetic mutation knockin (KI) animal models imply that altered function of the arginine-serine-rich (RS) domain is crucial for severe DCM. To test this hypothesis, we generated an RS deletion mouse model (Rbm20ΔRS). We showed Rbm20ΔRS mice manifested DCM with mis-splicing RBM20 target transcripts. found was mis-localized to sarcoplasm hearts and formed granules similar those detected KI animals. In contrast, lacking recognition major genes but did not or exhibit granule formation. Using vitro studies immunocytochemical staining, demonstrated only DCM-associated facilitated nucleocytoplasmic transport promoted assembly. Further, defined core nuclear localization signal (NLS) within RBM20. Mutation analysis phosphorylation sites suggested modification may be dispensable transport. Collectively, our findings revealed disruption domain-mediated caused by NLS mutations.

Language: Английский

Drug delivery systems for CRISPR-based genome editors DOI
Victoria J. Madigan, Feng Zhang, James E. Dahlman

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(11), P. 875 - 894

Published: Sept. 18, 2023

Language: Английский

Citations

80
Strategies for non-viral vectors targeting organs beyond the liver DOI
Jeonghwan Kim, Yulia Eygeris, Renee C. Ryals

et al.

Nature Nanotechnology, Journal Year: 2023, Volume and Issue: 19(4), P. 428 - 447

Published: Dec. 27, 2023

Language: Английский

Citations

59
CRISPR-Cas9 in Cardiovascular Medicine: Unlocking New Potential for Treatment DOI Creative Commons
Klaudia Bonowicz, Dominika Jerka, Klaudia Piekarska

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(2), P. 131 - 131

Published: Jan. 17, 2025

Cardiovascular diseases (CVDs) remain a significant global health challenge, with many current treatments addressing symptoms rather than the genetic roots of these conditions. The advent CRISPR-Cas9 technology has revolutionized genome editing, offering transformative approach to targeting disease-causing mutations directly. This article examines potential in treatment various CVDs, including atherosclerosis, arrhythmias, cardiomyopathies, hypertension, and Duchenne muscular dystrophy (DMD). technology's ability correct single-gene high precision efficiency positions it as groundbreaking tool cardiovascular therapy. Recent developments have extended capabilities include mitochondrial critical advancement for dysfunctions often linked disorders. Despite its promise, challenges remain, off-target effects, ethical concerns, limitations delivery methods, which hinder translation into clinical practice. also explores regulatory considerations surrounding gene editing technologies, emphasizing implications somatic versus germline modifications. Future research efforts should aim enhance accuracy CRISPR-Cas9, improve systems targeted tissues, ensure safety efficacy long term. Overcoming obstacles could enable not only treat but potentially cure genetically driven diseases, heralding new era medicine health.

Language: Английский

Citations

2
Recent advances in CRISPR-based genome editing technology and its applications in cardiovascular research DOI Creative Commons
Zhenhua Li, Jun Wang, Jingping Xu

et al.

Military Medical Research, Journal Year: 2023, Volume and Issue: 10(1)

Published: March 10, 2023

Abstract The rapid development of genome editing technology has brought major breakthroughs in the fields life science and medicine. In recent years, clustered regularly interspaced short palindromic repeats (CRISPR)-based toolbox been greatly expanded, not only with emerging CRISPR-associated protein (Cas) nucleases, but also novel applications through combination diverse effectors. Recently, transposon-associated programmable RNA-guided systems have uncovered, adding myriads potential new tools to toolbox. CRISPR-based revolutionized cardiovascular research. Here we first summarize advances involving newly identified Cas orthologs, engineered variants systems, then discuss CRISPR-Cas precise editing, such as base prime editing. We highlight progress research using technologies, including generation genetically modified vitro animal models diseases (CVD) well treating different types CVD. Finally, current limitations future prospects technologies are discussed.

Language: Английский

Citations

34
RNA-binding proteins in cardiovascular biology and disease: the beat goes on DOI
Mirko Völkers, Thomas Preiß, Matthias W. Hentze

et al.

Nature Reviews Cardiology, Journal Year: 2024, Volume and Issue: 21(6), P. 361 - 378

Published: Jan. 2, 2024

Language: Английский

Citations

16
Mechanisms of RBM20 Cardiomyopathy: Insights From Model Systems DOI
Zachery R. Gregorich, Yanghai Zhang, Timothy J. Kamp

et al.

