Gene Editing Therapy in Cardiovascular Disease: 2026 ACC Scientific Statement

Authors, Journal, Affiliations, Type, DOI

• Authors: Amrut V. Ambardekar MD FACC (Chair), Ami Bhatt MD FACC, Menno Hoekstra PhD, Melissa A. Kelly MS CGC, Kiran Musunuru MD PhD FACC, Pradeep Natarajan MD FACC
• Journal: Journal of the American College of Cardiology 2026
• Approved by ACC Clinical Policy Approval Committee March 2026; informed by ACC Heart House Roundtable June 2025
• Type: ACC Scientific Statement (consensus)
• DOI: https://doi.org/10.1016/j.jacc.2026.02.5092

Overview

This 2026 ACC Scientific Statement provides the cardiovascular clinician with a comprehensive overview of gene editing therapy (GET) in CVD — covering the four main editing mechanisms (CRISPR-Cas9, base editing, prime editing, epigenome editing), two delivery platforms (AAV vectors for cardiac; lipid nanoparticles for hepatic), and the clinical trial landscape through December 2025. The most advanced applications are in ATTR-CM and lipid disorders (PCSK9/ANGPTL3/LPA gene editing). No consensus clinical recommendations are issued because GET has not yet progressed beyond clinical trials in cardiovascular medicine. The statement highlights that only ~1% of eligible patients receive guideline-recommended genetic testing, and that AAV-based GET has caused fatalities in DMD trials, underscoring that delivery vehicle choice is the central determinant of safety.

Keywords

Gene editing therapy, CRISPR-Cas9, base editing, prime editing, epigenome editing, lipid nanoparticle, adeno-associated virus, ATTR-CM, familial hypercholesterolemia, PCSK9, ANGPTL3, LPA, TTR, nexiguran ziclumeran, MAGNITUDE, VERVE-102, Heart-2 trial, germline, off-target effects, xenotransplantation

Key Takeaways

Introduction

• ACC convened the "Advancing Gene Editing Therapy for CVD Heart House Roundtable" June 2025 followed by a writing committee (Oct 2025); literature reviewed to December 31, 2025
• No clinical practice recommendations are made — GET has not progressed beyond clinical trials in CVD

Definitions and Background — GET Mechanisms

• CRISPR-Cas9 (nuclease; "molecular scissors"): Guide RNA (gRNA, ~100 bases) directs Cas9 enzyme to target genomic site to create double-strand breaks → NHEJ repair causes random indels, disrupting gene function; most useful for disrupting regulatory sequences or overexpressed genes
• Base editing ("pencil and eraser"): Nickase Cas9 (nCas9) coupled to a deaminase enzyme makes single-base substitutions without double-strand cuts — cytidine base editor (C→T) or adenine base editor (A→G); most precise; best for inactivating specific bases or correcting defined point mutations
• Prime editing ("word processor"): nCas9 + reverse transcriptase + extended gRNA acting as template; enables any base change, small indels, and large insertions/deletions; broadest capability; most complex
• Epigenome editing: Dead Cas9 (dCas9) attached to chromatin-modifying or methylation enzymes — alters gene accessibility and expression without cutting or changing DNA sequence
• All four mechanisms have been deployed in at least one clinical trial (ex vivo or in vivo)
• Only FDA-approved GET (non-cardiac): Exagamglogene autotemcel (exa-cel) for sickle cell disease / beta-thalassemia — ex vivo Cas9 disruption of BCL11A enhancer to increase fetal hemoglobin

Application of GET in CVD — Patient Selection

• Monogenic diseases are primary targets — single large-effect variant amenable to single-gene disruption/correction; polygenic diseases require multiplexing, increasing off-target risk
• Dominant-negative variants (sufficient but deleterious protein) are better candidates than haploinsufficiency (insufficient protein) — inhibition of production is technically easier than restoring a defective protein
• Special challenges: allelic heterogeneity (different variants per patient require custom constructs); early disease onset may require early treatment; therapeutic threshold higher for non-dividing cardiomyocytes vs. hepatocytes; allele-specific targeting in heterozygotes adds complexity
• Current CVD GETs focus on monogenic conditions treated by genetic disruption of a pathogenic gene target — not true variant correction (with some prime editing exceptions)

