The incidence and the burden of cardiovascular disease (CVD), coronary heart disease (CHD), type 2 diabetes mellitus (T2DM), and the metabolic syndrome are greatly increasing in our societies. Together, they account for 31% of all deaths worldwide. This chapter focuses on the role of two revolutionary discoveries that are changing the future of medicine, induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 technology, in the study, and the cure of cardiovascular and metabolic diseases.We summarize the state-of-the-art knowledge about the possibility of editing iPSC genome for therapeutic applications without hampering their pluripotency and differentiation, using CRISPR/Cas technology, in the field of cardiovascular and metabolic diseases.

Department of Hematology Bone Marrow Transplantation and Cell Therapy of St Marina University Hospital Varna Bulgaria

Department of Stem Cell Biology and Transplantology Research Institute of the Medical University Varna Varna Bulgaria

Epigenetics Metabolism and Aging Unit Center for Translational Medicine International Clinical Research Center St'Anne University Hospital Brno Czech Republic

Liverpool Centre for Cardiovascular Science Liverpool United Kingdom

Zobrazit více v PubMed

Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676 PubMed DOI

Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872 PubMed DOI

Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318(5858):1917–1920 PubMed DOI

Gurdon JB (1962) The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J Embryol Exp Morphol 10:622–640 PubMed

Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385(6619):810–813 PubMed DOI

Tada M, Takahama Y, Abe K, Nakatsuji N, Tada T (2001) Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr Biol 11(19):1553–1558 PubMed DOI

Barrangou R (2015) The roles of CRISPR-Cas systems in adaptive immunity and beyond. Curr Opin Immunol 32:36–41 PubMed DOI

Horvath P, Barrangou R (2010) CRISPR/Cas, the immune system of bacteria and archaea. Science 327(5962):167–170 PubMed DOI

Marraffini LA, Sontheimer EJ (2008) CRISPR interference limits horizontal gene transfer in staphylococci by targeting DNA. Science 322(5909):1843–1845 PubMed DOI PMC

Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157(6):1262–1278 PubMed DOI PMC

Barrangou R, Marraffini LA (2014) CRISPR-Cas systems: prokaryotes upgrade to adaptive immunity. Mol Cell 54(2):234–244 PubMed DOI PMC

Szczepankowska A (2012) Role of CRISPR/cas system in the development of bacteriophage resistance. Adv Virus Res 82:289–338 PubMed DOI

Hille F, Richter H, Wong SP, Bratovic M, Ressel S, Charpentier E (2018) The biology of CRISPR-Cas: backward and forward. Cell 172(6):1239–1259 PubMed DOI

Deltcheva E, Chylinski K, Sharma CM, Gonzales K, Chao Y, Pirzada ZA, Eckert MR, Vogel J, Charpentier E (2011) CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III. Nature 471(7340):602–607 PubMed DOI PMC

Bolotin A, Quinquis B, Sorokin A, Ehrlich SD (2005) Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin. Microbiology 151(8):2551–2561 PubMed DOI

Makarova KS, Grishin NV, Shabalina SA, Wolf YI, Koonin EV (2006) A putative RNA-interference-based immune system in prokaryotes: computational analysis of the predicted enzymatic machinery, functional analogies with eukaryotic RNAi, and hypothetical mechanisms of action. Biol Direct 1:7 PubMed DOI PMC

Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, Romero DA, Horvath P (2007) CRISPR provides acquired resistance against viruses in prokaryotes. Science 315(5819):1709–1712 PubMed DOI

Deveau H, Barrangou R, Garneau JE, Labonte J, Fremaux C, Boyaval P, Romero DA, Horvath P, Moineau S (2008) Phage response to CRISPR-encoded resistance in Streptococcus thermophilus. J Bacteriol 190(4):1390–1400 PubMed DOI

Garneau JE, Dupuis ME, Villion M, Romero DA, Barrangou R, Boyaval P, Fremaux C, Horvath P, Magadan AH, Moineau S (2010) The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature 468(7320):67–71 PubMed DOI

Makarova KS, Aravind L, Wolf YI, Koonin EV (2011) Unification of Cas protein families and a simple scenario for the origin and evolution of CRISPR-Cas systems. Biol Direct 6:38 PubMed DOI PMC

Bhaya D, Davison M, Barrangou R (2011) CRISPR-Cas systems in bacteria and archaea: versatile small RNAs for adaptive defense and regulation. Annu Rev Genet 45:273–297 PubMed DOI

Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337(6096):816–821 PubMed DOI PMC

Xu Y, Li Z (2020) CRISPR-Cas systems: overview, innovations and applications in human disease research and gene therapy. Comput Struct Biotechnol J 18:2401–2415 PubMed DOI PMC

Zaragoza C, Gomez-Guerrero C, Martin-Ventura JL, Blanco-Colio L, Lavin B, Mallavia B, Tarin C, Mas S, Ortiz A, Egido J (2011) Animal models of cardiovascular diseases. J Biomed Biotechnol 2011:497841 PubMed DOI PMC

King AJ (2012) The use of animal models in diabetes research. Br J Pharmacol 166(3):877–894 PubMed DOI PMC