Circulation Genomic and Precision Medicine, Journal Year: 2024, Volume and Issue: 17(1)

Published: Jan. 30, 2024

RBM20 (RNA-binding motif protein 20) is a vertebrate- and muscle-specific RNA-binding that belongs to the serine-arginine-rich family of splicing factors. The gene was first identified as dilated cardiomyopathy–linked over decade ago. Early studies in Rbm20 knockout rodents implicated disrupted target genes causative mechanism. Clinical show pathogenic variants are linked aggressive cardiomyopathy with early onset heart failure high mortality. Subsequent employing variant knock-in animal models revealed specific portion arginine-serine-rich domain not only disrupt but also hinder nucleocytoplasmic transport lead formation biomolecular condensates sarcoplasm. Conversely, mice harboring disease-associated RRM (RNA recognition motif) do evidence adverse remodeling or exhibit sudden death despite genes. Thus, whether splicing, condensates, both contribute under debate. Beyond this, additional questions remain, such there sexual dimorphism presentation cardiomyopathy. What clinical features why some individuals develop more severe disease than others? In this review, we summarize reported observations discuss potential mechanisms derived from vivo vitro human-induced pluripotent stem cell–derived cardiomyocytes. Potential therapeutic strategies treat discussed.

Language: Английский

Citations

12
Recent Therapeutic Gene Editing Applications to Genetic Disorders DOI Creative Commons
Éric Deneault

Current Issues in Molecular Biology, Journal Year: 2024, Volume and Issue: 46(5), P. 4147 - 4185

Published: April 30, 2024

Recent years have witnessed unprecedented progress in therapeutic gene editing, revolutionizing the approach to treating genetic disorders. In this comprehensive review, we discuss progression of milestones leading emergence clustered regularly interspaced short palindromic repeats (CRISPR)-based technology as a powerful tool for precise and targeted modifications human genome. CRISPR-Cas9 nuclease, base prime editing taken center stage, demonstrating remarkable precision efficacy ex vivo genomic modifications. Enhanced delivery systems, including viral vectors nanoparticles, further improved efficiency safety advancing their clinical translatability. The exploration CRISPR-Cas systems beyond commonly used Cas9, such development Cas12 Cas13 variants, has expanded repertoire tools, enabling more intricate interventions. Outstandingly, represents significant leap forward, given its unparalleled versatility minimization off-target effects. These innovations paved way multitude previously incurable disorders, ranging from monogenic diseases complex polygenic conditions. This review highlights latest innovative studies field, emphasizing breakthrough technologies preclinical trials, applications realm medicine. However, challenges effects ethical considerations remain, necessitating continued research refine profiles frameworks.

Language: Английский

Citations

12
Breaking genetic shackles: The advance of base editing in genetic disorder treatment DOI Creative Commons

Fang Xu,

Caiyan Zheng,

Weihui Xu

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: March 6, 2024

The rapid evolution of gene editing technology has markedly improved the outlook for treating genetic diseases. Base editing, recognized as an exceptionally precise modification tool, is emerging a focus in realm disease therapy. We provide comprehensive overview fundamental principles and delivery methods cytosine base editors (CBE), adenine (ABE), RNA editors, with particular on their applications recent research advances treatment have also explored potential challenges faced by treatment, including aspects such targeting specificity, safety, efficacy, enumerated series possible solutions to propel clinical translation technology. In conclusion, this article not only underscores present state but envisions its tremendous future, providing novel perspective It vast medicine, support progression medicine development innovative approaches

Language: Английский

Citations

10
Focused Ultrasound and Microbubble-Mediated Delivery of CRISPR-Cas9 Ribonucleoprotein to Human Induced Pluripotent Stem Cells DOI

Kyle Hazel,

Davindra Singh,

Stephanie He

et al.

Molecular Therapy, Journal Year: 2025, Volume and Issue: 33(3), P. 986 - 996

Published: Jan. 10, 2025

Language: Английский

Citations

1
Striated muscle-specific base editing enables correction of mutations causing dilated cardiomyopathy DOI Creative Commons
Markus Grosch, Laura Schraft,

Adrian Chan

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 22, 2023

Dilated cardiomyopathy is the second most common cause for heart failure with no cure except a high-risk transplantation. Approximately 30% of patients harbor heritable mutations which are amenable to CRISPR-based gene therapy. However, challenges related delivery editing complex and off-target concerns hamper broad applicability CRISPR agents in heart. We employ combination viral vector AAVMYO superior targeting specificity muscle tissue base editors repair patient cardiac splice factor Rbm20, aggressive dilated cardiomyopathy. Using optimized conditions, we >70% cardiomyocytes two Rbm20 knock-in mouse models that have generated serve as an vivo platform our strategy. Treatment juvenile mice restores localization defect RBM20 75% cells splicing targets including TTN. Three months after injection, dilation ejection fraction reach wild-type levels. Single-nuclei RNA sequencing uncovers restoration transcriptional profile across all major cell types whole-genome reveals evidence aberrant editing. Our study highlights potential combined achieve treatment hereditary diseases.

Language: Английский

Citations

21