In Vivo Delivery

• Two delivery platforms: viral vectors (AAV) vs. nonviral (LNP)
• Viral — AAV: Multiple serotypes with tissue-specific tropism; rarely integrates; persists long-term in organs; cardiotropic serotypes (e.g. AAV9) required for heart delivery
  • AAV disadvantages: Pre-existing neutralizing antibodies limit efficacy; new anti-AAV antibodies prevent re-dosing; require immunosuppression; limited cargo size (~4.7 kb) forces split vectors with higher doses and toxicity; greater cumulative off-target edits; integration at double-strand break sites carries genotoxic risk; AAV9 preferred for myocardial targets
• Nonviral — LNP: Encapsulates editing payload in lipid sphere; easier large-scale manufacturing; low immunogenicity → re-dosing feasible; naturally accumulates in liver with IV administration; GalNAc conjugation ensures hepatic specificity via asialoglycoprotein receptor binding; prior clinical experience (COVID-19 vaccines, patisiran/vutrisiran)
  • LNP limitation: Only hepatically expressed proteins are viable targets — rationale for focus on lipid disorders (PCSK9/ANGPTL3/LPA) and ATTR-CM (TTR, liver-produced)
• Strategic rule: AAV for cardiac targets; LNP for liver-targeted disease

GET in ATTR-CM

• TTR protein exclusively expressed by liver; destabilized monomers misfold → amyloid fibrils in heart, nerves, ligaments; both ATTRv-CM (variant TTR gene) and ATTRwt-CM (aging) treated by hepatic TTR knockdown
• TTR gene knockout appears safe: transgenic TTR-null mice phenotypically normal; ~10-year clinical experience with hepatic TTR silencing (patisiran, inotersen, vutrisiran, eplontersen) in polyneuropathy supports absence of serious consequences (vitamin A supplementation required)
• Older age of ATTR-CM onset limits germline transmission concern (most patients past reproductive age)
• Nexiguran ziclumeran (nex-z / NTLA-2001; Intellia Therapeutics): LNP-delivered CRISPR-Cas9 TTR knockout; Phase 1 open-label (n=36; 50% NYHA III; 31% ATTRv; median 18 months): mean serum TTR −89% at 28 days, −90% at 12 months, sustained through 24 months; disease stable in 66%; NYHA improved 47%; KCCQ +8 pts; safety: 5 infusion reactions, 2 transient AST elevations, 1 unrelated death (see sources/nexz-crispr-attrcm-nejm-2024)
• MAGNITUDE Phase 3 trial (NCT06128629): Large placebo-controlled RCT testing nex-z for CV events and death in ATTR-CM — paused October 2025 for concerns about risk of severe hepatotoxicity in a small percentage of participants, including one death from liver failure

GET in Lipid Disorders

• Lipid metabolism genes are excellent LNP-GET targets: hepatic expression + loss-of-function variants confer lower CVD risk (genetic validation of targets)
• PCSK9 targeting (Heart-2 Phase 1b, VERVE-102; GalNAc-LNP base editor): Patients with HeFH or premature CAD on max oral therapy — interim: mean LDL-C reduction −53%, maximum −69% (NCT06164730); YOLT-101 and ART002 separately showed >50% LDL-C reduction
• ANGPTL3 targeting (CTX310; CRISPR Therapeutics Phase 1): 15 patients with severe hyperlipidemia; highest dose cohort: mean LDL-C −49%, triglycerides −55%; few adverse events; VERVE-201 (Pulse-1, Phase 1b) for HoFH/refractory hypercholesterolaemia ongoing
• LPA targeting (apolipoprotein[a] gene): CTX320 — dose-dependent editing of primary human hepatocytes in vitro >80%; Lp(a) −94% in non-human primates at 7 months; VERVE-301 advanced to clinical development; CRISPR Therapeutics initiating Phase 1 for Lp(a) elevation + CVD
• APOC3 targeting: CorrectSequence Therapeutics base editing trial for familial chylomicronemia syndrome initiated
• Hypertension target: Angiotensinogen (AGT): Hepatically expressed; CTX340 advanced to clinical development for refractory hypertension

Preliminary GET in Other CVDs (Animal Models Only)

• Duchenne muscular dystrophy (DMD): Proof-of-concept preclinical; AAV-based CRISPR in dogs rescued dystrophin initially but Cas9-specific humoral + CTL responses eliminated dystrophin-expressing cells; Clinical fatality: 27-year-old patient died 8 days after AAV-based CRISPR epigenome editing due to innate immune response to AAV vector aggravated by advanced disease; first two boys treated with AAV-CRISPR-Cas12 showed minimal evidence of long-term dystrophin rescue
• HCM: Preliminary base editing of MYH7 p.R430Q in human cardiomyocytes in vitro + knock-in mice (MYH6 p.R403Q) showing promising results
• Dilated cardiomyopathy, syndromic aortopathies: Animal model proof-of-concept; all limited by AAV delivery challenges
• Xenotransplantation (CRISPR in end-stage HF): 10 porcine genes edited for immune compatibility in first porcine-to-human cardiac xenotransplant — 4 pig genes knocked out, 6 human genes inserted; limited long-term survival but concept established