El Refaey M, Xu L, Gao Y, Canan BD, Adesanya TMA, Warner SC, Akagi K, Symer DE, Mohler PJ, Ma J, Janssen PML, Han R (2017) In vivo genome editing restores dystrophin expression and cardiac function in dystrophic mice. Circ Res 121(8):923–929 PubMed DOI PMC

Amoasii L, Hildyard JCW, Li H, Sanchez-Ortiz E, Mireault A, Caballero D, Harron R, Stathopoulou TR, Massey C, Shelton JM, Bassel-Duby R, Piercy RJ, Olson EN (2018) Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science 362(6410):86–91 PubMed DOI PMC

Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG, MacLennan DH, Seidman JG, Seidman CE (2003) Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science 299(5611):1410–1413 PubMed DOI

Kaneko M, Hashikami K, Yamamoto S, Matsumoto H, Nishimoto T (2016) Phospholamban ablation using CRISPR/Cas9 system improves mortality in a murine heart failure model. PLoS One 11(12):e0168486 PubMed DOI PMC

Chung JY, Ain QU, Song Y, Yong SB, Kim YH (2019) Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance. Genome Res 29(9):1442–1452 PubMed DOI PMC

Furuhashi M, Tuncman G, Gorgun CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA et al (2007) Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447(7147):959–965 PubMed DOI PMC

Srifa W, Kosaric N, Amorin A, Jadi O, Park Y, Mantri S, Camarena J, Gurtner GC, Porteus M (2020) Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice. Nat Commun 11(1):2470 PubMed DOI PMC

Wang X, Huang R, Zhang L, Li S, Luo J, Gu Y, Chen Z, Zheng Q, Chao T, Zheng W, Qi X, Wang L, Wen Y et al (2018) A severe atherosclerosis mouse model on the resistant NOD background disease. Models Mech 11(10):33852

Lin X, Pelletier S, Gingras S, Rigaud S, Maine CJ, Marquardt K, Dai YD, Sauer K, Rodriguez AR, Martin G, Kupriyanov S, Jiang L, Yu L et al (2016) CRISPR-Cas9-mediated modification of the NOD mouse genome with Ptpn22R619W mutation increases autoimmune diabetes. Diabetes 65(8):2134–2138 PubMed DOI PMC

Lee H, Yoon DE, Kim K (2020) Genome editing methods in animal models. Anim Cells Syst 24(1):8–16 DOI

Roh JI, Lee J, Park SU, Kang YS, Lee J, Oh AR, Choi DJ, Cha JY, Lee HW (2018) CRISPR-Cas9-mediated generation of obese and diabetic mouse models. Exp Anim 67(2):229–237 PubMed DOI PMC

Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, Foell J, de la Fuente J, Grupp S, Handgretinger R, Ho TW, Kattamis A, Kernytsky A et al (2020) CRISPR-Cas9 gene editing for sickle cell disease and beta-thalassemia. N Engl J Med 384:252–260 PubMed DOI

Musunuru K, Sheikh F, Gupta RM, Houser SR, Maher KO, Milan DJ, Terzic A, Wu JC (2018) Induced pluripotent stem cells for cardiovascular disease modeling and precision medicine: a scientific statement from the American Heart Association. Circulation 11(1):e000043 PubMed

Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR et al (2012) Truncations of titin causing dilated cardiomyopathy. N Engl J Med 366(7):619–628 PubMed DOI PMC

Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC, Swist S, Gorham J, Yang L, Schafer S, Sheng CC, Haghighi A, Homsy J, Hubner N et al (2015) Heart disease. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science 349(6251):982–986 PubMed DOI PMC

Staff PO (2018) Correction: functional abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from titin-mutated patients with dilated cardiomyopathy. PLoS One 13(11):e0207548 DOI

Levine E, Rosero SZ, Budzikowski AS, Moss AJ, Zareba W, Daubert JP (2008) Congenital long QT syndrome: considerations for primary care physicians. Cleve Clin J Med 75(8):591–600 PubMed DOI

Alders M, Bikker H, Christiaans I (1993) Long QT syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews. University of Washington, Seattle

Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A et al (2009) Prevalence of the congenital long-QT syndrome. Circulation 120(18):1761–1767 PubMed DOI PMC

Wang Y, Liang P, Lan F, Wu H, Lisowski L, Gu M, Hu S, Kay MA, Urnov FD, Shinnawi R, Gold JD, Gepstein L, Wu JC (2014) Genome editing of isogenic human induced pluripotent stem cells recapitulates long QT phenotype for drug testing. J Am Coll Cardiol 64(5):451–459 PubMed DOI PMC

Kim MJ, Lee EY, You YH, Yang HK, Yoon KH, Kim JW (2020) Generation of iPSC-derived insulin-producing cells from patients with type 1 and type 2 diabetes compared with healthy control. Stem Cell Res 48:101958 PubMed DOI

Balboa D, Saarimaki-Vire J, Otonkoski T (2019) Concise review: human pluripotent stem cells for the modeling of pancreatic beta-cell. Pathol Stem Cells 37(1):33–41 DOI

