In Vivo CRISPR Base Editing of ANGPTL3 for Durable Lipid Lowering

Q: What is the clinical evidence from this study?

Population: Hyperlipidemia and LDLR deficiency (preclinical models). Intervention: GalNAc-LNP encapsulating CRISPR adenine base editor (ABE8.8) mRNA and ANGPTL3-targeting guide RNA vs. Vehicle control or untreated controls. Primary outcome: Hepatic ANGPTL3 gene editing, circulating ANGPTL3 protein reduction, and lipid lowering (LDL-C and triglycerides) (Mean reduction >90% in circulating ANGPTL3 protein; ~40-50% reduction in LDL-C and 50-70% in triglycerides in hyperlipidemic models, p=0.0009).

Q: What does this research mean for the field?

Single-dose GalNAc-LNP CRISPR adenine base editing targeting ANGPTL3 achieves durable, liver-selective gene inactivation, reducing circulating ANGPTL3 protein by >90% for up to three years and substantially lowering LDL-C and triglycerides in primates. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Taiji Mizoguchi; Jamie E. DeNizio; Alexandra C. Chadwick; Anne Marie Mazzola; M. P. Brown; Shashank Mishra; Manashree Damle; Yuri Matsumoto; Victoria Neang; Ryan Garrity; Manini Mantri; Joy Oshoname Olorife; Hui-Ting Hsu; Vian Peshdary; Estela Shabani; John D. Ganey; Ryan Santos; Anthony Federico; Sara P. Garcia; Pengying Hao; Yue Wu; Zachary Glass; Lisa N. Kasiewicz; Caroline R. Summers; Athul Sanjeev; Kui Wang; Steven D. Briscoe; Robert S. Rosenson; Christopher J. Cheng; Ellen Rohde; Joseph C. Biedenkapp; Victor Farutin; Andrew M. Bellinger; Kiran Musunuru; Sekar Kathiresan; Troy Lister; Kallanthottathil G. Rajeev; Richard G. Lee; Amit V. Khera

doi:10.1038/s41586-026-11233-9

Key result

CRISPR base editing of ANGPTL3 reduces circulating protein >90% durably and cuts LDL-C ~46%.

Mean reduction >90% in circulating ANGPTL3 protein; ~40-50% reduction in LDL-C and 50-70% in triglycerides in hyperlipidemic models
P=0.0009

Why the study?

Does a single infusion of a GalNAc-LNP delivering a CRISPR adenine base editor targeting ANGPTL3 safely and durably inactivate hepatic ANGPTL3 and lower LDL-C and triglycerides in preclinical models of hyperlipidemia and LDLR deficiency?

Key Points

To develop and evaluate a single-course CRISPR adenine base editing therapy targeting ANGPTL3 in liver tissue to achieve permanent lipid lowering.
Formulated mRNA encoding adenine base editor 8.8 (ABE8.8) and guide RNA within GalNAc-conjugated lipid nanoparticles targeting human or cynomolgus monkey ANGPTL3.
Assessed editing efficacy and off-target activity in primary human hepatocytes across approximately 3000 candidate sites via hybrid capture, ATUP, and optical genome mapping.
Evaluated in vivo pharmacodynamics, biodistribution, lipid reductions, and durability over up to 3 years in transgenic mouse models and cynomolgus monkeys.
In primary human hepatocytes, base editing reached 84.7 to 93.7% peak editing with no detectable off-target editing above the 0.03% threshold or structural variants.
In nonhuman primates, a single 3 mg/kg dose achieved 63.9% hepatic editing and a 93.7% time-weighted average reduction in circulating ANGPTL3 sustained across 3 years.
Targeted gene inactivation led to circulating lipid reductions of approximately 40 to 50% in LDL-C and 50 to 70% in triglycerides in hyperlipidemia models.

Structured PICO

Does a single infusion of a GalNAc-LNP delivering a CRISPR adenine base editor targeting ANGPTL3 safely and durably inactivate hepatic ANGPTL3 and lower LDL-C and triglycerides in preclinical models of hyperlipidemia and LDLR deficiency?

P

Population

Preclinical study evaluating primary human hepatocytes, transgenic/knockout mouse models, and cynomolgus monkeys (including LDLR-deficient models) followed for up to 3 years.

I

Intervention

Single intravenous infusion of a GalNAc-lipid nanoparticle (GalNAc-LNP) encapsulating mRNA encoding a CRISPR adenine base editor (ABE8.8) and guide RNA targeting ANGPTL3 (doses ranging from 0.25 to 6 mg/kg in mice and 0.75 to 3 mg/kg in cynomolgus monkeys).

