Fouzul Kansul

Background: Cardiovascular disease (CVD) is a leading cause of global morbidity and mortality, accounting for nearly 20 million deaths per year [1,2]. Despite significant advancements in pharmacologic and interventional therapies, CVD treatments primarily target symptoms rather than underlying genetic causes [1-3]. CRISPR-Cas9, an RNA-guided genome editing tool, has emerged as a promising platform for in vivo therapeutic gene editing. Recent advances, including first in-human trials and improved in-vivo delivery systems, have expanded its relevance to cardiovascular therapeutics [4-6].

Methods: A targeted literature review was conducted of key preclinical studies, translational research, and early-phase clinical trials evaluating CRISPR-Cas9 applications in cardiovascular disease. Articles published between 2020 and 2026 were identified through a PubMed database search using the keywords “CRISPR-Cas9”, “cardiovascular disease”, and “gene editing”.

Results: Preclinical studies of CRISPR-Cas9 provide a strong foundation for clinical translation. A study by Roshanravan et.al demonstrated that a CRISPR-Cas9 knockout of PCSK9 in mouse liver models reduced cholesterol by over 40% [3]. Genome editing in patient-derived iPSC cardiomyocytes successfully corrected mutations linked to dilated cardiomyopathy, hypertrophic cardiomyopathy, and Duchenne’s muscular dystrophy [3,7]. Reviews of atherosclerosis-directed editing further identified ANGPTL3 and APOC3 as important knockout targets for atherogenic dyslipidemia [6,7].

Clinical translation studies of CTX310, an in vivo therapy targeting hepatic ANGPTL3, demonstrated dose-dependent reduction in circulating ANGPTL3 protein, which is linked to lower LDL cholesterol, lower triglycerides, and reduced cardiovascular risk. Substantial reductions of 70-80% were seen at doses of 0.7 mg/kg and higher [4]. Gillmore et. al showed that NTLA-2001, targeting hepatic transthyretin (TTR) protein in hereditary ATTR-CM, produced mean serum TTR reductions of 52% at 0.1 mg/kg and 87% at 0.3 mg/kg at 28 days, with few adverse effects [5]. Another study used nexiguran ziclumeran (nex-z) to achieve successful TTR reduction (89% TTR suppression at 28 days, 90% at 12 months) in ATTR-CM patients [6]. New advancements to delivery systems are also assessed, with Yin et. al evaluating ultrasound stimulation and echogenic liposome (ELIP)-based CRISPR delivery systems to enhance local uptake of cardiomyocytes [8].

Conclusions: CRISPR-Cas9 is promising for cardiovascular therapeutics, with early clinical data demonstrating significant reductions in atherogenic lipids, circulating ANGPTL3, and amyloidogenic TTR proteins following single-dose administration [4-6]. Preclinical and delivery system advances support the broader applications of CRISPR-Cas9 across lipid disorders, amyloid disease, and inherited cardiomyopathies [1-3, 8,7]. Long-term safety and off-target editing evaluation is needed prior to widespread clinical adoption.

Work Cited:

[1] Sharma G, Sharma AR, Bhattacharya M, Lee SS, Chakraborty C. CRISPR-Cas9: A Preclinical and Clinical Perspective for the Treatment of Human Diseases. Mol Ther. 2021 Feb 3;29(2):571-586. doi: 10.1016/j.ymthe.2020.09.028. Epub 2020 Sep 20. PMID: 33238136; PMCID: PMC7854284.

[2] Sheikh Beig Goharrizi MA, Ghodsi S, Memarjafari MR. Implications of CRISPR-Cas9 Genome Editing Methods in Atherosclerotic Cardiovascular Diseases. Curr Probl Cardiol. 2023 May;48(5):101603. doi: 10.1016/j.cpcardiol.2023.101603. Epub 2023 Jan 20. PMID: 36682390.

[3] Roshanravan N, Tutunchi H, Najafipour F, Dastouri M, Ghaffari S, Jebeli A. A glance at the application of CRISPR/Cas9 gene-editing technology in cardiovascular diseases. J Cardiovasc Thorac Res. 2022;14(2):77-83. doi: 10.34172/jcvtr.2022.14. Epub 2022 Jun 14. PMID: 35935390; PMCID: PMC9339732.

[4] Laffin LJ, Nicholls SJ, Scott RS, Clifton PM, Baker J, Sarraju A, Singh S, Wang Q, Wolski K, Xu H, Nielsen J, Patel N, Duran JM, Nissen SE. Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3. N Engl J Med. 2025 Nov 27;393(21):2119-2130. doi: 10.1056/NEJMoa2511778. Epub 2025 Nov 8. PMID: 41211945.

[5] Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML, Seitzer J, O’Connell D, Walsh KR, Wood K, Phillips J, Xu Y, Amaral A, Boyd AP, Cehelsky JE, McKee MD, Schiermeier A, Harari O, Murphy A, Kyratsous CA, Zambrowicz B, Soltys R, Gutstein DE, Leonard J, Sepp-Lorenzino L, Lebwohl D. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. 2021 Aug 5;385(6):493-502. doi: 10.1056/NEJMoa2107454. Epub 2021 Jun 26. PMID: 34215024.

[6] Fontana M, Solomon SD, Kachadourian J, Walsh L, Rocha R, Lebwohl D, Smith D, Täubel J, Gane EJ, Pilebro B, Adams D, Razvi Y, Olbertz J, Haagensen A, Zhu P, Xu Y, Leung A, Sonderfan A, Gutstein DE, Gillmore JD. CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy. N Engl J Med. 2024 Dec 12;391(23):2231-2241. doi: 10.1056/NEJMoa2412309. Epub 2024 Nov 16. PMID: 39555828.

[7] Vermersch E, Jouve C, Hulot JS. CRISPR/Cas9 gene-editing strategies in cardiovascular cells. Cardiovasc Res. 2020 Apr 1;116(5):894-907. doi: 10.1093/cvr/cvz250. PMID: 31584620.

[8] Yin X, Harmancey R, Frierson B, Wu JG, Moody MR, McPherson DD, Huang SL. Efficient Gene Editing for Heart Disease via ELIP-Based CRISPR Delivery System. Pharmaceutics. 2024 Feb 29;16(3):343. doi: 10.3390/pharmaceutics16030343. PMID: 38543237; PMCID: PMC10974117.