Perez-Alcantara M, Honore C, Wesolowska-Andersen A, Gloyn AL, McCarthy MI, Hansson M, Beer NL, van de Bunt M (2018) Patterns of differential gene expression in a cellular model of human islet development, and relationship to type 2 diabetes predisposition. Diabetologia 61(7):1614–1622 PubMed DOI PMC

Furuyama K, Chera S, van Gurp L, Oropeza D, Ghila L, Damond N, Vethe H, Paulo JA, Joosten AM, Berney T, Bosco D, Dorrell C, Grompe M et al (2019) Diabetes relief in mice by glucose-sensing insulin-secreting human alpha-cells. Nature 567(7746):43–48 PubMed DOI PMC

Carroll D (2011) Genome engineering with zinc-finger nucleases. Genetics 188(4):773–782 PubMed DOI PMC

Jasin M (1996) Genetic manipulation of genomes with rare-cutting endonucleases. Trends Genet 12(6):224–228 PubMed DOI

Porteus MH, Carroll D (2005) Gene targeting using zinc finger nucleases. Nat Biotechnol 23(8):967–973 PubMed DOI

Porteus MH, Baltimore D (2003) Chimeric nucleases stimulate gene targeting in human cells. Science 300(5620):763 PubMed DOI

Chandrasegaran S, Smith J (1999) Chimeric restriction enzymes: what is next? Biol Chem 380(7):841–848 PubMed PMC

Bibikova M, Carroll D, Segal DJ, Trautman JK, Smith J, Kim YG, Chandrasegaran S (2001) Stimulation of homologous recombination through targeted cleavage by chimeric nucleases. Mol Cell Biol 21(1):289–297 PubMed DOI PMC

Miller JC, Holmes MC, Wang J, Guschin DY, Lee YL, Rupniewski I, Beausejour CM, Waite AJ, Wang NS, Kim KA, Gregory PD, Pabo CO, Rebar EJ (2007) An improved zinc-finger nuclease architecture for highly specific genome editing. Nat Biotechnol 25(7):778–785 PubMed DOI

Soldner F, Laganiere J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe LI, Myers RH, Lindquist S, Zhang L, Guschin D, Fong LK et al (2011) Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Cell 146(2):318–331 PubMed DOI PMC

Kiskinis E, Sandoe J, Williams LA, Boulting GL, Moccia R, Wainger BJ, Han S, Peng T, Thams S, Mikkilineni S, Mellin C, Merkle FT, Davis-Dusenbery BN et al (2014) Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell 14(6):781–795 PubMed DOI PMC

Arendt T, Stieler JT, Holzer M (2016) Tau and tauopathies. Brain Res Bull 126(3):238–292 PubMed DOI

Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, Lahaye T, Nickstadt A, Bonas U (2009) Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326(5959):1509–1512 PubMed DOI

Christian M, Cermak T, Doyle EL, Schmidt C, Zhang F, Hummel A, Bogdanove AJ, Voytas DF (2010) Targeting DNA double-strand breaks with TAL effector nucleases. Genetics 186(2):757–761 PubMed DOI PMC

Kim Y, Kweon J, Kim A, Chon JK, Yoo JY, Kim HJ, Kim S, Lee C, Jeong E, Chung E, Kim D, Lee MS, Go EM et al (2013) A library of TAL effector nucleases spanning the human genome. Nat Biotechnol 31(3):251–258 PubMed DOI

Sun N, Zhao H (2014) Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs. Biotechnol Bioeng 111(5):1048–1053 PubMed DOI

Iizuka H, Kagoya Y, Kataoka K, Yoshimi A, Miyauchi M, Taoka K, Kumano K, Yamamoto T, Hotta A, Arai S, Kurokawa M (2015) Targeted gene correction of RUNX1 in induced pluripotent stem cells derived from familial platelet disorder with propensity to myeloid malignancy restores normal megakaryopoiesis. Exp Hematol 43(10):849–857 PubMed DOI

Park CY, Kim J, Kweon J, Son JS, Lee JS, Yoo JE, Cho SR, Kim JH, Kim JS, Kim DW (2014) Targeted inversion and reversion of the blood coagulation factor 8 gene in human iPS cells using TALENs. Proc Natl Acad Sci U S A 111(25):9253–9258 PubMed DOI PMC

Woodruff G, Young JE, Martinez FJ, Buen F, Gore A, Kinaga J, Li Z, Yuan SH, Zhang K, Goldstein LS (2013) The presenilin-1 DeltaE9 mutation results in reduced gamma-secretase activity, but not total loss of PS1 function, in isogenic human stem cells. Cell Rep 5(4):974–985 PubMed DOI

Brookhouser N, Raman S, Potts C, Brafman DA (2017) May I cut in? Gene editing approaches in human induced pluripotent stem cells. Cell 6(1):5 DOI

Horii T, Tamura D, Morita S, Kimura M, Hatada I (2013) Generation of an ICF syndrome model by efficient genome editing of human induced pluripotent stem cells using the CRISPR system. Int J Mol Sci 14(10):19774–19781 PubMed DOI PMC

