https://orcid.org/0000-0002-5881-6796
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ABSTRACT
Introduction
After understanding the genetic basis of cardiovascular disorders, the discovery of prime editing (PE), has opened new horizons for finding their cures. PE strategy is the most versatile editing tool to change cardiac genetic background for therapeutic interventions. The optimization of elements, prediction of efficiency, and discovery of the involved genes regulating the process have not been completed. The large size of the cargo and multi-elementary structure makes the in vivo heart delivery challenging.
Areas covered
Updated from recent published studies, the fundamentals of the PEs, their application in cardiology, potentials, shortcomings, and the future perspectives for the treatment of cardiac-related genetic disorders will be discussed.
Expert Opinion
The ideal PE for the heart should be tissue-specific, regulatable, less immunogenic, high transducing, and safe. However, low efficiency, sup-optimal PE architecture, the large size of required elements, the unclear role of transcriptomics on the process, unpredictable off-target effects, and its context-dependency are subjects that need to be considered. It is also of great importance to see how beneficial or detrimental cell cycle or epigenomic modifier is to bring changes into cardiac cells. The PE delivery is challenging due to the size, multi-component properties of the editors and liver sink.
Article highlights
As the most versatile and precise editing strategy, prime editing can bring a durable cure for most genetic cardiac diseases.
Several generations of prime editors have been developed that can correct most cardiac genetic disorders.
Despite fast progression, the optimization of PE elements and heart-specific delivery methods need further studies to be functional in vivo.
The most important challenge of PE is the delivery method due to its large size and current limitations of viral and non-viral vectors.
Non-viral delivery such as RNP and VLP have advantages of safety, transient expression, and low immune induction that can be employed for PE transduction.
Myocardial cells are different from other cells due to their quiescent status, and long half-life, therefore genome editing by PE is a promising approach but needs improvements.
Abbreviations
| AAV | = | Adeno-associated virus |
| BFP | = | Blue fluorescent protein |
| BEs | = | base editors |
| CRISPR | = | clustered regularly interspaced short palindromic repeats |
| Cas9 | = | CRISPR-associated nuclease 9 |
| CHD | = | Chronic heart disease |
| DCM | = | dilated cardiomyopathy |
| DMD | = | Duchene muscular dystrophy |
| DSB | = | double-strand DNA break |
| DsDNA | = | Double-stranded DNA |
| GFP | = | Green fluorescent protein |
| hiPSC | = | human induced pluripotent stem cell |
| HCM | = | hypertrophic cardiomyopathy |
| HDR | = | homology-directed repair, |
| IPSCs | = | induced pluripotent stem cells |
| Kbp | = | kilo base pair |
| LNP | = | Lipid nanoparticle |
| LDL | = | Low-density lipoprotein |
| MMEJ | = | microhomology-mediated end joining |
| NHEJ | = | non-homologous end joining |
| PAM | = | protospacer adjacent motif |
| PBS | = | primer binding site |
| pegRNA | = | prime editing guide RNA |
| PEs | = | Prime editors |
| RNP | = | ribonucleoprotein complexes |
| RT | = | reverse transcriptase |
| RTT | = | reverse transcriptase template |
| SNP | = | single nucleotide polymorphism |
| sgRNA | = | single guide RNA |
| VLP | = | virus-like particle |
Declaration of interests
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.