Pharmacological Reviews最新文献

{"title":"Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.","authors":"Xiaodong Cheng, Hua Liu, Wenbo Zhang, Wenli Yang, Fang Mei","doi":"10.1016/j.pharmr.2025.100078","DOIUrl":"10.1016/j.pharmr.2025.100078","url":null,"abstract":"<p><p>Vascular remodeling is a complex process involving the coordinated actions of multiple cellular signaling pathways in various cell types, leading to structural and functional changes in blood vessels. These changes can be adaptive, as in wound healing, or maladaptive, as seen in chronic vascular diseases such as atherosclerosis, hypertension, and retinopathy. Exchange proteins directly activated by cAMP (EPACs) are key players in cAMP-mediated cell signaling, distinct from the more traditionally studied protein kinase A pathway. EPAC proteins are guanine nucleotide exchange factors for the small G proteins Rap1 and Rap2. Recent studies have also revealed noncanonical functions of EPAC1 involving the formation of biomolecular condensates. EPAC proteins regulate various cellular processes, including cell adhesion, migration, proliferation, and differentiation. In this review, we discuss the roles of EPACs in vascular remodeling and diseases associated with the process, as well as the potential of EPACs as therapeutic targets for proliferative vascular diseases. SIGNIFICANCE STATEMENT: Vascular remodeling is associated with various human diseases, such as atherosclerosis, stroke, and retinopathy. Understanding the roles of exchange proteins directly activated by cAMP signaling in vascular remodeling provides insights into the mechanisms underlying vascular diseases and facilitates the development of targeted therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100078"},"PeriodicalIF":17.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances and challenges in experimental models of posttraumatic epilepsy for therapeutic interventions.","authors":"Doodipala Samba Reddy, Victoria M Golub, Sreevidya Ramakrishnan, Severn B Churn, Lee A Shapiro, Jaclyn Iannucci, Asla Pitkänen, Aristea S Galanopoulou, Rama Maganti, Detlev Boison","doi":"10.1016/j.pharmr.2025.100080","DOIUrl":"10.1016/j.pharmr.2025.100080","url":null,"abstract":"<p><p>Epilepsy affects over 80 million people worldwide, with approximately 40% experiencing refractory seizures. Despite some progress in deciphering the complex process of epileptogenesis, which transforms a healthy brain into one susceptible to epilepsy, there are still no therapies available to prevent this condition. Traumatic brain injury (TBI) is a leading cause of epilepsy in both military and civilian populations, often leading to the complex condition of posttraumatic epilepsy (PTE). Defined as recurrent seizures following TBI, PTE lacks effective treatment options, highlighting the need for improved experimental models and translational interventions. Unveiling disease-modifying therapeutics for epilepsy is a top priority in the field of neurology research. One major obstacle in PTE research is the lack of robust models that accurately reflect the multifaceted and heterogeneous nature of human PTE. Hence, developing disease-modifying treatments requires innovative models that facilitate the identification of novel therapeutic approaches. Establishing clinically relevant animal models is critical for elucidating the pathophysiological mechanisms of epileptogenesis and identifying effective therapies for PTE management. This article describes the opportunities and challenges associated with advances in PTE experimental models, including the call for common data elements to be developed for PTE. Inspired by insights from a 2023 workshop supported by the American Epilepsy Society, this review explores progress in animal models, experimental protocols, biomarkers, and principles of therapeutic interventions for TBI-induced seizures and posttraumatic epileptogenesis. It evaluates the PTE research landscape and critically discusses current strategies, innovations, hurdles and future directions for establishing models that ultimately lead to the development of disease-modifying agents and targeted therapeutic approaches for PTE prevention. SIGNIFICANCE STATEMENT: Posttraumatic epilepsy (PTE) lacks specific therapies due to limited experimental models. Here, we outline the proceedings of the 2023 American Epilepsy Society-supported National Workshop on PTE, covering small and large animal models for PTE research. This article provides insights into recent advancements in experimental paradigms and analyzes the validity and application of these models in identifying interventions to prevent epileptogenesis following traumatic brain injury. We address challenges and obstacles in discovering PTE therapies, offering clinical data context and common themes.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 5","pages":"100080"},"PeriodicalIF":17.