Fine JD, Eady RA, Bauer EA, Bauer JW, Bruckner-Tuderman L, Heagerty A, Hintner H, Hovnanian A, Jonkman MF, Leigh I, McGrath JA, Mellerio JE, Murrell DF et al (2008) The classification of inherited epidermolysis bullosa (EB): report of the Third international consensus meeting on diagnosis and classification of EB. J Am Acad Dermatol 58(6):931–950 PubMed DOI

Shinkuma S, McMillan JR, Shimizu H (2011) Ultrastructure and molecular pathogenesis of epidermolysis bullosa. Clin Dermatol 29(4):412–419 PubMed DOI

Shinkuma S, Guo Z, Christiano AM (2016) Site-specific genome editing for correction of induced pluripotent stem cells derived from dominant dystrophic epidermolysis bullosa. Proc Natl Acad Sci U S A 113(20):5676–5681 PubMed DOI PMC

Nayler S, Gatei M, Kozlov S, Gatti R, Mar JC, Wells CA, Lavin M, Wolvetang E (2012) Induced pluripotent stem cells from ataxia-telangiectasia recapitulate the cellular phenotype. Stem Cells Transl Med 1(7):523–535 PubMed DOI PMC

Hamasaki M, Hashizume Y, Yamada Y, Katayama T, Hohjoh H, Fusaki N, Nakashima Y, Furuya H, Haga N, Takami Y, Era T (2012) Pathogenic mutation of ALK2 inhibits induced pluripotent stem cell reprogramming and maintenance: mechanisms of reprogramming and strategy for drug identification. Stem Cells 30(11):2437–2449 PubMed DOI

Raya A, Rodriguez-Piza I, Guenechea G, Vassena R, Navarro S, Barrero MJ, Consiglio A, Castella M, Rio P, Sleep E, Gonzalez F, Tiscornia G, Garreta E et al (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460(7251):53–59 PubMed DOI PMC

Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R et al (2006) A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 38(5):525–527 PubMed DOI

Kim BY, Jeong S, Lee SY, Lee SM, Gweon EJ, Ahn H, Kim J, Chung SK (2016) Concurrent progress of reprogramming and gene correction to overcome therapeutic limitation of mutant ALK2-iPSC. Exp Mol Med 48(6):e237 PubMed DOI PMC

Park CY, Halevy T, Lee DR, Sung JJ, Lee JS, Yanuka O, Benvenisty N, Kim DW (2015) Reversion of FMR1 methylation and silencing by editing the triplet repeats in fragile X iPSC-derived neurons. Cell Rep 13(2):234–241 PubMed DOI

Wang G, McCain ML, Yang L, He A, Pasqualini FS, Agarwal A, Yuan H, Jiang D, Zhang D, Zangi L, Geva J, Roberts AE, Ma Q et al (2014) Modeling the mitochondrial cardiomyopathy of Barth syndrome with induced pluripotent stem cell and heart-on-chip technologies. Nat Med 20(6):616–623 PubMed DOI PMC

Mosqueira D, Mannhardt I, Bhagwan JR, Lis-Slimak K, Katili P, Scott E, Hassan M, Prondzynski M, Harmer SC, Tinker A, Smith JGW, Carrier L, Williams PM et al (2018) CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Eur Heart J 39(43):3879–3892 PubMed DOI PMC

Song HY, Chien CS, Yarmishyn AA, Chou SJ, Yang YP, Wang ML, Wang CY, Leu HB, Yu WC, Chang YL, Chiou SH (2019) Generation of GLA-knockout human embryonic stem cell lines to model autophagic dysfunction and exosome secretion in fabry disease-associated hypertrophic cardiomyopathy. Cell 8:4

Te Riele AS, Agullo-Pascual E, James CA, Leo-Macias A, Cerrone M, Zhang M, Lin X, Lin B, Sobreira NL, Amat-Alarcon N, Marsman RF, Murray B, Tichnell C et al (2017) Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis. Cardiovasc Res 113(1):102–111 DOI

Kodo K, Ong SG, Jahanbani F, Termglinchan V, Hirono K, InanlooRahatloo K, Ebert AD, Shukla P, Abilez OJ, Churko JM, Karakikes I, Jung G, Ichida F et al (2016) iPSC-derived cardiomyocytes reveal abnormal TGF-beta signalling in left ventricular non-compaction cardiomyopathy. Nat Cell Biol 18(10):1031–1042 PubMed DOI PMC

Young CS, Hicks MR, Ermolova NV, Nakano H, Jan M, Younesi S, Karumbayaram S, Kumagai-Cresse C, Wang D, Zack JA, Kohn DB, Nakano A, Nelson SF et al (2016) A single CRISPR-Cas9 deletion strategy that targets the majority of DMD patients restores dystrophin function in hiPSC-derived muscle cells. Cell Stem Cell 18(4):533–540 PubMed DOI PMC

