Search

Lysosomal storage diseases like mucopolysaccharidosis type I (MPS I) cause pathology before birth and result in early morbidity and mortality. Here, the authors show that in utero base editing mediates multi-organ phenotypic and survival benefits in a mouse model recapitulating a common human MPSI mutation.

Hybrid gRNAs significantly increase targeted editing in the liver while simultaneously reducing unwanted bystander editing in humanized mouse models.

The PAH P281L variant is one of the most common variants identified in phenylketonuria (PKU) patients. Here, the authors use base editing, enabled by lipid nanoparticle/mRNA technology, to directly correct the P281L variant in the liver in PKU mice and definitively treat the disease within 2 days.

Lipid concentration in the serum is one of the most important risk factors for coronary artery disease and can be targeted for therapeutic intervention. A genome-wide association study in >100,000 individuals of European ancestry now finds 95 significantly associated loci that also affect lipid traits in non-European populations. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and those that contribute to normal variation in lipid traits and to extreme lipid phenotypes.

Genome editing is being rapidly adopted into all fields of biomedical research, including the cardiovascular field. In this Review, Strong and Musunuru discuss the applications of genome-editing technology, including zinc finger nucleases, TALENs, and CRISPR/Cas9 systems, throughout cardiovascular disease research, their current limitations, and the prospect ofin vivogenome-editing therapies in the future.

A non-coding polymorphism at a locus associated with myocardial infarction in humans creates a CCAAT/enhancer binding protein transcription factor binding site and alters the hepatic expression of the SORT1 gene. These authors show that modulating Sort1 levels in mouse liver alters levels of plasma low-density lipoprotein cholesterol and very low-density lipoprotein, potentially explaining why polymorphisms at this locus are associated with heart disease.

Despite the wealth of research into C-reactive protein (CRP), it remains unclear which patient populations would benefit from and should be targeted for high-sensitivity assay CRP testing. In this important Review, Musunuru et al. address the relevance of CRP in a variety of scenarios encountered in clinical practice—from primary prevention of cardiovascular disease, stroke and diabetes mellitus, to secondary prevention of cardiovascular disease.

This Perspective provides a practical and clinically relevant framework rooted in benefit–risk analyses to evaluate genomic CRISPR off-targets. Such an approach is applicable to currently available as well as future technologies.

Platform-based approaches for gene-editing therapies could markedly improve development efficiency, reduce costs and increase access for patients with rare diseases. Although gene editing has shown remarkable clinical success for a small number of Mendelian disease indications, broader adoption faces substantial hurdles. We propose strategies to overcome these challenges through modular platforms for nonclinical and chemistry, manufacturing and controls (CMC) data reuse, risk-based manufacturing quality, and streamlined umbrella clinical trials for regulatory efficiency and accelerated approval.

Analysis of the imprinted KLF14 locus shows that the type 2 diabetes risk alleles in this region act in adipocytes to reduce KLF14 expression and modulate the expression of almost 400 genes in trans, leading to a shift in body-fat distribution and insulin resistance specifically in females.

mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to immune checkpoint inhibitors.

Recent reports suggest that molecular therapies targeting ANGPTL3 and its encoded protein angiopoietin-like protein 3 have clinical potential comparable to therapies targeting PCSK9 and its encoded protein proprotein convertase subtilisin/kexin type 9. By mainly affecting triglyceride-rich lipoproteins, ANGPTL3 inhibition might prove complementary to LDL cholesterol lowering with PCSK9 blockade.

Kasiewicz et al. describe a structure-guided rational design approach to optimize a new GalNAc-Lipid nanoparticle that enables delivery of a base editing therapy in both low-density lipoprotein receptor-deficient and wild-type nonclinical models.

Adeno-associated viruses with size-optimized genomes encoding compact adenine base editors enable therapeutic base editing in mice at low doses and high editing efficiencies.

Viral-mediated base editing in utero enables therapeutic editing of two metabolic genes in mice.

In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood.

Exome-wide genetic analysis on >300,000 individuals identifies associations with plasma lipid traits. Loci significantly associated with cholesterol and triglycerides are examined together to determine the effects of alleles on type 2 diabetes and coronary artery disease risk.

Prime editors are efficiently delivered to mouse organs with AAV vectors.

Genome-wide association studies have correlated a common allelic block with reduced incidence of heart failure, but the causal mechanism remains unclear. New research suggests that the C151R coding variant in the BAG3 gene is involved in the cardioprotective effect of the haplotype block by increasing cardiomyocyte protection from stress.

In an adult mouse model of tyrosinaemia, a base editor correcting an A-to-G splice-site mutation in the Fah gene restores the translation of the functional enzyme, promoting the repopulation of the liver with the corrected cells.

Sekar Kathiresan et al. report genome-wide association studies for polygenic dyslipidemia. From a meta-analysis of seven genome-wide association studies and follow-up in five replication studies, they identify 11 new genetic associations for LDL cholesterol, HDL cholesterol and triglycerides.

Generating organized kidney tissues from human pluripotent stem cell is a major challenge. Here, Freedman et al. describe a differentiation system forming spheroids and tubular structures, characteristic of these kidney structures, and using CRISPR/Cas9, delete PKD1/2, to model polycystic kidney disease.

Circular RNAs are widely expressed in eukaryotic cells but their functions and mechanisms of action are still being elucidated. Here the authors show that circANRILmodulates rRNA maturation and confers protection again atherosclerosis.

John Chambers and colleagues report a genome-wide association study for markers of liver function. They identify 42 loci associated with concentrations of one or more liver enzymes in plasma, and use a range of functional genomic analyses to suggest candidate genes at these loci.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Heribert Schunkert and colleagues report a meta-analysis of 14 genome-wide association studies of coronary disease (CAD) followed by replication in additional cohorts. They confirm 10 previously associated loci and identify 13 loci newly associated with CAD.

The Myocardial Infarction Genetics Consortium reports results of a genome-wide association study of early-onset myocardial infarction. The study analyzed common SNPs, common CNVs and rare CNVs and identified SNP alleles at three new loci associated with disease risk.

In vivo delivery of CRISPR-Cas9 corrects mutation in newborn mouse liver.

Cowan and colleagues have developed a method to efficiently differentiate human pluripotent stem cells into functional white or brown adipocytes, through the transient expression of PPARG2 alone or in combination with CEBP and PRDM16. The programmed cells are able to give rise to ectopic fat pads with white or brown adipose tissue characteristics.

The Impact of Genomic Variation on Function Consortium is combining single-cell mapping, genomic perturbations and predictive modelling to investigate relationships between human genomic variation, genome function and phenotypes and will provide an open resource to the community.