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolution of lipid-lowering drugs in the management of cardiovascular disease risk: From the first cardiovascular disease risk-reducing therapies to the novel challenging strategies.","authors":"Doriane Henry, Eric Baugé, Bart Staels, Fanny Lalloyer","doi":"10.1016/j.pharmr.2025.100086","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100086","url":null,"abstract":"<p><p>Before the Framingham Heart Study, the concept of cardiovascular disease (CVD) risk factors did not exist, and CVDs were seen as a consequence of aging. The first 2 reports in 1957 and 1961 identified high cholesterol levels as a major risk factor for CVD, highlighting the importance of lipid management to reduce CVD risk. Since then, the growing knowledge of CVD pathophysiology has led to the development of many drug classes to manage dyslipidemia and consequently, cardiovascular disease risk. Unfortunately, many of them, such as high-density lipoprotein-targeted or triglyceride-modulating drugs, have so far failed in clinical trials due to a lack of efficacy in cardiovascular disease protection or due to the appearance of side effects. Interestingly, low-density lipoprotein-targeted statin therapy revolutionized cardiovascular risk management and remains today the reference treatment in primary and secondary CVD prevention. In the last decades, novel low-density lipoprotein-targeted drugs, such as ezetimibe, proprotein convertase subtilisin/kexin type 9-targeted therapies, and bempedoic acid, have been approved by the Food and Drug Administration and have now found their place among the therapeutic arsenal of hypolipidemic drugs used in CVD risk management, in case of intolerance to statins or often in association with statins. This review focuses on the historical evolution of development strategies and on the successes and failures of lipid-lowering drugs to reduce cardiovascular disease risk, from the mid-20th century to the present, and concludes with novel challenging strategies in progress. SIGNIFICANCE STATEMENT: This review highlights the evolution of lipid-lowering therapies in atherosclerotic cardiovascular disease management, from statins to proprotein convertase subtilisin/kexin type 9 inhibitors. It underscores key successes, limitations, and emerging strategies, offering essential insights into their current and future roles in reducing atherosclerotic cardiovascular disease risk for a broad medical and scientific audience.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100086"},"PeriodicalIF":17.3,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metal-based antibody, nanobody, and peptide conjugates: Potential for breast cancer therapy.","authors":"Busra Kaya, Devina Laurencia, Maseeha Farha Ayoub, Mahan Gholam Azad, Mahendiran Dharmasivam, Des R Richardson","doi":"10.1016/j.pharmr.2025.100087","DOIUrl":"https://doi.org/10.1016/j.pharmr.2025.100087","url":null,"abstract":"<p><p>Globally, breast cancer (BC) remains the leading cause of cancer death in women. BC profoundly impacts the physical and psychological well being of millions of families worldwide and significantly burdens the healthcare system and the economy. Although chemotherapy remains a key component in BC treatment, its effectiveness is often limited by severe side effects and the development of drug resistance, highlighting the urgent need for innovative therapeutic strategies. One strategy to minimize side effects involves conjugating anticancer agents with tumor-targeting molecules such as antibodies, nanobodies, or peptides to enhance their selective delivery to cancer cells. The success of platinum-based drugs such as cisplatin and carboplatin has urged the exploration of other metal-based complexes as therapeutic agents for BC. Metals, including copper, zinc, and gold, are considered promising candidates for anticancer therapy because of their well established cytotoxic properties and relatively low cost. This review examines the use of metal-based agents conjugated to tumor-targeting molecules for the treatment of BC. Additionally, we propose a novel approach to conjugate innovative thiosemicarbazone-copper complexes with a targeting moiety, aiming to overcome 2 major clinical challenges of current anticancer drugs: side effects and drug resistance. SIGNIFICANCE STATEMENT: Metal-based drugs possess potent anticancer properties through diverse mechanisms. However, current agents like cisplatin face 2 major challenges common to most anticancer therapies: toxic side effects and drug resistance. One strategy to address these issues is the conjugation of anticancer agents to specific tumor-targeting moieties, such as antibodies, nanobodies, or peptides. To further limit resistance development, drug conjugates can be designed to include a potent, multitargeted payload, such as a thiosemicarbazone-copper complex that targets lysosomes.