Correction of diverse muscular dystrophy mutations in human engineered heart muscle by single-site genome editing

Long, Chengzu; Li, Hui; Tiburcy, Malte; Rodriguez-Caycedo, Cristina; Kyrychenko, Viktoriia; Zhou, Huanyu; Zhang, Yu; Min, Yi Li; Shelton, John M.; Mammen, Pradeep P.A.; Liaw, Norman Y.; Zimmermann, Wolfram H.; Bassel‐Duby, Rhonda; Schneider, Jay W.; Olson, Eric N.

doi:10.1126/sciadv.aap9004

Cited by 210 publications

(204 citation statements)

References 43 publications

Supporting

Mentioning

196

Contrasting

Unclassified

Order By: Relevance

“…In vivo genome editing with the CRISPR- Cas9 system restored muscle function by correcting the Dmd mutation in a mouse model of Duchenne muscular dystrophy in both the germline and the postnatal stage 176–180 . In a proof-of-principle study, genome editing technology also corrected mutations in human iPSC- derived cardiomyocytes from patients with Duchenne muscular dystrophy 181–185 . Corrected iPSC-derived cardiomyocytes had restored dystrophin expression and improved cardiomyocyte functional performance in vitro, such as improved contraction and suppression of arrhythmia (FIG.…”

Section: Future Perspectivesmentioning

confidence: 99%

Therapeutic approaches for cardiac regeneration and repair

2018

Self Cite

View full text Add to dashboard Cite

Ischaemic heart disease is a leading cause of death worldwide. Injury to the heart is followed by loss of the damaged cardiomyocytes, which are replaced with fibrotic scar tissue. Depletion of cardiomyocytes results in decreased cardiac contraction, which leads to pathological cardiac dilatation, additional cardiomyocyte loss, and mechanical dysfunction, culminating in heart failure. This sequential reaction is defined as cardiac remodelling. Many therapies have focused on preventing the progressive process of cardiac remodelling to heart failure. However, after patients have developed end-stage heart failure, intervention is limited to heart transplantation. One of the main reasons for the dramatic injurious effect of cardiomyocyte loss is that the adult human heart has minimal regenerative capacity. In the past 2 decades, several strategies to repair the injured heart and improve heart function have been pursued, including cellular and noncellular therapies. In this Review, we discuss current therapeutic approaches for cardiac repair and regeneration, describing outcomes, limitations, and future prospects of preclinical and clinical trials of heart regeneration. Substantial progress has been made towards understanding the cellular and molecular mechanisms regulating heart regeneration, offering the potential to control cardiac remodelling and redirect the adult heart to a regenerative state.

show abstract

Section: Future Perspectivesmentioning

confidence: 99%

Therapeutic approaches for cardiac regeneration and repair

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…© 2017. Published by The Company of Biologists Ltd.; reprinted/adapted from Long et al . © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.…”

Section: Cardiac Organoids Modeling Human Cardiac Diseases In Vitromentioning

confidence: 99%

“…Tafazzin has been identified as a mitochondrial acyl‐transferase, involved in the biogenesis of cardiolipin, a phospholipid, almost exclusively found in mitochondrial membranes, which is mainly related to progressive cardiomyopathy and a weakened immune system . In correlated lethal degeneration of cardiac and skeletal muscle DMD, 3,000 different mutations in the X‐linked dystrophin gene have been identified . These mutations are clustered in specific hotspot areas of the dystrophin gene (exons 45–55 and exons 2–10), which renders genomic correction challenging.…”

Section: Cardiac Organoids Modeling Human Cardiac Diseases In Vitromentioning

confidence: 99%

Human Cardiac Organoids for Disease Modeling

Nugraha

Buono

Boehmer

et al. 2018

Clin Pharma and Therapeutics

104

View full text Add to dashboard Cite

Human cardiac drug discovery and disease modeling face challenges in recapitulating cellular complexity and animal‐to‐human translation due to the limitations of conventional 2D cell culture and animal models. The development of human cardiac organoid technologies could help in stimulating and maintaining differentiated cell functions for extended periods of time. By closely mimicking in vivo organ functions in vitro they could thereby help in overcoming the obstacles mentioned above. Through the construction of human cardiac organoids from pluripotent stem cell–derived cells, derived from patients with specific known genotypes and phenotypes, more complex and robust in vitro tools have recently become available for disease modeling. In this review, we will describe the relevance and importance of evolving organoid platforms in disease biology. We further provide examples of cardiac organoid platforms, which may lead the way toward future personalized medicine and drug discovery.

show abstract

“…Using 3D engineered heart muscle, they found that a single cut was enough to skip the defective exon, resulting in the restoration of dystrophin protein expression and muscle function [7]. “We found that correcting less than half of the cardiomyocytes (heart muscle cells) was enough to rescue cardiac function to near-normal levels in human-engineered heart tissue,” explained Chengzu Long (UT Southwestern), the study's lead author [8].…”

Section: The Power Of Strengthmentioning

confidence: 99%