Search Results (636)

The myocyte enhancer factor 2 (MEF2) transcription factor family plays crucial roles in differentiation, lineage specification, stress responses, and tissue homeostasis. Recent investigations have shown that the dysregulation of MEF2A, MEF2B, MEF2C, and MEF2D is associated with tumorigenesis, tumor progression, and adverse clinicopathological features in several cancers. MEF2B has a particularly important role in B-cell malignancies, where recurrent mutations deregulate BCL6 and promote lymphoma progression. MEF2A, MEF2C, and MEF2D also regulate malignant phenotypes, including proliferation, migration, invasion, apoptosis, drug resistance, angiogenesis, inflammation, and immune evasion, by the mechanism of regulating cell-cycle regulators, apoptosis-related genes, EMT-related genes, and other transcriptional programs. This review summarizes the mechanisms by which MEF2 family members contribute to tumor initiation and progression, with added emphasis on MEF2B mutations and MEF2D fusions. We also discuss clinical associations with overall survival and recurrence in solid tumors and hematologic malignancies. Because MEF2 proteins are transcription factors with broad physiological functions, we evaluate therapeutic strategies: RNA interference, genetic perturbation, small molecules that alter MEF2-dependent transcription, and PROTAC or oligonucleotide-PROTAC. These platforms remain promising but require MEF2-specific validation, tumor-selective delivery, and careful toxicity assessment. Full article

Inhalable ribonucleic acid (RNA) nanomedicines are emerging as versatile therapeutics for respiratory diseases and pulmonary metastases, enabling localized delivery of messenger RNA (mRNA), small interfering RNA (siRNA), antisense oligonucleotides, microRNA (miRNA) mimics, self-amplifying RNA, and genome-editing systems. This review synthesizes the available evidence and argues that the field has moved beyond asking whether RNA can reach the lungs. The more consequential translational question is whether RNA cargo, nanocarrier, excipients, manufacturing process, inhalation device, and pulmonary target cell can be integrated into a reproducible therapeutic product. Current research demonstrates progress in disease-corrective mRNA expression, silencing of inflammatory and fibrotic pathways, mucosal vaccination, antiviral therapy, and localized cancer treatment, alongside advances in ionizable lipid nanoparticles, lipid–polymer hybrids, chitosan and polyethyleneimine (PEI) polyplexes, dendrimers, peptide carriers, biomimetic systems, and dry-powder formulations. Translational maturity, however, remains uneven. Many studies demonstrate carrier feasibility, reporter expression, or preclinical activity, whereas fewer establish device-compatible aerosolization, preservation of RNA integrity during processing, traversal of pulmonary barriers, target-cell engagement, repeat-dose tolerability, and clinically meaningful benefit. Development should therefore be target-defined, analytically gated, device-specific, and outcome-centered. Inhalable RNA nanomedicines are best understood as integrated pulmonary products whose success depends on preserving RNA function throughout manufacturing, aerosolization, post-deposition barrier navigation, intracellular delivery, and disease-relevant pharmacodynamic activity. Full article

Oligonucleotide therapeutics represent an expanding class of medicines that can regulate gene expression, RNA processing, protein translation, immune signaling, and biomolecular recognition through sequence-specific or structure-dependent mechanisms. Despite clinical progress, their application remains constrained by nuclease degradation, rapid clearance, inefficient tissue and cellular delivery, endosomal sequestration, off-target activity, immune recognition, and mechanism-specific requirements for target engagement. Chemical modification is central to oligonucleotide therapeutic development because it can mitigate some of these limitations while influencing target affinity, protein binding, pharmacokinetics, and intracellular activity. This review examines chemical modification strategies to improve the biological stability and functional performance of therapeutic oligonucleotides and is organized around major classes of chemical modification, including phosphate and backbone-linkage modifications, sugar and conformational modifications, backbone-replacement analogs, and conjugation-based approaches. Rather than presenting these chemistries as uniformly beneficial, this review emphasizes that the same modification can be enabling in one therapeutic mechanism and disruptive in another, so its value cannot be judged apart from the modality and molecular architecture in which it is placed. Clinically successful oligonucleotide designs are likely to rely on combinations of chemical features, including modified backbones, modified sugars, stereochemical control, terminal stabilization, and ligand- or formulation-based delivery strategies. Understanding how these features interact is essential to develop more predictable and mechanism-appropriate oligonucleotide therapeutics. Full article