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 6","pages":"100087"},"PeriodicalIF":17.3,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunomodulatory effects of calorie restriction and its mimetics: A new potential therapeutic approach for autoimmune diseases.","authors":"Monokesh K Sen, Eileen Liao, Duan Ni, Anjie Ge, Laura Piccio","doi":"10.1016/j.pharmr.2025.100063","DOIUrl":"10.1016/j.pharmr.2025.100063","url":null,"abstract":"<p><p>Calorie restriction (CR) is a well known intervention associated with multifaceted anti-aging and pro-longevity health benefits. It induces complex physiological cellular and molecular adaptations, resulting in the fine-tuning of metabolic and immune responses in both homeostatic and diseased states. It has thus been extensively studied both preclinically and clinically, uncovering its therapeutic potential against inflammatory conditions, particularly autoimmune diseases. CR mimetics (CRMs), that is, molecules that mimic CR's effects, have also been widely investigated to counteract inflammatory states associated with numerous diseases, including autoimmunity. However, a comprehensive overview of how CR and CRMs modulate different aspects of immune responses, thereby potentially modifying autoimmunity, is still lacking. Here, we reviewed the latest progress on the impacts of CR and CRMs on the immune system and the current evidence on their potential translation in the clinical management of people with autoimmune diseases. First, we summarized different types of CR and CRMs and their main mechanisms of action. We next reviewed comprehensively how CR and CRMs modulate immune cells and discussed up-to-date preclinical and clinical advances in using CR and CRMs in the context of some of the most common autoimmune diseases. Finally, challenges faced in CR-related research and its translation into the clinic are discussed. SIGNIFICANCE STATEMENT: Calorie restriction (CR) encompasses various approaches for daily or intermittent reduction in calorie intake while maintaining adequate nutrient intake. It acts through cell-intrinsic and -extrinsic pathways to modulate immune cell functions. CR is emerging as a strategy for autoimmune disease management. CR's effects could be partially mimicked by molecules called CR mimetics, which are proposed to achieve CR's effects without reducing food intake. CR and CR mimetics have been tested as promising potential therapeutics in preclinical and clinical autoimmune disease studies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100063"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets.","authors":"Fabio A Iannotti, Vincenzo Di Marzo","doi":"10.1016/j.pharmr.2025.100070","DOIUrl":"10.1016/j.pharmr.2025.100070","url":null,"abstract":"<p><p>The endocannabinoid system (eCB) is a complex signaling network discovered in mammals during the 1980s-1990s. It conventionally revolves around two arachidonic acid-derived mediators, N-arachidonoyl-ethanolamine (anandamide) and 2-arachidonoyl-glycerol; their main receptors, the cannabinoid receptors of type 1 (CB1) and type 2 (CB2), and the transient receptor potential vanilloid-1 channels; and the enzymes responsible for their biosynthesis and degradation. However, drawing on these discoveries, numerous eCB-like signaling lipids beyond the classical eCBs, have been unveiled, together with their receptors and metabolic enzymes, thus forming a more complex signaling network known as the endocannabinoidome (eCBome). This review explores the physiology, pharmacological complexity, and molecular targets of the mammalian eCBome, highlighting its versatility and redundancy in the context of global health. Emerging mediators, metabolic pathways and mechanisms, receptors, and their implications in human physiology and pathology are described, particularly concerning metabolic disorders, pain, inflammation, neurodegenerative diseases, and cancer. The importance of other \"eCBomes\" in nonmammalian forms of life that constitute the external and internal environments of mammals is also discussed for the first time in this context. The overarching objective of this article is to gain insights into the potential of eCBome-based therapeutic strategies aimed at enhancing both human and environmental well-being. SIGNIFICANCE STATEMENT: Lipid-based signaling molecules are ubiquitous in nature, yet their study remains challenging due to intricate regulatory mechanisms. Among lipid signaling pathways, the endocannabinoid (eCB) system and its extended version, the endocannabinoidome (eCBome), are particularly remarkable. Comprising hundreds of mediators, and dozens of receptors and metabolic enzymes, the eCBome regulates critical physiological processes not only in mammals but also across diverse organisms, including plants, fungi, and bacteria. This article examines the evolutionary and functional diversity of eCBomes and highlights their untapped potential as multikingdom therapeutic targets to address pressing challenges in global health.