CTX310

Details

CTX310 is an investigational in vivo CRISPR-Cas9 gene-editing drug product developed by CRISPR Therapeutics for a single-treatment, permanent reduction of atherogenic lipoproteins. It is a lipid-nanoparticle formulation co-encapsulating mRNA encoding Streptococcus pyogenes Cas9 and a single guide RNA targeting the hepatic ANGPTL3 gene, designed to install a loss-of-function mutation in hepatocytes. Unlike RNA-level ANGPTL3 inhibitors (antisense oligonucleotides, siRNA) or the monoclonal antibody evinacumab, CTX310 is intended as a once-in-a-lifetime intervention rather than chronic therapy.

Key Facts

Composition and Delivery

• Two components co-encapsulated in one lipid nanoparticle: polyadenylated Cas9 mRNA and a 100-mer single-stranded guide RNA (sources/CRISPR-Cas9-NEJM-2025 — high)
• The Cas9 mRNA contains methylated pseudouridine to reduce inflammatory response (sources/CRISPR-Cas9-NEJM-2025 — high)
• LNP is composed of four components: an ionizable lipid, a polyethylene glycol lipid, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol (sources/CRISPR-Cas9-NEJM-2025 — high)
• Hepatocyte uptake by apolipoprotein E–mediated LDL receptor uptake, scavenger receptor–mediated uptake, and potentially other receptors; endosomal escape releases the payload into the cytoplasm with importin-mediated nuclear delivery (sources/CRISPR-Cas9-NEJM-2025 — high)
• Off-target editing was not observed in preclinical studies (sources/CRISPR-Cas9-NEJM-2025 — high)
• Target rationale: ANGPTL3 is produced almost exclusively by the liver, making it accessible to LNP-mediated hepatic delivery (sources/CRISPR-Cas9-NEJM-2025 — high)

Phase 1 Trial (CTX310-01; ACTRN12623000809639)

• Phase 1A, multicenter, open-label, single-ascending-dose first-in-human trial; six sites in Australia, New Zealand and the United Kingdom; 27 screened, 15 treated (sources/CRISPR-Cas9-NEJM-2025 — high)
• Dose levels and cohort sizes: 0.1 mg/kg (n=3), 0.3 (n=3), 0.6 (n=3), 0.7 (n=2), 0.8 (n=4), calculated on total RNA administered and based on estimated lean body weight (sources/CRISPR-Cas9-NEJM-2025 — high)
• Administered as a single intravenous infusion after premedication with a glucocorticoid and an antihistamine (sources/CRISPR-Cas9-NEJM-2025 — high)
• Population: uncontrolled hypercholesterolemia, moderate-to-severe hypertriglyceridemia, or mixed dyslipidemia refractory to maximally tolerated therapy; median age 53 years; 87% male; 40% clinical ASCVD; 40% familial hypercholesterolemia; mean LDL cholesterol 155 mg/dL (sources/CRISPR-Cas9-NEJM-2025 — high)
• Background lipid-lowering therapy was unchanged through 60 days, isolating the observed lipid changes to CTX310 (sources/CRISPR-Cas9-NEJM-2025 — high)

Safety

• No dose-limiting toxic effects and no serious adverse events related to CTX310 (sources/CRISPR-Cas9-NEJM-2025 — high)
• All adverse events were grade 1–2 apart from one grade 5 event: a death 179 days after the 0.1 mg/kg dose, reported by the investigators as unrelated to CTX310 (sources/CRISPR-Cas9-NEJM-2025 — high)
• Second serious adverse event: hospitalisation for a spinal disk herniation 7 months after the 0.3 mg/kg dose, also not attributed to CTX310 (sources/CRISPR-Cas9-NEJM-2025 — high)
• Infusion-related reactions in 20% (grade 2; back pain and nausea beginning minutes after infusion start; two at 0.6 mg/kg, one at 0.8 mg/kg); managed by pausing the infusion with supportive care, and all participants completed dosing (sources/CRISPR-Cas9-NEJM-2025 — high)
• Allergic reaction in 7% (upper-torso rash the day after the 0.3 mg/kg dose, resolved next day) (sources/CRISPR-Cas9-NEJM-2025 — high)
• Aminotransferase elevation in 7%: grade 2, 3–5× baseline, in a participant with elevated baseline transaminases at the 0.8 mg/kg dose; peaked day 4, less than twice baseline by day 7, normalised by day 14, with no rise in bilirubin, alkaline phosphatase or prothrombin time (sources/CRISPR-Cas9-NEJM-2025 — high)