Primary hyperlipoproteinemias represent a heterogeneous group of inherited lipid metabolism disorders characterized by persistent abnormalities in plasma lipoproteins, a markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD) and, in selected phenotypes, acute pancreatitis. Traditionally classified according to the Fredrickson phenotypic system, these disorders are now increasingly understood through a multidimensional framework integrating molecular genetics, intracellular lipid trafficking, inflammatory signaling, and systemic metabolic regulation. Recent advances have identified both monogenic and polygenic determinants underlying disease expression, including pathogenic variants affecting LDLR, APOB, PCSK9, APOE, and lipoprotein lipase pathways, as well as the cumulative contribution of multiple common lipid-associated variants. Furthermore, emerging evidence highlights the role of endoplasmic reticulum stress, oxidative imbalance, adipose–hepatic crosstalk, intestinal lipid absorption, and inflammatory mediators in modulating lipoprotein metabolism and cardiovascular risk. Novel regulators such as angiopoietin-like proteins (ANGPTLs), microRNAs, and pathways involved in cholesterol efflux and remnant lipoprotein clearance have further refined our understanding of disease heterogeneity and therapeutic responsiveness. Familial hypercholesterolemia and familial combined hyperlipidemia exemplify the complex interplay between genetic susceptibility, metabolic dysfunction, and environmental influences that shape phenotype severity and long-term cardiovascular outcomes. Advances in diagnostic strategies, including genetic testing, polygenic risk scores, apolipoprotein profiling, and vascular imaging, have significantly improved risk stratification and personalized management. Simultaneously, innovative therapies—including PCSK9 inhibitors, ANGPTL3-targeted agents, antisense oligonucleotides, and RNA-silencing technologies—are reshaping treatment paradigms and expanding options for high-risk patients. This chapter synthesizes contemporary insights into the pathogenesis of primary hyperlipoproteinemias, emphasizing the transition from traditional lipid-based classification toward precision medicine approaches focused on lifetime cardiovascular risk, molecular characterization, and individualized therapeutic intervention. Full article

Reversible genetic medicines are emerging as controllable alternatives to permanent genome editing by enabling programmable modulation of RNA sequence, transcript abundance, chromatin state, and gene expression without irreversible genomic alteration. However, reversibility is not a single binary property: transient editor exposure, decay of the molecular effect, recovery of cellular function, and clinical capacity to stop, redose, or counteract treatment may diverge. This review therefore distinguishes mechanistic, functional, and clinical reversibility while examining targeted delivery systems for RNA-editing and epigenome-editing therapeutics. Key payloads include ADAR-recruiting oligonucleotides, CRISPR-Cas13 RNA editors, guide RNAs, chemically modified RNAs, editor-encoding mRNAs, dCas9 transcriptional regulators, DNA methylation editors, histone-modifying systems, and CRISPRoff-like platforms. We evaluate extracellular and intracellular delivery barriers, including nuclease degradation, immune recognition, renal clearance, liver uptake, cellular entry, endosomal escape, cytoplasmic release, nuclear localization, chromatin access, editing-window duration, off-target activity, immunogenicity, repeat-dosing feasibility, manufacturing, quality control, potency assays, and regulatory translation. Overall, delivery systems for reversible genetic medicines should be judged by tissue selectivity, functional editing, duration of action, reversibility after treatment withdrawal, safety, manufacturability, and clinical controllability. Full article