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100070"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"5-HT_2A receptors: Pharmacology and functional selectivity.","authors":"Benjamin R Cummins, Gerald B Billac, David E Nichols, Charles D Nichols","doi":"10.1016/j.pharmr.2025.100059","DOIUrl":"10.1016/j.pharmr.2025.100059","url":null,"abstract":"<p><p>Serotonin 5-HT_2A receptors were one of the first serotonin receptors to be pharmacologically characterized. In mammals, they are expressed throughout the body in nearly every cell and tissue type, with the highest density in cortical layer V of the brain. They are involved in several aspects of normal physiological processes and behaviors and have been implicated in the etiology of neuropsychiatric diseases such as schizophrenia. Atypical antipsychotics have targeted blockade of 5-HT_2A receptors as part of their therapeutic mechanism. More recently, 5-HT_2A receptors have come to prominence for their role as the primary target for psychedelic drugs, which activate this receptor subtype to produce their characteristic behavioral effects. 5-HT_2A receptor agonists like psilocybin, dimethyltryptamine, and lysergic acid diethylamide have each demonstrated long-lasting therapeutic efficacy in clinical trials for psychiatric disorders such as major depression and substance use disorders. There is a significant effort in both academia and industry to develop new agonists of 5-HT_2A receptors with therapeutic efficacy. There are 3 primary scaffolds for agonists: tryptamines, ergolines, and phenylalkylamines, each engaging different subsets of amino acid residues in the receptor binding pocket. Differences can lead to differential responses between ligands for functionally selective outcomes. Here, we provide a historical perspective on 5-HT_2A receptors, their key structural features and motifs involved in ligand-receptor interactions, and how these interactions can affect signaling pathways downstream of the receptor. Understanding how ligands interact with the 5-HT_2A receptor will fundamentally inform future drug discovery to optimize therapeutics for a variety of disorders. SIGNIFICANCE STATEMENT: Psychedelic drugs have demonstrated long-lasting therapeutic efficacy for several conditions in multiple clinical trials. Their target, serotonin 5-HT_2A receptors, are GPCRs with complex pharmacology. Having knowledge of how ligands interact with 5-HT_2A receptors in the orthosteric binding pocket at the structural level to induce specific signal transduction pathways will inform on efforts to design and develop functionally selective drugs to potentially treat a variety of diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100059"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144151422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Senotherapy for chronic lung disease.","authors":"Peter J Barnes","doi":"10.1016/j.pharmr.2025.100069","DOIUrl":"10.1016/j.pharmr.2025.100069","url":null,"abstract":"<p><p>Chronic respiratory diseases are an enormous burden on healthcare and the third ranked cause of death globally. There is now compelling evidence that acceleration of lung aging and associated cellular senescence is a key driving mechanism of several chronic lung diseases, particularly chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Senescent cells, arising from oxidative stress and unrepaired damage, can accumulate in the lung and develop a senescence-associated secretory phenotype, spreading senescence and resulting in disease progression. In addition, there is a reduction in normally protective antiaging molecules, such as sirtuins, in the lungs. The role of cellular senescence in chronic lung disease has driven interest in senotherapy that targets senescent cells as a novel approach to treating respiratory diseases, and includes repurposing of existing drugs or developing new therapies. Senomorphics, which prevent the development of senescence and inhibit senescence-associated secretory phenotype mediators, include inhibitors of phosphoinositide-3-kinase-mechanistic target of rapamycin signaling, novel antioxidants, and sirtuin activators. Senolytics remove senescent cells by inducing apoptosis and include inhibitors of antiapoptotic proteins, such as B-cell lymphoma-extra large, inhibitors of forkhead box O-4-p53 interaction, heat shock protein 90 inhibitors, and cardiac glycosides. Senotherapies have been effective in animal models of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, and several clinical trials are currently underway. The safety of these treatments after long-term administration requires further study, but this could potentially to be a promising approach to treating chronic lung