Kyrychenko V, Kyrychenko S, Tiburcy M, Shelton JM, Long C, Schneider JW, Zimmermann WH, Bassel-Duby R, Olson EN (2017) Functional correction of dystrophin actin binding domain mutations by genome editing. JCI Insight 2:18 DOI

Saarimaki-Vire J, Balboa D, Russell MA, Saarikettu J, Kinnunen M, Keskitalo S, Malhi A, Valensisi C, Andrus C, Eurola S, Grym H, Ustinov J, Wartiovaara K et al (2017) An activating STAT3 mutation causes neonatal diabetes through premature induction of pancreatic differentiation. Cell Rep 19(2):281–294 PubMed DOI

Tiyaboonchai A, Cardenas-Diaz FL, Ying L, Maguire JA, Sim X, Jobaliya C, Gagne AL, Kishore S, Stanescu DE, Hughes N, De Leon DD, French DL, Gadue P (2017) GATA6 plays an important role in the induction of human definitive endoderm, development of the pancreas, and functionality of pancreatic beta cells. Stem Cell Rep 8(3):589–604 DOI

Ma S, Viola R, Sui L, Cherubini V, Barbetti F, Egli D (2018) Beta cell replacement after gene editing of a neonatal diabetes-causing mutation at the insulin locus. Stem Cell Rep 11(6):1407–1415 DOI

Yusa K, Rashid ST, Strick-Marchand H, Varela I, Liu PQ, Paschon DE, Miranda E, Ordonez A, Hannan NR, Rouhani FJ, Darche S, Alexander G, Marciniak SJ et al (2011) Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478(7369):391–394 PubMed DOI PMC

Smith C, Abalde-Atristain L, He C, Brodsky BR, Braunstein EM, Chaudhari P, Jang YY, Cheng L, Ye Z (2015) Efficient and allele-specific genome editing of disease loci in human iPSCs. Mol Ther 23(3):570–577 PubMed DOI

Caron J, Pene V, Tolosa L, Villaret M, Luce E, Fourrier A, Heslan JM, Saheb S, Bruckert E, Gomez-Lechon MJ, Nguyen TH, Rosenberg AR, Weber A et al (2019) Low-density lipoprotein receptor-deficient hepatocytes differentiated from induced pluripotent stem cells allow familial hypercholesterolemia modeling, CRISPR/Cas-mediated genetic correction, and productive hepatitis C virus infection. Stem Cell Res Ther 10(1):221 PubMed DOI PMC

Fulgencio-Covian A, Alvarez M, Pepers BA, Lopez-Marquez A, Ugarte M, Perez B, van Roon-Mom WMC, Desviat LR, Richard E (2020) Generation of a gene-corrected human isogenic line (UAMi006-A) from propionic acidemia patient iPSC with an homozygous mutation in the PCCB gene using CRISPR/Cas9 technology. Stem Cell Res 49:102055 PubMed DOI

Esteve J, Blouin JM, Lalanne M, Azzi-Martin L, Dubus P, Bidet A, Harambat J, Llanas B, Moranvillier I, Bedel A, Moreau-Gaudry F, Richard E (2019) Targeted gene therapy in human-induced pluripotent stem cells from a patient with primary hyperoxaluria type 1 using CRISPR/Cas9 technology. Biochem Biophys Res Commun 517(4):677–683 PubMed DOI

Kalra S, Montanaro F, Denning C (2016) Can human pluripotent stem cell-derived cardiomyocytes advance understanding of muscular dystrophies? J Neuromusc Dis 3(3):309–332 DOI

Piga D, Salani S, Magri F, Brusa R, Mauri E, Comi GP, Bresolin N, Corti S (2019) Human induced pluripotent stem cell models for the study and treatment of Duchenne and Becker muscular dystrophies. Ther Adv Neurol Disord 12:1756286419833478 PubMed DOI PMC

Macadangdang J, Guan X, Smith AS, Lucero R, Czerniecki S, Childers MK, Mack DL, Kim DH (2015) Nanopatterned human iPSC-based model of a dystrophin-null cardiomyopathic phenotype. Cell Mol Bioeng 8(3):320–332 PubMed DOI

Echigoya Y, Lim KRQ, Nakamura A, Yokota T (2018) Multiple exon skipping in the Duchenne muscular dystrophy hot spots: prospects and challenges. J Personal Med 8(4):41 DOI

Guo Y, VanDusen NJ, Zhang L, Gu W, Sethi I, Guatimosim S, Ma Q, Jardin BD, Ai Y, Zhang D, Chen B, Guo A, Yuan GC et al (2017) Analysis of cardiac myocyte maturation using CASAAV, a platform for rapid dissection of cardiac myocyte gene function in vivo. Circ Res 120(12):1874–1888 PubMed DOI PMC

Zhu X, Fang J, Jiang DS, Zhang P, Zhao GN, Zhu X, Yang L, Wei X, Li H (2015) Exacerbating pressure overload-induced cardiac hypertrophy: novel role of adaptor molecule SRC homology 2-B3. Hypertension 66(3):571–581 PubMed DOI