Long non-coding RNAs (lncRNAs) constitute an important group of regulatory RNA molecules involved in the control of gene expression at the epigenetic, transcriptional, and post-transcriptional levels. In recent years, their crucial role in the pathophysiology of cardiovascular diseases, particularly coronary heart disease, has become increasingly evident. The aim of this review is to present current knowledge regarding the mechanisms of lncRNA action in the cardiovascular system, their involvement in the molecular processes associated with myocardial ischaemia, and their potential diagnostic and therapeutic applications. We discuss the molecular mechanisms responsible for the regulation of cardiomyocyte apoptosis, oxidative stress, mitochondrial dysfunction, angiogenesis, coronary vessel remodelling, and cardiac fibrosis. Particular attention is paid to selected lncRNAs involved in coronary heart disease, including MIAT, MALAT1, ANRIL, and H19, which influence inflammatory processes, vascular smooth muscle cell proliferation, responses to hypoxia, and cardiac fibrosis. The potential of lncRNAs as diagnostic and prognostic biomarkers in coronary artery disease is also discussed. Current evidence suggests that molecules such as MALAT1, MIAT, LIPCAR, and HCG11 may have considerable diagnostic and prognostic value, including for predicting major adverse cardiovascular events and the no-reflow phenomenon following percutaneous coronary intervention. Furthermore, contemporary therapeutic strategies targeting lncRNAs are presented, including antisense oligonucleotides, siRNAs, and CRISPR/Cas9 genome-editing technologies. Despite promising preclinical findings, the clinical application of lncRNA-based therapies remains limited by challenges related to safety, delivery of therapeutic molecules, and translation of experimental findings into clinical practice. Nevertheless, lncRNAs represent a promising avenue for the development of precision medicine and may play an important role in the future diagnosis and treatment of cardiovascular diseases. Full article

The intricate intercellular communication within the tumor microenvironment (TME) critically drives cancer progression and therapeutic resistance. Natural killer (NK) cells are potent sentinels of the innate immune system, but their antitumor functions are often severely compromised by the TME’s immunosuppressive networks. Moving beyond protein-coding genes, non-coding RNAs (ncRNAs)—with microRNAs (miRNAs) playing a foundational role alongside long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs)—have emerged as vital components of the regulatory networks influencing immune responses. Rather than dictating immune cell fate, these diverse transcriptomic classes form complex networks that modulate NK cell functional states and TME immunosuppression. This review systematically elucidates the molecular mechanisms by which these ncRNA networks influence NK cell biology in the TME. We dissect three core regulatory axes driven by extracellular vesicle (EV)-mediated communication, competitive endogenous RNA crosstalk, and epigenetic remodeling: the extrinsic suppression of NK cells by EV-derived and secreted ncRNAs from TME-resident cells, the reciprocal modulation of TME components by NK cell-derived ncRNAs, and the intrinsic regulation of NK cell functions by endogenous ncRNAs. Furthermore, we critically assess the clinical translational potential of targeting these networks. We highlight specific ncRNAs as non-invasive prognostic biomarkers and summarize targeted therapeutic interventions using antisense oligonucleotides, small interfering RNAs, and nano-delivery systems. Modulating these core ncRNA nodes to mitigate TME immunosuppression offers a novel paradigm for precision oncology, holding substantial promise for enhancing immune checkpoint blockade and NK cell-directed immunotherapies. Full article