diseases. SIGNIFICANCE STATEMENT: Cellular senescence induced by oxidative stress is a key driving mechanism in chronic lung diseases, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and may account for disease progression. Senotherapies, including senomorphics that inhibit senescent cells and senolytics that eliminate them, are promising therapeutic approaches to these common diseases, either with repurposed drugs or several new drugs that are in development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100069"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asthma therapeutics: Past, present, and future.","authors":"Sarah L Rhoads, Lior Seluk, Michael E Wechsler","doi":"10.1016/j.pharmr.2025.100062","DOIUrl":"10.1016/j.pharmr.2025.100062","url":null,"abstract":"<p><p>Asthma is a disease of airway inflammation and bronchial hyperresponsiveness affecting over 300 million individuals worldwide. Although described as early as 460 BC, the recognition of asthma as a disease, and the development and implementation of therapies to control it, emerged in the early 1900s. The subsequent century introduced the utilization of immunotherapy, inhaled medications, and anti-inflammatory corticosteroids for disease control. Since the beginning of the 21st century, however, the emergence of novel asthma pharmacotherapies has accelerated greatly. Our understanding of various asthma phenotypes and their underlying mechanisms (endotypes) has crystallized, leading to an era of precision medicine. Management strategies increasingly use targeted biologic medications aimed at interrupting key components of the inflammatory cascade. Monoclonal antibodies targeting the IgE, thymic stromal lymphopoietin, or interleukin-4, -5, and -13 pathways have revolutionized the care we provide our patients, resulting in a reduction in exacerbations and oral corticosteroid (OCS) dose, while improving lung function and asthma-related quality of life. Although they are able to provide relief for many sufferers of severe disease, and even remission in some, these biologic therapies are still in their infancy. Because their roles become further established, new therapeutic targets and modalities offer significant promise of an even greater personalized medicine approach. This review addresses historical standard-of-care strategies for asthma treatment, current recommendations, and a glimpse into future novel therapies that are likely to help millions worldwide. SIGNIFICANCE STATEMENT: Asthma affects hundreds of millions of individuals worldwide. In the last few decades, asthma treatment paradigms have transformed from recommendations to use anti-inflammatory and bronchodilatory inhalation-based therapies including corticosteroids and beta-agonists, to more precisely targeted add-on biologic therapies that employ monoclonal antibodies addressing specific mechanistic pathways associated with specific patient characteristics. Future therapies promise utilization of personalized medicine to a greater extent with novel therapeutic approaches to help improve the health and quality of life of those suffering from asthma.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100062"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmaceutical perspectives on oligonucleotide therapeutics and delivery systems.","authors":"Dalton W Staller, Flobater I Gawargi, Sanjali S Panigrahi, Paras K Mishra, Ram I Mahato","doi":"10.1016/j.pharmr.2025.100065","DOIUrl":"10.1016/j.pharmr.2025.100065","url":null,"abstract":"<p><p>Gene therapy has a pivotal role in treating new diseases. In addition to the recent mRNA-based COVID-19 vaccines produced by Pfizer-BioNTech and Moderna against severe acute respiratory syndrome corona virus 2, several new gene therapies have recently been approved as effective treatments for fatal genetic disorders such as Duchenne's muscular dystrophy, familial transthyretin amyloidosis, hemophilia A, hemophilia B, spinal muscle atrophy, early cerebral autoleukodystrophy, and β-thalassemia. This review provides novel insights into RNA therapeutics focusing on endogenous RNA species, RNA structure and function, and chemical modifications that improve the stability and distribution of RNAs. Furthermore, it includes updated knowledge on clinically approved gene therapies rendering a comprehensive understanding of the biochemical basis and clinical application of gene therapies. SIGNIFICANCE STATEMENT: There have recently been significant advances in clinical translation of RNA therapeutics. This review discusses the diverse types of RNA species, RNA structure and function, backbone and chemical modifications to RNAs, and every RNA therapeutic approved for clinical use at the time of writing.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100065"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144294765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}