Zhang M, D'Aniello C, Verkerk AO, Wrobel E, Frank S, Ward-van Oostwaard D, Piccini I, Freund C, Rao J, Seebohm G, Atsma DE, Schulze-Bahr E, Mummery CL et al (2014) Recessive cardiac phenotypes in induced pluripotent stem cell models of Jervell and Lange-Nielsen syndrome: disease mechanisms and pharmacological rescue. Proc Natl Acad Sci U S A 111(50):5383–5392 DOI

Christidi E, Huang HM, Brunham LR (2018) CRISPR/Cas9-mediated genome editing in human stem cell-derived cardiomyocytes: applications for cardiovascular disease modelling and cardiotoxicity screening. Drug Discov Today Technol 28:13–21 PubMed DOI

Teo AK, Wagers AJ, Kulkarni RN (2013) New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism. Cell Metab 18(6):775–791 PubMed DOI

Teo AK, Windmueller R, Johansson BB, Dirice E, Njolstad PR, Tjora E, Raeder H, Kulkarni RN (2013) Derivation of human induced pluripotent stem cells from patients with maturity onset diabetes of the young. J Biol Chem 288(8):5353–5356 PubMed DOI PMC

Desai T, Shea LD (2017) Advances in islet encapsulation technologies. Nat Rev Drug Discov 16(5):338–350 PubMed DOI

Vaithilingam V, Bal S, Tuch BE (2017) Encapsulated islet transplantation: where do we stand? Rev Diabet Stud 14(1):51–78 PubMed DOI PMC

Hay DC, Zhao D, Fletcher J, Hewitt ZA, McLean D, Urruticoechea-Uriguen A, Black JR, Elcombe C, Ross JA, Wolf R, Cui W (2008) Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells 26(4):894–902 PubMed DOI

Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, North PE, Dalton S, Duncan SA (2010) Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51(1):297–305 PubMed DOI

Baxter M, Withey S, Harrison S, Segeritz CP, Zhang F, Atkinson-Dell R, Rowe C, Gerrard DT, Sison-Young R, Jenkins R, Henry J, Berry AA, Mohamet L et al (2015) Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes. J Hepatol 62(3):581–589 PubMed DOI PMC

Takayama K, Morisaki Y, Kuno S, Nagamoto Y, Harada K, Furukawa N, Ohtaka M, Nishimura K, Imagawa K, Sakurai F, Tachibana M, Sumazaki R, Noguchi E et al (2014) Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes. Proc Natl Acad Sci U S A 111(47):16772–16777 PubMed DOI PMC

Perlmutter DH (2006) Pathogenesis of chronic liver injury and hepatocellular carcinoma in alpha-1-antitrypsin deficiency. Pediatr Res 60(2):233–238 PubMed DOI

Eriksson S, Hagerstrand I (1974) Cirrhosis and malignant hepatoma in alpha 1-antitrypsin deficiency. Acta Med Scand 195(6):451–458 PubMed

Rashid ST, Corbineau S, Hannan N, Marciniak SJ, Miranda E, Alexander G, Huang-Doran I, Griffin J, Ahrlund-Richter L, Skepper J, Semple R, Weber A, Lomas DA et al (2010) Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Investig 120(9):3127–3136 PubMed DOI PMC

Cayo MA, Cai J, DeLaForest A, Noto FK, Nagaoka M, Clark BS, Collery RF, Si-Tayeb K, Duncan SA (2012) JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology 56(6):2163–2171 PubMed DOI

Rader DJ, Cohen J, Hobbs HH (2003) Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Investig 111(12):1795–1803 PubMed DOI PMC

Harada-Shiba M, Arai H, Ishigaki Y, Ishibashi S, Okamura T, Ogura M, Dobashi K, Nohara A, Bujo H, Miyauchi K, Yamashita S, Yokote K (2018) Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017. J Atheroscler Thromb 25(8):751–770 PubMed DOI PMC

Liu Y, Conlon DM, Bi X, Slovik KJ, Shi J, Edelstein HI, Millar JS, Javaheri A, Cuchel M, Pashos EE, Iqbal J, Hussain MM, Hegele RA et al (2017) Lack of MTTP activity in pluripotent stem cell-derived hepatocytes and cardiomyocytes abolishes apoB secretion and increases cell stress. Cell Rep 19(7):1456–1466 PubMed DOI PMC

Hovnanian A, Rochat A, Bodemer C, Petit E, Rivers CA, Prost C, Fraitag S, Christiano AM, Uitto J, Lathrop M, Barrandon Y, de Prost Y (1997) Characterization of 18 new mutations in COL7A1 in recessive dystrophic epidermolysis bullosa provides evidence for distinct molecular mechanisms underlying defective anchoring fibril formation. Am J Med Genet 61(3):599–610

Jackow J, Guo Z, Hansen C, Abaci HE, Doucet YS, Shin JU, Hayashi R, DeLorenzo D, Kabata Y, Shinkuma S, Salas-Alanis JC, Christiano AM (2019) CRISPR/Cas9-based targeted genome editing for correction of recessive dystrophic epidermolysis bullosa using iPS cells. Proc Natl Acad Sci U S A 116(52):26846–26852 PubMed DOI PMC