The identification of microRNAs (miRNAs) has resulted in significant advancements in research, particularly regarding their utilization as diagnostic and therapeutic targets. This has generated enthusiasm for exploring the potential of non-coding RNAs (ncRNAs) in treating cancer and other diseases, with miRNAs and long non-coding RNAs (lncRNAs) showing particular promise. Over the past twelve years, there has been significant research into RNA-based treatments. Antisense oligonucleotides and small interfering RNAs are the most commonly used. Certain products have received Federal and Drug Administration approval. Notably, the findings from clinical trials have been inconsistent, with certain investigations indicating notable effectiveness and others reporting only minimal efficacy or safety concerns. Consequently, clinical trials are currently underway to evaluate the efficacy of novel treatment options, including antimiRNAs, in addressing these challenges. There is an increasing interest in the use of long non-coding RNA (lncRNA)-based therapies. The potential for drugs developed using this technology is significant. Significant advancements in preclinical and clinical trials have emerged, indicating promising potential for future developments. MiRNAs are playing an increasingly important role in the diagnosis and prediction of acute coronary syndrome manifestations. Its utilization, whether as a comprehensive approach or in conjunction with existing biomarkers, may be implemented in the foreseeable future, especially in instances of uncertainty regarding diagnosis. The primary objective of this review is to deliver a thorough and detailed assessment of recent progress in the field of microRNA detection and characterization. A key focus of this assessment will be on their clinical translation. Secondly, an exploration of the prevailing knowledge in the field of RNA therapies as potential targets for diagnosis and treatment in the cardiovascular system will be conducted. The most recent challenges and perspectives on the road to clinical application are presented herein. The aim of the present seminar is to furnish a thorough report on the recent advancements in the detection and characterization of miRNAs and lncRNAs, with specific emphasis on their clinical translation. In summary, the paper herein presents an exploration of the most recent challenges and perspectives on the road to clinical application. Full article

Background/Objectives: Elevated lipoprotein(a) [Lp(a)] is an independent cardiovascular risk factor associated with atherosclerotic cardiovascular disease and calcific aortic valve disease. Historically, therapeutic options for reducing Lp(a) have been limited. This study aimed to characterize the clinical development landscape of emerging Lp(a)-targeted therapies, evaluate endpoint assessment strategies, and summarize available efficacy evidence from investigational agents. Methods: A qualitative clinical trial landscape review was conducted using ClinicalTrials.gov. Interventional Phase I–III studies evaluating therapies specifically targeting Lp(a) were identified through a structured registry search performed on 5 November 2025. Eligible studies were screened according to predefined inclusion and exclusion criteria. Extracted data included trial characteristics, therapeutic class, endpoint methodologies, and published efficacy outcomes. Data were synthesized narratively. Results: Twenty clinical trials met the eligibility criteria. Three therapeutic classes were identified: antisense oligonucleotides (ASOs), small interfering RNA (siRNA)-based therapies, and small-molecule inhibitors. Pelacarsen represented the sole ASO program, whereas siRNA-based therapies constituted the largest therapeutic category. Five studies were designed as cardiovascular outcomes trials. Percent change from baseline in circulating Lp(a) concentration was the most frequently used efficacy endpoint. Published data demonstrated substantial reductions in Lp(a) concentrations across all major therapeutic platforms. Available non-head-to-head published evidence showed substantial Lp(a) reductions across several investigational agents, including siRNA-based therapies, pelacarsen, and muvalaplin, although differences between studies preclude direct comparison between therapeutic platforms. Conclusions: The Lp(a) therapeutic landscape has rapidly evolved, with RNA-based therapies demonstrating unprecedented reductions in circulating Lp(a) concentrations. Ongoing cardiovascular outcomes trials will determine whether these reductions translate into meaningful cardiovascular benefits, establish Lp(a) as a therapeutic target in cardiovascular prevention and clarify the long-term safety and risk–benefit profile of Lp(a)-targeted therapies. Full article

