Pub Date : 2025-01-01Epub Date: 2024-12-17DOI: 10.1146/annurev-pharmtox-061724-080811
Paul McGonigle
Advances in molecular biology and molecular genetics as well as major scientific breakthroughs in immunology and oncology have led to the rapid growth of biologic therapeutics. Their success has resulted in significant changes to virtually every step in the drug discovery and development process. Biologics are produced by living organisms, and screening libraries are generated by immunization or phage display. Lead optimization utilizes sophisticated protein engineering to improve drug-like properties and targeting specificity. The manufacturing process for biologics is complex and requires highly specialized facilities. Determination of pharmacology and safety must overcome the complications associated with species specificity. Initial clinical testing must proceed more slowly and carefully due to the limited predictive utility of preclinical data. In summary, the drug discovery and development process has been dramatically altered by biologic therapeutics and will continue to evolve with the introduction of messenger RNA-based therapeutics and the application of artificial intelligence.
{"title":"How Biologics Have Changed the Drug Discovery Landscape.","authors":"Paul McGonigle","doi":"10.1146/annurev-pharmtox-061724-080811","DOIUrl":"10.1146/annurev-pharmtox-061724-080811","url":null,"abstract":"<p><p>Advances in molecular biology and molecular genetics as well as major scientific breakthroughs in immunology and oncology have led to the rapid growth of biologic therapeutics. Their success has resulted in significant changes to virtually every step in the drug discovery and development process. Biologics are produced by living organisms, and screening libraries are generated by immunization or phage display. Lead optimization utilizes sophisticated protein engineering to improve drug-like properties and targeting specificity. The manufacturing process for biologics is complex and requires highly specialized facilities. Determination of pharmacology and safety must overcome the complications associated with species specificity. Initial clinical testing must proceed more slowly and carefully due to the limited predictive utility of preclinical data. In summary, the drug discovery and development process has been dramatically altered by biologic therapeutics and will continue to evolve with the introduction of messenger RNA-based therapeutics and the application of artificial intelligence.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"29-46"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399198","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}
Pub Date : 2025-01-01Epub Date: 2024-12-17DOI: 10.1146/annurev-pharmtox-090324-021727
Paul A Insel, Susan G Amara, Amrita Ahluwalia
The reviews in Volume 65 of the Annual Review of Pharmacology and Toxicology cover a wide variety of topics in pharmacology and toxicology focused upon the pathway from preclinical studies to clinical trials. Many of these reviews discuss the identification and validation of new therapeutic targets and/or novel therapeutic approaches. Examples include reviews that focus on the treatment of obesity, neuropsychiatric disorders, Parkinson's disease, substance use disorders, liver fibrosis, cardiac arrythmias, chronic intestinal inflammation, prostate cancer, immuno-oncology, sickle cell disease, and snakebite envenoming. Other topics include drug discovery of biologics, microphysiological systems, and human induced pluripotent stem cell-derived organoids and organ-on-chip technology integrated with artificial intelligence methodologies. Together, these and other reviews give new insights into the assessment of aspects of toxicology and provide readers a glimpse of advances in pharmacology and toxicology that we believe will advance health care and environmental safety.
{"title":"Introduction to the Theme \"Novel Therapeutics with the Potential to Advance Health Care\".","authors":"Paul A Insel, Susan G Amara, Amrita Ahluwalia","doi":"10.1146/annurev-pharmtox-090324-021727","DOIUrl":"10.1146/annurev-pharmtox-090324-021727","url":null,"abstract":"<p><p>The reviews in Volume 65 of the <i>Annual Review of Pharmacology and Toxicology</i> cover a wide variety of topics in pharmacology and toxicology focused upon the pathway from preclinical studies to clinical trials. Many of these reviews discuss the identification and validation of new therapeutic targets and/or novel therapeutic approaches. Examples include reviews that focus on the treatment of obesity, neuropsychiatric disorders, Parkinson's disease, substance use disorders, liver fibrosis, cardiac arrythmias, chronic intestinal inflammation, prostate cancer, immuno-oncology, sickle cell disease, and snakebite envenoming. Other topics include drug discovery of biologics, microphysiological systems, and human induced pluripotent stem cell-derived organoids and organ-on-chip technology integrated with artificial intelligence methodologies. Together, these and other reviews give new insights into the assessment of aspects of toxicology and provide readers a glimpse of advances in pharmacology and toxicology that we believe will advance health care and environmental safety.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"1-5"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339827","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}
Pub Date : 2025-01-01Epub Date: 2024-12-17DOI: 10.1146/annurev-pharmtox-022724-095035
Zehra Yildirim, Kyle Swanson, Xuekun Wu, James Zou, Joseph Wu
In the high-stakes arena of drug discovery, the journey from bench to bedside is hindered by a daunting 92% failure rate, primarily due to unpredicted toxicities and inadequate therapeutic efficacy in clinical trials. The FDA Modernization Act 2.0 heralds a transformative approach, advocating for the integration of alternative methods to conventional animal testing, including cell-based assays that employ human induced pluripotent stem cell (iPSC)-derived organoids, and organ-on-a-chip technologies, in conjunction with sophisticated artificial intelligence (AI) methodologies. Our review explores the innovative capacity of iPSC-derived clinical trial in a dish models designed for cardiovascular disease research. We also highlight how integrating iPSC technology with AI can accelerate the identification of viable therapeutic candidates, streamline drug screening, and pave the way toward more personalized medicine. Through this, we provide a comprehensive overview of the current landscape and future implications of iPSC and AI applications being navigated by the research community and pharmaceutical industry.