Laurent LC, Ulitsky I, Slavin I, Tran H, Schork A, Morey R, Lynch C, Harness JV, Lee S, Barrero MJ, Ku S, Martynova M, Semechkin R et al (2011) Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8(1):106–118 PubMed DOI PMC

Nash BM, Wright DC, Grigg JR, Bennetts B, Jamieson RV (2015) Retinal dystrophies, genomic applications in diagnosis and prospects for therapy. Transl Pediatr 4(2):139–163 PubMed PMC

Sanjurjo-Soriano C, Erkilic N, Baux D, Mamaeva D, Hamel CP, Meunier I, Roux AF, Kalatzis V (2020) Genome editing in patient iPSCs corrects the most prevalent USH2A mutations and reveals intriguing mutant mRNA expression profiles molecular therapy. Methods Clin Dev 17:156–173 DOI

Ou Z, Niu X, He W, Chen Y, Song B, Xian Y, Fan D, Tang D, Sun X (2016) The combination of CRISPR/Cas9 and iPSC technologies in the gene therapy of human beta-thalassemia in mice. Sci Rep 6:32463 PubMed DOI PMC

Galanello R, Origa R (2010) Beta-thalassemia. Orphanet J Rare Dis 5:11 PubMed DOI PMC

Song B, Fan Y, He W, Zhu D, Niu X, Wang D, Ou Z, Luo M, Sun X (2015) Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system. Stem Cells Dev 24(9):1053–1065 PubMed DOI

Hanna J, Wernig M, Markoulaki S, Sun CW, Meissner A, Cassady JP, Beard C, Brambrink T, Wu LC, Townes TM, Jaenisch R (2007) Treatment of sickle cell anemia mouse model with iPS cells generated from autologous skin. Science 318(5858):1920–1923 PubMed DOI

Wu SS, Li QC, Yin CQ, Xue W, Song CQ (2020) Advances in CRISPR/Cas-based gene therapy in human genetic diseases. Theranostics 10(10):4374–4382 PubMed DOI PMC

Xu S, Luk K, Yao Q, Shen AH, Zeng J, Wu Y, Luo HY, Brendel C, Pinello L, Chui DHK, Wolfe SA, Bauer DE (2019) Editing aberrant splice sites efficiently restores beta-globin expression in beta-thalassemia. Blood 133(21):2255–2262 PubMed DOI PMC

Roux LN, Petit I, Domart R, Concordet JP, Qu J, Zhou H, Joliot A, Ferrigno O, Aberdam D (2018) Modeling of aniridia-related keratopathy by CRISPR/Cas9 genome editing of human limbal epithelial cells and rescue by recombinant PAX6 protein. Stem Cells 36(9):1421–1429 PubMed DOI

Deinsberger J, Reisinger D, Weber B (2020) Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis. NPJ Regen Med 5:15 PubMed DOI PMC

Doss MX, Sachinidis A (2019) Current challenges of iPSC-based disease modeling and therapeutic implications. Cell 8:5

Yamanaka S (2020) Pluripotent stem cell-based cell therapy-promise and challenges cell. Stem Cells 27(4):523–531

Giallongo S, Rehakova D, Raffaele M, Lo Re O, Koutna I, Vinciguerra M (2021) Redox and epigenetics in human pluripotent stem cells differentiation. Antioxid Redox Signal 34(4):335–349 PubMed DOI

Hotta A, Yamanaka S (2015) From genomics to gene therapy: induced pluripotent stem cells meet genome editing. Annu Rev Genet 49:47–70 PubMed DOI

Tao Y, Zhang SC (2016) Neural subtype specification from human pluripotent stem cells. Stem Cells 19(5):573–586

Du Y, Wang J, Jia J, Song N, Xiang C, Xu J, Hou Z, Su X, Liu B, Jiang T, Zhao D, Sun Y, Shu J et al (2014) Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Stem Cells 14(3):394–403

Inamura M, Kawabata K, Takayama K, Tashiro K, Sakurai F, Katayama K, Toyoda M, Akutsu H, Miyagawa Y, Okita H, Kiyokawa N, Umezawa A, Hayakawa T et al (2011) Efficient generation of hepatoblasts from human ES cells and iPS cells by transient overexpression of homeobox gene HEX. Mol Ther 19(2):400–407 PubMed DOI

Takayama K, Inamura M, Kawabata K, Katayama K, Higuchi M, Tashiro K, Nonaka A, Sakurai F, Hayakawa T, Furue MK, Mizuguchi H (2012) Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4alpha transduction. Mol Ther 20(1):127–137 PubMed DOI

Chambers SM, Fasano CA, Papapetrou EP, Tomishima M, Sadelain M, Studer L (2009) Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27(3):275–280 PubMed DOI PMC

Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Sudhof TC, Wernig M (2011) Induction of human neuronal cells by defined transcription factors. Nature 476(7359):220–223 PubMed DOI PMC

Chanda S, Ang CE, Davila J, Pak C, Mall M, Lee QY, Ahlenius H, Jung SW, Sudhof TC, Wernig M (2014) Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Rep 3(2):282–296 DOI