Rare genetic diseases are heterogeneous across mechanisms, trajectories, and treatment responses. To date, approved therapies remain available for only a small proportion of rare genetic diseases. Oligonucleotide-based RNA therapeutics, particularly antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), offer a promising therapeutic avenue for rare genetic diseases with sequence-level precision. However, traditional preclinical paths may mis-predict human outcomes when disease biology diverges from animal models. New approach methodologies (NAMs), including patient-derived induced pluripotent stem cells (iPSCs), organoid models, and clinical-trials-in-a-dish (CTiD), aim to bring human biology earlier into the translational pipeline. NAMs enable variant-to-function studies, efficacy screening, and safety triage at clinically relevant speed and scale. While critics argue that NAMs are unvalidated and cannot replace preclinical animal models, proponents report that they are increasingly able to recapitulate human phenotypes and predict clinical liabilities, although their predictive validity remains context-dependent. Here, a front-loaded human filter refers to the use of human-derived systems early in development to support mechanistic interpretation, candidate prioritization, and early liability assessment before broader nonclinical evaluation. Recent studies pairing NAMs with ASOs support rapid, patient-specific preclinical screening in selected settings, while also showing the need for broader evidence on delivery, pharmacology, safety, and clinical relevance. This review places these developments within the translational realities of oligonucleotide-based therapeutics, including model fidelity, ASO chemistry and optimization, delivery challenges, pharmacology, regulatory pathways for individualized ASOs, and accessibility. We also propose a pragmatic validation framework to assess the scientific and translational credibility of NAMs across rare genetic diseases. Full article

Clinical genomics has traditionally focused on protein-coding variation, yet many pathogenic mechanisms arise through alterations in RNA processing, stability, localisation, translation, and surveillance. Prior reviews have addressed individual RNA layers, splicing, non-coding RNAs, RNA therapeutics, or RNA diagnostics in isolation. This review presents an integrated, mechanism-matched framework linking RNA-level disease mechanisms to diagnostic reasoning and therapeutic selection across all major RNA layers, offering a practical resource for clinical geneticists and translational researchers. I examine how splicing defects, pseudoexon inclusion, polyadenylation disruption, RNA editing loss, untranslated-region variants, premature termination codons, stop-loss variants, RNA-binding protein dysfunction, non-coding RNA dysregulation, altered codon usage, ribosome stalling, and surveillance pathway failure, including nonsense-mediated decay, nonstop decay, and no-go decay, each create distinct and mechanistically addressable disease states. A central argument of this review is that treatment selection must be mechanism-matched rather than gene- or variant-class-based: splice defects may require antisense oligonucleotide (ASO)-mediated correction or small-molecule splice modulation; toxic transcripts may require ASO- or siRNA-mediated silencing; haploinsufficiency may require mRNA replacement or transcript rescue; premature termination codons are candidates for readthrough only when transcript and protein context are favourable. I further argue that RNA sequencing, long-read transcriptomics, allele-specific expression analysis, and functional assays are essential for both diagnosis and therapeutic stratification. The framework described here moves clinical variant interpretation beyond descriptive classification toward mechanism-based, RNA-centric precision medicine. Full article

Survivin (BIRC5) is a key inhibitor of apoptosis that is highly overexpressed in many cancers, where it promotes tumour cell survival, mitotic progression, and resistance to therapy. Because survivin is largely absent from normal adult tissues, it represents a selective and promising target for cancer treatment. Antisense oligonucleotides (ASOs) provide a precise approach to silence survivin by targeting its transcripts. Preclinical studies have shown that ASO-mediated reduction of survivin is associated with increased cancer cell death, inhibition of tumour growth, and enhanced sensitivity to other treatments. Early-phase clinical trials of survivin-targeting ASOs have shown evidence of target engagement but ultimately failed to demonstrate consistent clinical benefit and/or encountered dose-limiting toxicities, which hindered their further development. This review outlines survivin’s central role in cancer biology, the principles of ASO therapeutics (sequence design, mechanisms of action, chemical modifications, and delivery strategies), and the progress in preclinical and clinical development of survivin-targeting ASOs, while also discussing key challenges that may contribute to their clinical limitations, including inefficient delivery, off-target effects, and systemic toxicities. Collectively, the current status of survivin-targeting ASOs underscores the need for synergistic optimization of delivery platforms and molecular chemistry to improve efficacy and safety, thereby enabling their use in personalised and combination cancer treatment approaches. Full article

