Table 1 Recent applications of genome editing in the treatment of CVD
Diseases | Models | Mutations | Strategies | Outcomes | References |
|---|---|---|---|---|---|
DMD | Mice hiPSC-CMs | Deletion of Dmd exon44 | Skipping and/or reframing of exon43 or 45 by single sgRNA targeting splice acceptor or donor site | Restore dystrophin expression and improve muscle function | [144] |
| Â | Mice hiPSC-CMs | Deletion of Dmd exon43, 45 or 52 | Skipping and/or reframing of exon44 or 53 by single sgRNA targeting splice acceptor or donor site | Rescue the dystrophic phenotype, reduce necrotic cells and centralized nuclei | [171] |
| Â | Pigs hiPSC-CMs | Deletion of Dmd exon52 | Deletion of exon51 by dual sgRNAs targeting flanking sequences | Improve muscle function and mobility and prevent malignant arrhythmias | [172] |
|  | Mice | A nonsense mutation in Dmd exon23 | Deletion of exon23 or 21–23 by dual sgRNAs targeting flanking sequences | Restore dystrophin expression and improve cardiac function without inducing serious adverse effects | |
| Â | Mice hiPSC-CMs | Deletion of Dmd exon51 | Skipping of exon50 by destroying splice donor site using ABEmax in vivo; reframing of exon52 by PE in vitro | Restore dystrophin protein expression and normalize contractile abnormalities | [146] |
| Â | Mice | A 4Â bp deletion in Dmd exon4 | Skipping of exon4 by destroying splice donor site using CBE | Improve cardiac function and increase life span | [160] |
| Â | Mice | A nonsense mutation in Dmd exon53 | Correction of the stop codon by ABE | A near complete rescue of dystrophin in hearts without obvious toxicity | [173] |
HCM | Mouse embryos | A missense mutation in Myh6 c.1211C > T (p. Arg404Trp) | Correction of the mutant nucleotide by ABEmax | Abolish HCM phenotypes in mice born from edited embryos | [141] |
|  | hiPSC-CMs | Biallelic variants in LZTR1 (paternal c.1943-256C > T create a new splice donor site and maternal c.27dupG) | Disruption of the SNP-induced splice donor site in the paternal allele by single sgRNA | Reverse the NS-associated hypertrophic phenotype including cell size, contractile and electrophysiological properties | [174] |
| Â | Human pronuclear stage zygotes | A dominant 4Â bp deletion in MYBPC3 exon16 | HDR by microinjection of sgRNA, Cas9 protein and ssODN | Heterozygous gene mutations can be corrected in human gametes or early embryos | [175] |
DCM | hiPSC-CMs | A 2Â bp insertion in TTN exon327 c.70692_70693insAT | HDR by nucleofection of CRISPR/Cas9 RNP complex targeting the mutated allele and ssODN | Normalize titin protein level and contractile function | [140] |
| Â | hiPSC-CMs | A 1Â bp deletion in TTN exon276 | Reframing of the mutant allele by single sgRNA targeting the mutant site | Increase full-length TTN protein levels and sarcomere function | [176] |
|  | hiPSC-CMs | Missense mutations in RBM20 c.1901G > A (p. Arg634Gln) and c.1906C > A (p. Arg636Ser) | Correction of the mutant nucleotide by ABEmax and PE | Restore RBM20 nuclear localization and eliminate RNP granules in the cytoplasm | [177] |
|  | Mice | A missense mutation in Rbm20 c.1907C > A (p. Arg636Gln) | Correction of the mutant nucleotide by ABEmax | Restore RBM20 nuclear localization, eliminate RNP granules, restore cardiac size and function, and increase life span | [177] |
Cardiac arrhythmia | Humanized mice | A 3Â bp deletion in PLN c.40_42AGA (p.Arg14del) | Disruption of the mutant allele by single sgRNA targeting the mutant site | Improve cardiac function and reduce sustained ventricular tachycardia susceptibility | [178] |
Atherosclerosis | Mice | – | Disrupting liver Pcsk9 gene by adenovirus/AAV-delivered sgRNA targeting coding sequences | Disrupt Pcsk9 genes and chronically decrease serum cholesterol levels | |
|  | Mice macaques cynomolgus monkeys | – | Disruption of the splice donor site of liver PCSK9 exon1 by AAV/LNP/eVLP-delivered ABE | Reduce plasma PCSK9 and LDL levels |