{"id":139062,"date":"2025-11-12T04:53:16","date_gmt":"2025-11-12T09:53:16","guid":{"rendered":"https:\/\/cardiologynownews.org\/?p=139062"},"modified":"2026-02-06T20:54:32","modified_gmt":"2026-02-07T01:54:32","slug":"first-in-human-trial-of-crispr-gene-editing-angptl3-safely-lowered-cholesterol-triglycerides","status":"publish","type":"post","link":"https:\/\/cardiologynownews.org\/?p=139062","title":{"rendered":"First-in-human Trial of CRISPR Gene-editing ANGPTL3 Safely Lowered Cholesterol and Triglycerides"},"content":{"rendered":"<p>Key Points:<\/p>\n<ul>\n<li>CTX310 is a first-in-class in vivo CRISPR-Cas9 therapy designed to permanently disrupt hepatic ANGPTL3, a gene that regulates lipid metabolism.<\/li>\n<li>In the Phase 1 CRISP-ANGPTL3 trial, a single infusion of CTX310 safely reduced ANGPTL3 levels by up to 80%, LDL-C by 49%, and triglycerides by 55% at 60 days.<\/li>\n<li>No dose-limiting toxicities or serious treatment-related adverse events were observed across escalating doses up to 0.8 mg\/kg.<\/li>\n<\/ul>\n<p><!--more--><\/p>\n<p>Despite decades of lipid-lowering therapies, adherence and lifelong treatment remain major barriers in managing atherosclerotic cardiovascular disease. A therapy capable of permanently lowering LDL cholesterol and triglycerides after a single dose could transform preventive cardiology.<\/p>\n<p>At the 2025 American Heart Association Scientific Sessions, <a href=\"https:\/\/providers.clevelandclinic.org\/provider\/steven-nissen\/4268279\">Dr. Steven E. Nissen<\/a> presented the Phase 1 CRISP-ANGPTL3 trial, simultaneously published in <a href=\"https:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa2511778\"><em>The New England Journal of Medicine<\/em><\/a>. The study evaluated CTX310, a lipid nanoparticle\u2013delivered CRISPR-Cas9 system developed by CRISPR Therapeutics, which edits the <em>ANGPTL3<\/em> gene directly in hepatocytes to permanently disable its function.<\/p>\n<p>CRISP-ANGPTL3 <em>(<\/em><a href=\"https:\/\/www.anzctr.org.au\/Trial\/Registration\/TrialReview.aspx?ACTRN=12623000809639\"><em>ACTRN12623000809639<\/em><\/a><em>) <\/em>was a multicenter, open-label, ascending-dose Phase 1 trial conducted across Australia, New Zealand, and the UK. Fifteen adults (ages 31\u201368) with uncontrolled hypercholesterolemia, mixed dyslipidemia, or severe hypertriglyceridemia, despite maximally tolerated lipid-lowering therapy, received a single IV dose of CTX310 at one of five escalating levels: 0.1, 0.3, 0.6, 0.7, or 0.8 mg\/kg of estimated lean body weight. All participants were maintained on stable background lipid-lowering therapy throughout follow-up. The primary endpoint was adverse events, including dose-limiting toxic effects, and secondary endpoints included percent changes from baseline in <em>ANGPTL3<\/em>, LDL-C, triglycerides, and apolipoprotein B over 60\u201390 days.<\/p>\n<p>CTX310 was well tolerated at all dose levels. No dose-limiting toxicities occurred. Mild, transient infusion reactions (20%) and short-lived aminotransferase elevations (7%) resolved without sequelae. One death occurred 179 days after the lowest dose. At higher doses, results were striking as ANGPTL<em>3<\/em> levels were lowered by 73\u201380%, LDL cholesterol by 48.9%, triglycerides by 55.2%, whereas apolipoprotein B levels were reduced by 33.4%.<\/p>\n<p>For patients with familial hypercholesterolemia, severe hypertriglyceridemia, or refractory mixed dyslipidemia, CTX310 could represent a paradigm shift: a one-time genetic intervention instead of lifelong pharmacotherapy. If validated in larger phase 2\u20133 trials, this strategy could usher in a new era of gene-editing\u2013based cardiovascular prevention.<\/p>\n<p>The authors conclude that <em>\u201ca single infusion of CTX310 produced lipid reductions comparable to potent chronic therapies, with the potential for long-term benefit\u201d.\u00a0 <\/em>These findings establish the first human proof-of-concept for in vivo CRISPR-Cas9 gene editing of a cardiovascular\/metabolic target. Importantly, investigators stressed the need for long-term surveillance for up to 15 years which will allow for the monitoring of durability and safety, including risks of off-target edits or delayed toxicity.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Key Points: CTX310 is a first-in-class in vivo CRISPR-Cas9 therapy designed to permanently disrupt hepatic ANGPTL3, a gene that regulates lipid metabolism. In the Phase 1 CRISP-ANGPTL3 trial, a single infusion of CTX310 safely reduced ANGPTL3 levels by up to 80%, LDL-C by 49%, and triglycerides by 55% at 60 days. No dose-limiting toxicities or [&hellip;]<\/p>\n","protected":false},"author":40617,"featured_media":139064,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[906,8],"tags":[907,908,74,45,82,928,47,72,216,66,185],"ppma_author":[1071],"class_list":{"0":"post-139062","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-aha-2025","8":"category-news","9":"tag-aha-2025","10":"tag-aha2025","11":"tag-cholesterol","12":"tag-conference","13":"tag-coronary-artery-disease","14":"tag-crispr-cas9","15":"tag-featured","16":"tag-hypertension","17":"tag-lipids","18":"tag-myocardial-infarction","19":"tag-news","20":"author-joseph-nasr-md"},"authors":[{"term_id":1071,"user_id":40617,"is_guest":0,"slug":"joseph-nasr-md","display_name":"Joseph Nasr MD","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/530a343d3e08798e23303e3dcee6bf2f19a4e0175dee36ab2ec2fe9681868aa3?s=96&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/139062","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/users\/40617"}],"replies":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=139062"}],"version-history":[{"count":2,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/139062\/revisions"}],"predecessor-version":[{"id":139066,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/posts\/139062\/revisions\/139066"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=\/wp\/v2\/media\/139064"}],"wp:attachment":[{"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=139062"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=139062"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=139062"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/cardiologynownews.org\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=139062"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}