Efficacy

• ANGPTL3 percentage change at 30 days was +9.6% at 0.1 mg/kg, +9.4% at 0.3, −32.7% at 0.6, −79.7% at 0.7, and −73.2% at 0.8 — the two lowest doses produced no target reduction (sources/CRISPR-Cas9-NEJM-2025 — high)
• The 0.8 mg/kg cohort (n=4) achieved mean reductions of 48.9% in LDL cholesterol and 55.2% in triglycerides at 60 days, with wide individual ranges (LDL-C −86.6 to −19.5%) (sources/CRISPR-Cas9-NEJM-2025 — high)
• LDL-C and TG fell simultaneously — the authors note no existing therapy achieves substantial reduction of both (sources/CRISPR-Cas9-NEJM-2025 — high)
• Efficacy was similar to evinacumab, the approved anti-ANGPTL3 monoclonal antibody (sources/CRISPR-Cas9-NEJM-2025 — high)
• The authors conclude that the magnitude of ANGPTL3 and lipid reduction at the highest doses suggests extensive hepatocyte gene editing was probably achieved (sources/CRISPR-Cas9-NEJM-2025 — high)

Development Context

• Developed by CRISPR Therapeutics; the sponsor funded the trial and employs several authors (sources/CRISPR-Cas9-NEJM-2025 — high)
• Part of a broader CRISPR Therapeutics hepatic gene-editing pipeline that also includes CTX320 (LPA, for Lp(a) elevation) and CTX340 (AGT, for refractory hypertension) (sources/gene-editing-acc-2026 — very high)
• The competitor ANGPTL3 program VERVE-201 / Pulse-1 (Verve Therapeutics) uses a different modality — an mRNA-encoded adenine base editor delivered by GalNAc-LNP — and targets homozygous familial hypercholesterolemia (sources/gene-editing-acc-2026 — very high)

Contradictions / Open Questions

• ANGPTL3 knockdown does not track lipid lowering. The 0.7 mg/kg cohort had the deepest ANGPTL3 reduction (−79.7%) but only −21.0% LDL cholesterol and −19.2% triglycerides, while 0.8 mg/kg had a shallower ANGPTL3 reduction (−73.2%) and roughly double the lipid effect. With n=2 and n=4 this may be sampling variation, but it raises the question of whether lipid lowering is fully ANGPTL3-mediated (sources/CRISPR-Cas9-NEJM-2025 — high)
• Durability is asserted, not demonstrated. The therapeutic premise is a permanent edit, but the report covers 60–90 days. Whether the edit is durable in humans — and whether hepatocyte turnover erodes the effect — is unknown (sources/CRISPR-Cas9-NEJM-2025 — high)
• No comparator, no outcomes. There is no placebo or active comparator arm and no cardiovascular outcome data; superiority or even equivalence to evinacumab or siRNA approaches is unestablished (sources/CRISPR-Cas9-NEJM-2025 — high)
• A grade 5 event in a 15-patient safety trial. The death 179 days after the lowest dose is reported as unrelated, but the trial is far too small to exclude a low-frequency treatment-related risk — precisely the concern that motivated the FDA's 15-year follow-up recommendation for genome-editing products (sources/CRISPR-Cas9-NEJM-2025 — high)
• Hepatotoxicity signal is present but mild. One participant had a transient grade 2 transaminase rise, and the authors note similar effects with other LNP-delivered therapies. This contrasts with the vupanorsen experience (discontinued for hepatic steatosis and transaminase elevation) and with the MAGNITUDE Phase 3 pause for a different LNP-CRISPR product — whether LNP-CRISPR hepatotoxicity is target-specific or a class effect remains unresolved (sources/CRISPR-Cas9-NEJM-2025 — high; sources/gene-editing-acc-2026 — very high)
• Sponsor-run trial. Funded by the developer, which employs several authors and performed the initial statistical analysis (independently confirmed at the Cleveland Clinic). Long-term safety surveillance will therefore rest largely on sponsor-conducted follow-up (sources/CRISPR-Cas9-NEJM-2025 — high)

Connections

• Related to concepts/ANGPTL3-Inhibition — CTX310 is the gene-editing modality within the ANGPTL3 inhibitor class
• Related to concepts/Lipid-Gene-Therapy — clinical-stage in vivo CRISPR-Cas9 editing of a hepatic lipid gene
• Related to entities/Evinacumab — anti-ANGPTL3 monoclonal antibody; directly comparable efficacy, chronic dosing
• Related to entities/CRISPR-Therapeutics — developer
• Related to concepts/Gene-Editing-Risk-Benefit-Framework — one-time durability versus irreversibility and 15-year follow-up
• Related to concepts/Familial-Hypercholesterolemia — 40% of the trial population; the eventual target indication
• Related to concepts/CRISPR-Cas9-in-Channelopathies — shared editing platform, different delivery and target organ

Sources

• sources/CRISPR-Cas9-NEJM-2025
• sources/gene-editing-acc-2026