Background/Objectives: Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive β-cell loss. Apolipoprotein CIII (apoCIII), a lipid metabolism regulator, is elevated in T1D and implicated in β-cell apoptosis. Antisense oligonucleotide–mediated apoCIII reduction delays diabetes onset in diabetes-prone BioBreeding (DPBB) rats. This study examined whether small-interfering RNA (siRNA) targeting apoCIII during the final prediabetic month preserves islet integrity and delays T1D onset. Methods: Two siRNAs targeting rat apoCIII were evaluated in 30-day-old DPBB rats for efficacy and off-target effects. Hepatic and plasma apoCIII levels were measured, and neighboring apolipoprotein gene expression was assessed. The most specific candidate (apoCIII-siRNA2) was selected. Duration of action was determined after a single injection. To study the effects of apoCIII-lowering treatment in vivo, islets from 25-day-old DPBB rats were transplanted into the anterior chamber of the eye of age-matched DPBB recipients. Rats received weekly intravenous injections of apoCIII-siRNA2 from day 30 until diabetes onset. Islet morphology, vascularization, and phagocyte infiltration were assessed by confocal imaging three and five weeks post-transplantation. Results: Both siRNAs reduced apoCIII, but one showed off-target effects and was excluded. A single injection of apoCIII-siRNA2 suppressed plasma apoCIII for approximately one week and weekly treatment maintained low circulating apoCIII levels. Five weeks after transplantation islet morphology and vascularization were preserved, and there was no increase in phagocyte infiltration. This resulted in a delayed onset of diabetes. Conclusions: siRNA-mediated apoCIII reduction delays pancreatic islet deterioration and T1D onset in DPBB rats, supporting apoCIII as a contributing factor to β-cell vulnerability and thereby a potential therapeutic target. Full article

Background/Objectives: Single-stranded oligonucleotides (ssODNs) are used as donor templates for therapeutic gene editing by CRISPR-Cas9 cleavage and homology-directed repair (HDR). Although ssODN sequence fidelity is critical to the safety and efficacy of editing, standard quality control methods cannot resolve individual nucleotide errors. Methods: We performed deep sequencing of ssODNs from three manufacturers and amplicons from edited hematopoietic stem/progenitor cells. Results: We find that synthesis errors are present in all ssODNs tested at rates that vary more than two-fold among manufacturers, at positions that are dependent on sequence context. These synthesis errors are propagated into the genome by HDR at frequencies proportional to their abundance in the ssODN. In our sickle cell mutation correction protocol, the most prevalent SNEs are predicted to produce benign β-globin variants, while the less frequent frameshift deletions are predicted to generate β-thalassemia-like alleles. Conclusions: Current quality control standards are insufficient to detect these errors, and deep sequencing of ssODNs should be incorporated into regulatory submissions for clinical gene editing programs. Full article

Antisense oligonucleotides (ASOs) are a class of nucleic acid therapeutics that modulate gene expression through diverse mechanisms. Since their initial demonstration in inhibiting viral genes, advances in medicinal chemistry, pharmacology, and delivery have enabled robust and durable target engagement across multiple tissues. Chemical modifications to the backbone, ribose, and nucleobases have improved nuclease resistance, binding affinity, and pharmacokinetics, while conjugation and delivery technologies have expanded tissue accessibility. Beyond classical RNase H–mediated RNA degradation, ASOs regulate gene expression via splicing modulation, microRNA inhibition, transcriptional activation, and translation modulation, supporting both gene silencing and upregulation strategies. Multiple ASO drugs are now approved, particularly for genetic diseases, with many more in clinical development. This review outlines the evolution of antisense technology, key chemical and delivery innovations, ASO pharmacokinetics and intracellular trafficking, the mechanisms underlying gene regulation, and current clinical applications and future opportunities. Full article