Challenges — Genetic Testing in CVD

• Only ~1% of eligible CVD patients receive guideline-recommended genetic testing (genetics recommended for HCM, DCM, ARVC, channelopathies, FH, ATTR-CM); 90–95% of individuals with pathogenic CVD genomic variants are unaware of their variant
• Barriers: provider education gaps, limited referral access to genetics specialists, variable payor/institutional support, patient privacy concerns, insurance discrimination fears (GINA limitations for life/disability/LTC insurance)
• Population genomic screening (genome-first) reveals higher true prevalence than clinically ascertained: FH ~1:250–300 (not 1:500), ATTRv-CM ~1:230 globally — with lower penetrance than historically reported
• Penetrance complexity: FH due to APOB variants milder than LDLR-FH; accurate penetrance prediction is critical before treating younger/mildly affected individuals with irreversible GET
• ACMG secondary findings list (v3.1, 2022) includes LDLR, APOB, PCSK9 (FH) and TTR

Challenges — Clinical Trial Design for GET (Table 2)

• Patient population: Pre-clinical vs. advanced disease; younger vs. older (cancer risk window); reproductive potential vs. post-reproductive (germline risk); equipoise when effective alternatives exist
• Efficacy endpoints: Primary prevention endpoints; required follow-up duration for durable effect; non-inferiority vs. superiority design; value of one-time GET vs. lifelong pharmacotherapy
• Safety monitoring: FDA minimum 15 years of long-term follow-up required for gene therapies; post-approval registry obligations; sponsor financial insolvency scenario; offspring follow-up consideration; cancer from off-target editing may emerge decades later (no human case confirmed yet)

Ethical and Societal Considerations

• High one-time cost of GET vs. US multi-payor insurance model — unclear which payor covers at what timepoint; employer discrimination risk
• Equitable access: GET approval may create access disparities; transparency and oversight critical
• Germline transmission of somatic edits must be rigorously excluded
• GET represents potential transition from reactive disease management to durable molecular disease prevention — but requires scientific rigor, cautious optimism, and sustained ethical reflection

Limitations of the Document

• No clinical practice recommendations — all reviewed applications are still in clinical trials as of December 2025
• Literature reviewed only to December 2025; rapidly evolving field
• Writing committee members were unpaid ACC volunteers; no commercial input; but most members have active academic interests in gene therapy
• MAGNITUDE Phase 3 trial paused after statement writing completion — new hepatotoxicity safety signal not integrated into formal statement recommendations

Key Concepts Mentioned

• concepts/CRISPR-Cas9-in-Channelopathies — central editing platform
• concepts/AAV-Gene-Delivery — cardiac delivery vehicle; key limitations
• concepts/Gene-Silencing-Therapy — contrasted with GET (silencing = transient; editing = permanent)
• concepts/Gene-Editing-Risk-Benefit-Framework — patient selection; clinical trial design
• concepts/Lipid-Gene-Therapy — PCSK9/ANGPTL3/LPA/APOC3 editing trials
• concepts/Genetic-Testing-in-Cardiomyopathy — access barriers; ~1% testing rate
• concepts/Danon-Disease — clinical AAV9 trial context
• concepts/Pompe-Disease — clinical AAV9 trial context
• concepts/Arrhythmogenic-Cardiomyopathy — PKP2 gene therapy

Key Entities Mentioned

• entities/ATTR-Amyloidosis — primary CVD application of GET; MAGNITUDE pause
• entities/Nexiguran-Ziclumeran — NTLA-2001; Phase 1 nex-z data; MAGNITUDE Phase 3
• entities/Familial-Hypercholesterolemia — GET target via PCSK9/ANGPTL3

Wiki Pages Updated

• Created: wiki/sources/gene-editing-acc-2026.md
• Updated: wiki/entities/ATTR-Amyloidosis.md — MAGNITUDE trial pause (Oct 2025 hepatotoxicity/death)
• Updated: wiki/concepts/CRISPR-Cas9-in-Channelopathies.md — LNP delivery comparison; MAGNITUDE pause; DMD fatalities; base/prime/epigenome editing taxonomy
• Updated: wiki/concepts/AAV-Gene-Delivery.md — DMD clinical fatal AAV event; AAV-Cas12 DMD long-term failure; LNP vs AAV comparison section
• Updated: wiki/concepts/Gene-Editing-Risk-Benefit-Framework.md — clinical trial design considerations; genetic testing access crisis; primary prevention GET; germline concerns
• Created: wiki/concepts/Lipid-Gene-Therapy.md — PCSK9/ANGPTL3/LPA/APOC3/AGT editing trial landscape
• Updated: wiki/sourceindex.md
• Updated: wiki/wikiindex.md
• Updated: log.md