Cell-specific epigenetic editing holds very high therapeutic value for atherosclerosis, cardiomyopathy, and fibrosis, provided that delivery, specificity, and safety challenges are also addressed.
Abstract
BACKGROUND
Cell-specific epigenetic editing provides a new approach to the therapy of cardiovascular disease (CVD) by rewriting pathological chromatin and RNA marks in exactly those cell populations responsible for causing disease. CVD is caused by interactions of genetics and environment on cell-type-specific epigenomic programs. Interventions that alter DNA methylation, histone marks, or RNA modifications can therefore correct maladaptive gene expression without altering DNA sequence.
SUMMARY
Recently developed technologies such as dCas9 fused to writers/erasers allow programmable, locus-directed modulation of promoters, enhancers, and transcripts. Proof-of-principle in vivo work has shown durable target silencing, illustrating both the potency and persistence of epigenetic edits. To achieve therapeutic benefit, cell-targeting strategies and rigorous single-cell/multi-omic validation of on-target activity and off-target safety will be required. Major translational challenges include scalable, cardiac-selective delivery, immune responses to vectors/editors, long-term monitoring for unintended chromatin changes, and regulatory pathways for nongenotoxic but durable interventions.
KEY MESSAGES
Altogether, cell-specific epigenetic editing holds very high therapeutic value for atherosclerosis, cardiomyopathy, and fibrosis, provided that delivery, specificity, and safety challenges are also addressed.
Although cells within an organism share nearly identical genomes, their transcriptional programs differ markedly due to reversible chemical modifications known as epigenetic marks. These marks, including DNA methylation and histone modifications, regulate gene expression without altering DNA sequence and play a central role in development and disease. While epigenetic drugs such as DNA methyltransferase inhibitors have shown clinical benefit, their genome-wide activity often results in off-target toxicity limiting broader therapeutic applications. This has driven the development of locus-specific epigenetic editing strategies. Programmable epigenetic modifiers (PEMs) combine customizable DNA-binding platforms, such as CRISPR-dCas systems, transcription activator-like effectors (TALEs), or zinc fingers, with epigenetic effector domains to precisely install or remove regulatory marks at defined genomic loci. Because effective editing depends on the pre-existing epigenetic landscape, detection and characterization of target-site epigenetic states is a prerequisite for rational editor design, increasingly aided by machine-learning models that predict editing outcomes. In this review, we summarize current technologies for epigenetic mark detection and discuss the transition from global pharmacological approaches to programmable, modular editing systems that enable spatial and temporal control of gene regulation. We further address heritability and delivery constraints. Reversible, site-specific epigenetic editing represents a promising therapeutic paradigm for cancer, genetic disorders, and regenerative medicine.
It is argued that epigenetic editing is progressively establishing itself as a distinctive therapeutic modality characterized by durable efficacy and sequence-independent safety-reversibility as a theoretical safety mechanism has been validated preclinically, but the monitoring and intervention infrastructure required for its clinical implementation remains to be established.
Shiqi Chang, Di Lu, Yuyuan Jin et al.· Clinical Epigenetics· 0 citations
The mechanisms and roles of DNA methylation in epigenetic regulation are examined, the current landscape of DNA methylation modulators are evaluated, from traditional DNMT inhibitors to cutting-edge CRISPR-dCas9 fusion systems and protein-protein interaction disruptors, and their clinical relevance are evaluated.
Julie Gilbert, Francesco Calzaferri· Chemical Research in Toxicol...· 0 citations
CRISPR has emerged as a next-generation gene-editing tool with the potential to target the molecular pathways associated with ageing and related disorders. It functions through RNA-guided Cas nucleases, directing DNA cleavage and utilizing the native DNA repair machinery for genetic manipulations. Advances in CRISPR technology have significantly enhanced the precision and flexibility of techniques for genome editing. The enzyme Cas9's ability to cut DNA at exact site has revolutionized genome editing by enabling accurate modifications within living eukaryotic cells. This review critically examines recent developments in CRISPR-based technologies, including Cas9, Cas12, base editing, prime editing, and CRISPR-mediated gene regulation. It highlights their rising applications in ageing research, with more emphasis on neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The review also discusses the major pharmacological and translational challenges that currently limit clinical applications, including inefficient tissue-specific delivery, off-target genome editing, immunogenicity, manufacturing complexity, and long-term safety concerns. Also, recent progress in both, viral and non-viral delivery methods are critically evaluated, including adeno-associated viruses, lentivirus vectors, lipid nanoparticles, gold nanoparticles, exosomes, electroporation, and microinjection, is thoroughly discussed to highlight their therapeutic potential and translational limitations. Current studies indicate that CRISPR-based approaches have preclinical potential for targeting important hallmarks of ageing, particularly genomic instability, telomere attrition, and mitochondrial dysfunction. Other hallmarks of ageing, such as stem cell exhaustion, epigenetic modifications, and microbiome changes, are at earlier stages of development. Overall, this review describes future strategies for developing safe, precise, and clinically translatable CRISPR-based treatments to promote healthy ageing.
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This review presents an in-depth analysis of the most recent advances in small-molecule epigenetic modulators, focusing on their mechanisms of action, therapeutic applications, and the challenges impeding their clinical development, with the aim of informing the rational design and optimization of next-generation epigenetic treatment strategies for cancer.
Peng Jin, Yi Wang, Na Zhao et al.· Biochimica et biophysica act...· 0 citations
It is proposed that integrating precise editing, in vivo screening, single-cell multi-omics, and emerging artificial intelligence (AI)-assisted design may provide information and a design basis for future combined strategies that simultaneously target vulnerabilities in senescent cells and malignant populations.
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