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In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [RNA-seq]

ABSTRACT: In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [RNA-seq]

PROVIDER: PRJNA707032 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13865365_1.fastq.gz	Fastqsanger.gz
	SRR13865365_2.fastq.gz	Fastqsanger.gz
	SRR13865366_1.fastq.gz	Fastqsanger.gz
	SRR13865366_2.fastq.gz	Fastqsanger.gz
	SRR13865367_1.fastq.gz	Fastqsanger.gz

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In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [amplicon-seq]

Project description:The majority of known pathogenic point mutations in the human genome are C•G to T•A substitutions. Adenine base editors (ABEs), comprised of nuclease-impaired Cas9 fused to adenine deaminases, enable direct repair of these mutations, making them promising tools for precision in vivo genome editing therapies. However, prior to application in patients, thorough safety and efficacy studies in relevant model organisms are needed. Here, we apply adenine base editing in vivo in the liver of mice and cynomolgus macaques to install a splice site mutation in PCSK9 and reduce blood low-density lipoprotein (LDL) levels, a well-known risk factor for cardiovascular disease. Intravenous delivery of ABE-encoding mRNA and a locus-specific single guide (sg)RNA utilizing lipid nanoparticle (LNP) technology induce up to 67% editing in the liver of mice and up to 34% editing in the liver of macaques, leading to a reduction of plasma PCSK9 and LDL levels. We observed rapid clearance of ABE mRNA after LNP-mediated delivery, and neither sgRNA-dependent nor sgRNA-independent off-target mutations are detected in genomic DNA. Together, our findings support safety and feasibility of adenine base editing to treat patients with monogenetic liver diseases.

2021-04-13 | GSE168364 | GEO

In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [RNA-seq]

2021-04-13 | GSE168363 | GEO

In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels

Project description:In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels

| PRJNA707031 | ENA

In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [amplicon-seq]

Project description:In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels [amplicon-seq]

| PRJNA707033 | ENA

Targeting myeloid-PCSK9 enhancing cardio-protection beyond LDL cholesterol-lowering

Project description:Circulating Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels, known for regulating plasma cholesterol by degrading LDL receptors, correlate with acute myocardial infarction (AMI) risk. Recent studies suggest that PCSK9 improves cardiac function beyond LDL cholesterol levels after cardiac ischemic injury, but the precise role of PCSK9 in this process is not clarified yet. Our study reveals that PCSK9 deficiency induces heterogeneous changes in myeloid cells and macrophages, potentially protecting the heart in AMI regardless of LDL cholesterol homeostasis. Single-cell RNA sequencing identifies PCSK9-dependent cardiac macrophages (PDCMs) as reparative macrophages enriched in activator protein-1 (AP-1) transcription factor (TF)-related pathways. PDCMs enhance VEGF-C secretion and activate Akt signalling in cardiac endothelial cells, improving cardiac remodelling. Indeed, PCSK9 inhibitor-treated coronary artery disease (CAD) patients show increased myeloid cells with PDCM-like features. In sum, targeting myeloid-PCSK9 may offer cardio-protective effects through increased AP-1 activity and VEGF-C expression, providing a novel approach to prevent cardiac dysfunction in AMI.

2025-07-01 | GSE285004 | GEO

In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels.

Project description:Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle-based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.

| S-EPMC8352781 | biostudies-literature

In vivo adenine base editing of PCSK9 in mice and macaques reduces LDL-cholesterol levels

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-04-13 | GSE168365 | GEO

Targeting myeloid-PCSK9 enhancing cardio-protection beyond LDL cholesterol-lowering

Project description:Targeting myeloid-PCSK9 enhancing cardio-protection beyond LDL cholesterol-lowering

| PRJNA1200779 | ENA

PCSK9 deficiency results in a specific shedding of excess LDLR in female mice only: Role of hepatic cholesterol

Project description:PCSK9 promotes the lysosomal degradation of cell surface LDL receptor (LDLR). We analyzed how excess LDLR generated by PCSK9 deficiency is differently handled in male and female mice to possibly unveil the mechanism leading to the lower efficacy of PCSK9 mAb on LDL-cholesterol levels in women. Analysis of intact or ovariectomized PCSK9 knockout (KO) mice supplemented with placebo or 17β-estradiol (E2) demonstrated that female, but not male mice massively shed the soluble ectodomain of the LDLR in the plasma. Liver-specific PCSK9 KO or alirocumab-treated WT mice exhibit the same pattern. This shedding is distinct from the basal one and is inhibited by ZLDI-8, a metalloprotease inhibitor pointing at ADAM10/ADAM17. In PCSK9 KO female mice, ZLDI- 8 raises by 80 % the LDLR liver content in a few hours. This specific shedding is likely cholesterol-dependent: it is prevented in PCSK9 KO male mice that exhibit low intra-hepatic cholesterol levels without activating SREBP-2, and enhanced by mevalonate or high cholesterol feeding, or by E2 known to stimulate cholesterol synthesis via the estrogen receptor-α. Liver transcriptomics demonstrates that critically low liver cholesterol in ovariectomized female or knockout male mice also hampers the cholesterol-dependent G2/M transition of the cell cycle. Finally, higher levels of shed LDLR were measured in the plasma of women treated with PCSK9 mAb. PCSK9 knockout female mice hormonally sustain cholesterol synthesis and shed excess LDLR, seemingly like women. In contrast, male mice rely on high surface LDLR to replenish their stocks, despite 80 % lower circulating LDL.

2022-09-22 | GSE205008 | GEO

High throughput screening identifies microRNAs regulating PCSK9 and LDL receptor expression

Project description:High throughput screening identifies microRNAs regulating PCSK9 and LDL receptor expression

| PRJNA701607 | ENA