{"title":"Next-Gen Therapeutics: Pioneering Drug Discovery with iPSCs, Genomics, AI, and Clinical Trials in a Dish.","authors":"Zehra Yildirim, Kyle Swanson, Xuekun Wu, James Zou, Joseph Wu","doi":"10.1146/annurev-pharmtox-022724-095035","DOIUrl":"10.1146/annurev-pharmtox-022724-095035","url":null,"abstract":"<p><p>In the high-stakes arena of drug discovery, the journey from bench to bedside is hindered by a daunting 92% failure rate, primarily due to unpredicted toxicities and inadequate therapeutic efficacy in clinical trials. The FDA Modernization Act 2.0 heralds a transformative approach, advocating for the integration of alternative methods to conventional animal testing, including cell-based assays that employ human induced pluripotent stem cell (iPSC)-derived organoids, and organ-on-a-chip technologies, in conjunction with sophisticated artificial intelligence (AI) methodologies. Our review explores the innovative capacity of iPSC-derived clinical trial in a dish models designed for cardiovascular disease research. We also highlight how integrating iPSC technology with AI can accelerate the identification of viable therapeutic candidates, streamline drug screening, and pave the way toward more personalized medicine. Through this, we provide a comprehensive overview of the current landscape and future implications of iPSC and AI applications being navigated by the research community and pharmaceutical industry.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"71-90"},"PeriodicalIF":11.2,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279686","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}
Pub Date : 2024-09-13DOI: 10.1146/annurev-pharmtox-061724-080852
John Stagg, J. Silvio Gutkind
The advent of cancer immunotherapy based on PD-1 and CTLA-4 immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many cancers do not respond to ICB, highlighting the urgent need for additional approaches to achieve durable cancer remission. The large family of G protein–coupled receptors (GPCRs) is the target of more than 30% of all approved drugs, but GPCRs have been underexploited in cancer immunotherapy. In this review, we discuss the central role of GPCRs in immune cell migration and function and describe how single-cell transcriptomic studies are illuminating the complexity of the human tumor immune GPCRome. These receptors include multiple GPCRs expressed in CD8 T cells that are activated by inflammatory mediators, protons, neurotransmitters, and metabolites that accumulate in the tumor microenvironment, thereby promoting T cell dysfunction. We also discuss new opportunities to target GPCRs as a multimodal approach to enhance the response to ICB for a myriad of human malignancies.
以PD-1和CTLA-4免疫检查点阻断（ICB）为基础的癌症免疫疗法的出现彻底改变了癌症治疗。然而，许多癌症对 ICB 并无反应，这凸显了人们迫切需要其他方法来实现癌症的持久缓解。G蛋白偶联受体（GPCR）大家族是30%以上已批准药物的靶点，但GPCR在癌症免疫疗法中却未得到充分开发。在这篇综述中，我们将讨论 GPCR 在免疫细胞迁移和功能中的核心作用，并介绍单细胞转录组研究如何揭示人类肿瘤免疫 GPCR 组的复杂性。这些受体包括在 CD8 T 细胞中表达的多种 GPCR，它们会被肿瘤微环境中积累的炎症介质、质子、神经递质和代谢物激活，从而促进 T 细胞功能障碍。我们还讨论了靶向 GPCRs 的新机遇，它是一种多模式方法，可增强多种人类恶性肿瘤对 ICB 的反应。
{"title":"Targeting G Protein–Coupled Receptors in Immuno-Oncological Therapies","authors":"John Stagg, J. Silvio Gutkind","doi":"10.1146/annurev-pharmtox-061724-080852","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-061724-080852","url":null,"abstract":"The advent of cancer immunotherapy based on PD-1 and CTLA-4 immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, many cancers do not respond to ICB, highlighting the urgent need for additional approaches to achieve durable cancer remission. The large family of G protein–coupled receptors (GPCRs) is the target of more than 30% of all approved drugs, but GPCRs have been underexploited in cancer immunotherapy. In this review, we discuss the central role of GPCRs in immune cell migration and function and describe how single-cell transcriptomic studies are illuminating the complexity of the human tumor immune GPCRome. These receptors include multiple GPCRs expressed in CD8 T cells that are activated by inflammatory mediators, protons, neurotransmitters, and metabolites that accumulate in the tumor microenvironment, thereby promoting T cell dysfunction. We also discuss new opportunities to target GPCRs as a multimodal approach to enhance the response to ICB for a myriad of human malignancies.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"32 1","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265234","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}
Pub Date : 2024-09-13DOI: 10.1146/annurev-pharmtox-030424-112828
Kuanliang Shao, Runyu Zou, Zhuoyue Zhang, Laurens D.B. Mandemaker, Sarah Timbie, Ronald D. Smith, Amanda M. Durkin, Hanna M. Dusza, Florian Meirer, Bert M. Weckhuysen, Tanya L. Alderete, Roel Vermuelen, Douglas I. Walker