Yamamizu K, Piao Y, Sharov AA, Zsiros V, Yu H, Nakazawa K, Schlessinger D, Ko MS (2013) Identification of transcription factors for lineage-specific ESC differentiation. Stem Cell Rep 1(6):545–559 DOI

Sun AX, Yuan Q, Tan S, Xiao Y, Wang D, Khoo AT, Sani L, Tran HD, Kim P, Chiew YS, Lee KJ, Yen YC, Ng HH et al (2016) Direct induction and functional maturation of forebrain GABAergic neurons from human pluripotent stem cells. Cell Rep 16(7):1942–1953 PubMed DOI

Theka I, Caiazzo M, Dvoretskova E, Leo D, Ungaro F, Curreli S, Manago F, Dell'Anno MT, Pezzoli G, Gainetdinov RR, Dityatev A, Broccoli V (2013) Rapid generation of functional dopaminergic neurons from human induced pluripotent stem cells through a single-step procedure using cell lineage transcription factors. Stem Cells Transl Med 2(6):473–479 PubMed DOI PMC

Hester ME, Murtha MJ, Song S, Rao M, Miranda CJ, Meyer K, Tian J, Boulting G, Schaffer DV, Zhu MX, Pfaff SL, Gage FH, Kaspar BK (2011) Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol Ther 19(10):1905–1912 PubMed DOI PMC

Kwon C, Qian L, Cheng P, Nigam V, Arnold J, Srivastava D (2009) A regulatory pathway involving Notch1/beta-catenin/Isl1 determines cardiac progenitor cell fate. Nat Cell Biol 11(8):951–957 PubMed DOI PMC

Fonoudi H, Yeganeh M, Fattahi F, Ghazizadeh Z, Rassouli H, Alikhani M, Mojarad BA, Baharvand H, Salekdeh GH, Aghdami N (2013) ISL1 protein transduction promotes cardiomyocyte differentiation from human embryonic stem cells. PLoS One 8(1):e55577 PubMed DOI PMC

Bai F, Ho Lim C, Jia J, Santostefano K, Simmons C, Kasahara H, Wu W, Terada N, Jin S (2015) Directed differentiation of embryonic stem cells into cardiomyocytes by bacterial injection of defined transcription factors. Sci Rep 5:15014 PubMed DOI PMC

Pearl JI, Lee AS, Leveson-Gower DB, Sun N, Ghosh Z, Lan F, Ransohoff J, Negrin RS, Davis MM, Wu JC (2011) Short-term immunosuppression promotes engraftment of embryonic and induced pluripotent stem cells. Cell Stem Cell 8(3):309–317 PubMed DOI PMC

Vallabhajosyula P, Hirakata A, Shimizu A, Okumi M, Tchipashvili V, Hong H, Yamada K, Sachs DH (2013) Assessing the effect of immunosuppression on engraftment of pancreatic islets. Transplantation 96(4):372–378 PubMed DOI PMC

Kruse V, Hamann C, Monecke S, Cyganek L, Elsner L, Hubscher D, Walter L, Streckfuss-Bomeke K, Guan K, Dressel R (2015) Human induced pluripotent stem cells are targets for allogeneic and autologous natural killer (NK) cells and killing is partly mediated by the activating NK receptor DNAM-1. PLoS One 10(5):e0125544 PubMed DOI PMC

Zhao T, Zhang ZN, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474(7350):212–215 PubMed DOI

Zhao T, Zhang ZN, Westenskow PD, Todorova D, Hu Z, Lin T, Rong Z, Kim J, He J, Wang M, Clegg DO, Yang YG, Zhang K et al (2015) Humanized mice reveal differential immunogenicity of cells derived from autologous induced pluripotent stem cells. Cell Stem Cell 17(3):353–359 PubMed DOI

Liu X, Li W, Fu X, Xu Y (2017) The immunogenicity and immune tolerance of pluripotent stem cell derivatives. Front Immunol 8:645 PubMed DOI PMC

Takagi S, Mandai M, Gocho K, Hirami Y, Yamamoto M, Fujihara M, Sugita S, Kurimoto Y, Takahashi M (2019) Evaluation of transplanted autologous induced pluripotent stem cell-derived retinal pigment epithelium in exudative age-related macular degeneration ophthalmology. Retina 3(10):850–859 PubMed

Naeem M, Majeed S, Hoque MZ, Ahmad I (2020) Latest developed strategies to minimize the off-target effects in CRISPR-Cas-mediated. Genome Editing Cells 9:7

Liu G, Zhang Y, Zhang T (2020) Computational approaches for effective CRISPR guide RNA design and evaluation. Comput Struct Biotechnol J 18:35–44 PubMed DOI

Wienert B, Wyman SK, Richardson CD, Yeh CD, Akcakaya P, Porritt MJ, Morlock M, Vu JT, Kazane KR, Watry HL, Judge LM, Conklin BR, Maresca M et al (2019) Unbiased detection of CRISPR off-targets in vivo using DISCOVER-Seq. Science 364(6437):286–289 PubMed DOI PMC