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Recent advances in gene editing technologies are enabling the potential correction of devastating monogenic disorders through elimination of underlying genetic mutations. Duchenne muscular dystrophy (DMD) is an especially severe genetic disorder caused by mutations in the gene encoding dystrophin, a membrane-associated protein required for maintenance of muscle structure and function. Patients with DMD succumb to loss of mobility early in life, culminating in premature death from cardiac and respiratory failure. The disease has thus far defied all curative strategies. CRISPR gene editing has provided new opportunities to ameliorate the disease by eliminating DMD mutations and thereby restore dystrophin expression throughout skeletal and cardiac muscle. Proof-of-concept studies in rodents, large mammals, and human cells have validated the potential of this approach, but numerous challenges remain to be addressed, including optimization of gene editing, delivery of gene editing components throughout the musculature, and mitigation of possible immune responses. This paper provides an overview of recent work from our laboratory and others toward the genetic correction of DMD and considers the opportunities and challenges in the path to clinical translation. Lessons learned from these studies will undoubtedly enable further applications of gene editing to numerous other diseases of muscle and other tissues.

Ischaemic heart disease is a leading cause of death worldwide. Injury to the heart is followed by loss of the damaged cardiomyocytes, which are replaced with fibrotic scar tissue. Depletion of cardiomyocytes results in decreased cardiac contraction, which leads to pathological cardiac dilatation, additional cardiomyocyte loss, and mechanical dysfunction, culminating in heart failure. This sequential reaction is defined as cardiac remodelling. Many therapies have focused on preventing the progressive process of cardiac remodelling to heart failure. However, after patients have developed end-stage heart failure, intervention is limited to heart transplantation. One of the main reasons for the dramatic injurious effect of cardiomyocyte loss is that the adult human heart has minimal regenerative capacity. In the past 2 decades, several strategies to repair the injured heart and improve heart function have been pursued, including cellular and noncellular therapies. In this Review, we discuss current therapeutic approaches for cardiac repair and regeneration, describing outcomes, limitations, and future prospects of preclinical and clinical trials of heart regeneration. Substantial progress has been made towards understanding the cellular and molecular mechanisms regulating heart regeneration, offering the potential to control cardiac remodelling and redirect the adult heart to a regenerative state.

Key Points MicroRNAs (miRNAs) are short, single-stranded RNAs that suppress protein expression of often several related components of complex intracellular networks, making them very potent regulators. The functions of miRNAs are heightened under conditions of pathophysiological stress and disease, making them attractive candidates for therapeutic manipulation. Many gain- and loss-of-function studies have shown that miRNAs have prominent roles during many different diseases, including cardiovascular disorders. Several antimiR (miRNA inhibitor) chemistries exist that can induce potent and sustained inhibition of specific miRNAs. This Review provides an overview of the pharmacokinetic and pharmacodynamic properties of the different antimiR therapeutics and discusses some of their differences in comparison with more classical drugs. We present some recent representative examples of the therapeutic effects of antimiRs in the cardiovascular system, including in cardiac remodelling, metabolism, fibrosis, apoptosis, vascular diseases, inflammation and hypertension. Last, we consider some possible future directions and present some of the challenges and questions that remain in the path towards the development of miRNA-based therapeutics in general. MicroRNAs (miRNAs) are involved in the regulation of gene expression and have been implicated in the pathology of several diseases. Here, van Rooij and Olson discuss the chemistry of current miRNA inhibitors and evaluate miRNAs as potential therapeutic targets for cardiovascular disorders. In recent years, prominent roles for microRNAs (miRNAs) have been uncovered in several cardiovascular disorders. The ability to therapeutically manipulate miRNA expression and function through systemic or local delivery of miRNA inhibitors, referred to as antimiRs, has triggered enthusiasm for miRNAs as novel therapeutic targets. Here, we focus on the pharmacokinetic and pharmacodynamic properties of current antimiR designs and their relevance to cardiovascular indications, and evaluate the opportunities and obstacles associated with this new therapeutic modality.

Adverse cardiac remodeling after myocardial infarction (MI) causes structural and functional changes in the heart leading to heart failure. The initial post-MI pro-inflammatory response followed by reparative or anti-inflammatory response is essential for minimizing the myocardial damage, healing, and scar formation. Bone marrow–derived macrophages (BMDMs) are recruited to the injured myocardium and are essential for cardiac repair as they can adopt both pro-inflammatory or reparative phenotypes to modulate inflammatory and reparative responses, respectively. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the key mediators of the Hippo signaling pathway and are essential for cardiac regeneration and repair. However, their functions in macrophage polarization and post-MI inflammation, remodeling, and healing are not well established. Here, we demonstrate that expression of YAP and TAZ is increased in macrophages undergoing pro-inflammatory or reparative phenotype changes. Genetic deletion of YAP/TAZ leads to impaired pro-inflammatory and enhanced reparative response. Consistently, YAP activation enhanced pro-inflammatory and impaired reparative response. We show that YAP/TAZ promote pro-inflammatory response by increasing interleukin 6 ( IL6 ) expression and impede reparative response by decreasing Arginase-I ( Arg1 ) expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex. These changes in macrophages polarization due to YAP/TAZ deletion results in reduced fibrosis, hypertrophy, and increased angiogenesis, leading to improved cardiac function after MI. Also, YAP activation augmented MI-induced cardiac fibrosis and remodeling. In summary, we identify YAP/TAZ as important regulators of macrophage-mediated pro-inflammatory or reparative responses post-MI.