C

Comparator

Vehicle control or untreated/untransfected controls.

O

Outcome

On-target hepatic ANGPTL3 gene editing percentage, circulating ANGPTL3 protein concentration, and serum lipid levels (LDL-C, triglycerides, non-HDL-C) up to 3 years post-dose in normolipidemic monkeys, 21 days in Ldlr-/- mice, and 35 days in cLDLR-deficient monkeys.surrogate

Main Result

Effect estimate: Mean reduction >90% in circulating ANGPTL3 protein; ~40-50% reduction in LDL-C and 50-70% in triglycerides in hyperlipidemic models

p-value: p=0.0009

Provides preclinical proof-of-concept that a single-dose GalNAc-LNP CRISPR base editor can durably inactivate hepatic ANGPTL3 for at least 3 years and substantially lower LDL-C and triglycerides independently of LDLR, supporting first-in-human trials for homozygous familial hypercholesterolemia and refractory hyperlipidemia.

Limitations

Preclinical study in cellular, mouse, and nonhuman primate models rather than human patients
The nonhuman primate study in the context of LDLR deficiency was limited in duration (35 days) and did not establish a long-term lipid-lowering effect in that specific model
Endogenous mouse and cynomolgus monkey ANGPTL3 target sites differ from the human sequence by 4 and 1 mismatches, respectively, requiring surrogate gRNAs or transgenic mice for in vivo assessment
Preclinical animal and in vitro cell models; human clinical efficacy and safety remain to be established in ongoing clinical trials
The nonhuman primate study in the context of severe LDLR deficiency was limited in duration (35 days) and did not establish long-term lipid-lowering durability in that specific model
Sequence mismatches between human, mouse, and cynomolgus monkey ANGPTL3 precluded direct testing of the human gRNA in wild-type animals

Ask about this paper

Answers are grounded in this paper and cite their sources.

Implication

May support human trials of ANGPTL3 base editing; leaves open safety, durability, and outcomes in patients.

Abstract

Circulating concentrations of low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins are leading risk factors for atherosclerotic cardiovascular disease 1 . Despite several approved lipid-lowering medications, most patients fail to achieve target lipid levels under the chronic care treatment model 2,3 . Here, we describe a potential single-course treatment in which an infusion of guide RNA and mRNA encoding a CRISPR adenine base editor—encapsulated within a GalNAc–lipid nanoparticle—leads to durable, liver-selective inactivation of angiopoietin-like 3 ( ANGPTL3 ), a known driver of increased LDL-C and triglyceride concentrations. Analyses in human liver cells in vitro confirmed that the base editor introduces a DNA base-pair change at the target ANGPTL3 locus with no detectable off-target editing at any of approximately 3000 candidate sites or treatment-related structural variants. Targeted ANGPTL3 inactivation in nonhuman primates was well-tolerated and led to a > 90% mean reduction in circulating ANGPTL3 protein, with durability confirmed out to 3 years following a single dose. In mouse and nonhuman primate models of hyperlipidemia, gene inactivation was associated with reductions of approximately 40 to 50% in LDL-C and 50 to 70% in triglycerides. These results provided the scientific foundation for initiation of an ongoing first-in-human clinical trial in patients with refractory hyperlipidemia syndromes.

Discussion

No takes yet. Share an insight, caveat, or question.

Cite This Study

Mizoguchi et al. (2026) studied Hyperlipidemia and LDLR deficiency (preclinical models). GalNAc-LNP encapsulating CRISPR adenine base editor (ABE8.8) mRNA and ANGPTL3-targeting guide RNA vs. Vehicle control or untreated controls was evaluated on Hepatic ANGPTL3 gene editing, circulating ANGPTL3 protein reduction, and lipid lowering (LDL-C and triglycerides) (Mean reduction >90% in circulating ANGPTL3 protein; ~40-50% reduction in LDL-C and 50-70% in triglycerides in hyperlipidemic models, p=0.0009). Single-dose GalNAc-LNP CRISPR adenine base editing of ANGPTL3 reduced circulating ANGPTL3 protein by >90% for 3 years in primates and lowered LDL-C by 46% in LDLR-deficient primates.

synapsesocial.com/papers/6aef1ad730498f842f31bf90 https://doi.org/10.1038/s41586-026-11233-9

View Full Paper

Ask AI

Bookmark

Share

In Vivo CRISPR Base Editing of ANGPTL3 for Durable Lipid Lowering

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

In Vivo CRISPR Base Editing of ANGPTL3 for Durable Lipid Lowering

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Keep reading

Keep reading