CRISPR/Cas9 gene-editing strategies in cardiovascular cells

Abstract

Cardiovascular diseases are among the main causes of morbidity and mortality in Western countries and considered as a leading public health issue. Therefore, there is a strong need for new disease models to support the development of novel therapeutics approaches. The successive improvement of genome editing tools with zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and more recently with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) has enabled the generation of genetically modified cells and organisms with much greater efficiency and precision than before. The simplicity of CRISPR/Cas9 technology made it especially suited for different studies, both in vitro and in vivo, and has been used in multiple studies evaluating gene functions, disease modelling, transcriptional regulation, and testing of novel therapeutic approaches. Notably, with the parallel development of human induced pluripotent stem cells (hiPSCs), the generation of knock-out and knock-in human cell lines significantly increased our understanding of mutation impacts and physiopathological mechanisms within the cardiovascular domain. Here, we review the recent development of CRISPR–Cas9 genome editing, the alternative tools, the available strategies to conduct genome editing in cardiovascular cells with a focus on its use for correcting mutations in vitro and in vivo both in germ and somatic cells. We will also highlight that, despite its potential, CRISPR/Cas9 technology comes with important technical and ethical limitations. The development of CRISPR/Cas9 genome editing for cardiovascular diseases indeed requires to develop a specific strategy in order to optimize the design of the genome editing tools, the manipulation of DNA repair mechanisms, the packaging and delivery of the tools to the studied organism, and the assessment of their efficiency and safety.

Cardiac Organoids to Model and Heal Heart Failure and Cardiomyopathies

“…Most of these cardiomyopathies have a strong genetic component [ 3 , 4 , 11 ], which is however incompletely understood. Modeling of these cardiomyopathies is also challenging because of variability in the clinical expression, incomplete penetrance of diseases in carriers of pathogenic variants, and phenotypic overlap between different cardiomyopathies.…”

“…However, the genotype–phenotype relationships are incompletely understood and the underlying mechanisms leading to cardiomyopathies and complications are only progressively reported [ 5 , 6 , 7 , 8 ]. In addition, the recent emergence of small molecules targeting major contractile proteins of cardiomyocytes or genome editing techniques could quickly create opportunities to cure genetic cardiomyopathies [ 9 , 10 , 11 , 12 ]. There is thus a need for models that can recapitulate key features observed in human cardiomyopathies and can be used for disease modeling and therapeutic testing.…”

Application of CRISPR-Cas9 gene editing for congenital heart disease

“…Below, we will focus on CRISPR-Cas9 applications using CHD animal models; however, there are many reviews of CRISPR-Cas9 strategies for human heart diseases. 14,[67][68][69] Initially In addition, several genes reported to be commonly associated with CHDs (e.g., Myh and serum response factor) were targeted to develop an animal model and to study the pathogenesis of disease. 72) Later studies used human induced pluripotent stem cells (hiPSCs) [73][74][75] as model systems, which may enable a personalized medical approach to treat CHD patients.…”

CRISPR-Cas and Its Wide-Ranging Applications: From Human Genome Editing to Environmental Implications, Technical Limitations, Hazards and Bioethical Issues

“…This system is very useful to create disease models or to discover new etiological agents, allowing researchers to better understand their biology. Examples include cancer, neurological diseases, cardiovascular diseases, immunodeficiency, infectious diseases, sickle cell disease, hemophilia, metabolic diseases, cystic fibrosis, retinitis pigmentosa, and several others (reviewed in [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ]). In particular, the treatment and characterization of cancer is very promising, and hundreds of publications are available on this topic (for recent reviews, see for example [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]).…”