First recognized as regulators of development in worms and fruitflies, microRNAs are emerging as pivotal modulators of mammalian cardiovascular development and disease. Individual microRNAs modulate the expression of collections of messenger RNA targets that often have related functions, thereby governing complex biological processes. The wideranging functions of microRNAs in the cardiovascular system have provided new perspectives on disease mechanisms and have revealed intriguing therapeutic targets, as well as diagnostics, for a variety of cardiovascular disorders.

CRISPR-Cas9 has emerged as a powerful technology that relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. However, many therapeutic targets cannot currently be accessed due to the lack of carriers that can deliver RNPs systemically. Here, we report a generalizable methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells and edit tissues including muscle, brain, liver, and lungs. Intravenous injection facilitated tissue-specific, multiplexed editing of six genes in mouse lungs. High carrier potency was leveraged to create organ-specific cancer models in livers and lungs of mice though facile knockout of multiple genes. The developed carriers were also able to deliver RNPs to restore dystrophin expression in DMD mice and significantly decrease serum PCSK9 level in C57BL/6 mice. Application of this generalizable strategy will facilitate broad nanoparticle development for a variety of disease targets amenable to protein delivery and precise gene correction approaches. Therapeutic targets of CRISPR-Cas can often not be accessed due to lack of carriers to deliver RNPs systematically. Here, the authors engineer modified lipid nanoparticles for delivery of gene editing proteins to specific tissues.

The heart, an ancient organ and the first to form and function during embryogenesis, evolved by the addition of new structures and functions to a primitive pump. Heart development is controlled by an evolutionarily conserved network of transcription factors that connect signaling pathways with genes for muscle growth, patterning, and contractility. During evolution, this ancestral gene network was expanded through gene duplication and co-option of additional networks. Mutations in components of the cardiac gene network cause congenital heart disease, the most common human birth defect. The consequences of such mutations reveal the logic of organogenesis and the evolutionary origins of morphological complexity.

Key Points Numerous cell surface receptors modulate cellular motile functions through the control of dynamic actin polymerization. The status of cytoplasmic actin is sensed and communicated to the nucleus in order to elicit required changes in gene expression. The status of cytoskeletal actin dynamics is communicated to the nucleus by the shuttling of globular actin (G-actin)- and filamentous actin (F-actin)-binding proteins (G-ABPs and F-ABPs, respectively). Cytoskeletal F-actin complexes are often associated with additional proteins (F-ACAPs), which can also translocate to the nucleus. Myocardin-related transcription factors (MRTFs) are cofactors of the transcription factor serum response factor (SRF). MRTFs bind cytoplasmic G-actin and are released to translocate to the nucleus on stimulation of actin polymerization. The nuclear activity of MRTFs is subject to regulation by nuclear G-actin. G-actin regulates activity of the MRTF–SRF complex and the nuclear export of MRTF. The actin–MRTF–SRF circuit controls the expression of target genes that encode structural and regulatory components of the actin cytoskeleton. Thereby, positive and negative feedback loops can be activated to control cell motility by regulating actin dynamics. In addition to regulating the expression of cytoskeletal genes, SRF and members of the myocardin family regulate the expression of microRNAs, which provide additional feedback loops to modulate SRF signalling, cytoskeletal function and muscle development. Abnormalities in actin signalling mediated by the MRTF–SRF circuit are thought to have a key role in various diseases, including cancer, heart disease and vascular disorders. The link between cytoskeletal actin dynamics and correlated gene activities was unclear. However, the discovery that globular actin polymerization liberates myocardin family transcriptional cofactors to induce serum response factor, which modulates the expression of genes encoding effectors of actin dynamics, has helped bridge this gap in our knowledge. Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actin–MRTF–SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity.

Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical abnormalities of a variety of neuromuscular diseases are well known, no curative therapies have been developed to date. The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases. For example, Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene, has been successfully corrected in mice, dogs, and human cells through CRISPR/Cas9 editing. In this Review, we focus on the potential for, and challenges of, correcting muscular dystrophies by editing disease-causing mutations at the genomic level. Ideally, because muscle tissues are extremely long-lived, CRISPR technology could offer a one-time treatment for muscular dystrophies by correcting the culprit genomic mutations and enabling normal expression of the repaired gene.

The management of cardiovascular risk through lifestyle modification and pharmacotherapy is paramount to the prevention of cardiovascular disease. Epidemiological studies have identified obesity, dyslipidemia, diabetes, and hypertension as interrelated factors that negatively affect cardiovascular health. Recently, genetic and pharmacological evidence in model systems has implicated microRNAs as dynamic modifiers of disease pathogenesis. An expanded understanding of the function of microRNAs in gene regulatory networks associated with cardiovascular risk will enable identification of novel genetic mechanisms of disease and inform the development of innovative therapeutic strategies.