Although plastic pollution and exposure to plastic-related compounds have received worldwide attention, health risks associated with micro- and nanoplastics (MNPs) are largely unknown. Emerging evidence suggests MNPs are present in human biofluids and tissue, including blood, breast milk, stool, lung tissue, and placenta; however, exposure assessment is limited and the extent of human exposure to MNPs is not well known. While there is a critical need to establish robust and scalable biomonitoring strategies to assess human exposure to MNPs and plastic-related chemicals, over 10,000 chemicals have been linked to plastic manufacturing with no existing standardized approaches to account for even a fraction of these exposures. This review provides an overview of the status of methods for measuring MNPs and associated plastic-related chemicals in humans, with a focus on approaches that could be adapted for population-wide biomonitoring and integration with biological response measures to develop hypotheses on potential health effects of plastic exposures. We also examine the exposure risks associated with the widespread use of chemical additives in plastics. Despite advancements in analytical techniques, there remains a pressing need for standardized measurement protocols and untargeted, high-throughput analysis methods to enable comprehensive MNP biomonitoring to identify key MNP exposures in human populations. This review aims to merge insights into the toxicological effects of MNPs and plastic additives with an evaluation of analytical challenges, advocating for enhanced research methods to fully assess, understand, and mitigate the public health implications of MNPs.
{"title":"Advancements in Assays for Micro- and Nanoplastic Detection: Paving the Way for Biomonitoring and Exposomics Studies","authors":"Kuanliang Shao, Runyu Zou, Zhuoyue Zhang, Laurens D.B. Mandemaker, Sarah Timbie, Ronald D. Smith, Amanda M. Durkin, Hanna M. Dusza, Florian Meirer, Bert M. Weckhuysen, Tanya L. Alderete, Roel Vermuelen, Douglas I. Walker","doi":"10.1146/annurev-pharmtox-030424-112828","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-030424-112828","url":null,"abstract":"Although plastic pollution and exposure to plastic-related compounds have received worldwide attention, health risks associated with micro- and nanoplastics (MNPs) are largely unknown. Emerging evidence suggests MNPs are present in human biofluids and tissue, including blood, breast milk, stool, lung tissue, and placenta; however, exposure assessment is limited and the extent of human exposure to MNPs is not well known. While there is a critical need to establish robust and scalable biomonitoring strategies to assess human exposure to MNPs and plastic-related chemicals, over 10,000 chemicals have been linked to plastic manufacturing with no existing standardized approaches to account for even a fraction of these exposures. This review provides an overview of the status of methods for measuring MNPs and associated plastic-related chemicals in humans, with a focus on approaches that could be adapted for population-wide biomonitoring and integration with biological response measures to develop hypotheses on potential health effects of plastic exposures. We also examine the exposure risks associated with the widespread use of chemical additives in plastics. Despite advancements in analytical techniques, there remains a pressing need for standardized measurement protocols and untargeted, high-throughput analysis methods to enable comprehensive MNP biomonitoring to identify key MNP exposures in human populations. This review aims to merge insights into the toxicological effects of MNPs and plastic additives with an evaluation of analytical challenges, advocating for enhanced research methods to fully assess, understand, and mitigate the public health implications of MNPs.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"6 1","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265233","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}
Pub Date : 2024-09-11DOI: 10.1146/annurev-pharmtox-020524-012013
Helene Gilgenkrantz, Rola Al Sayegh, Sophie Lotersztajn
Liver fibrosis develops in response to chronic liver injury and is characterized by a sustained inflammatory response that leads to excessive collagen deposition by myofibroblasts. The fibrogenic response is governed by the release of inflammatory mediators from innate, adaptive, and innate-like lymphoid cells and from nonprofessional immune cells (i.e., epithelial cells, hepatic myofibroblasts, and liver sinusoidal endothelial cells). Upon removal of the underlying cause, liver fibrosis can resolve via activation of specific immune cell subsets. Despite major advances in the understanding of fibrosis pathogenesis, there is still no approved antifibrotic therapy. This review summarizes our current knowledge of the immune cell landscape and the inflammatory mechanisms underlying liver fibrosis progression and regression. We discuss how reprogramming immune cell phenotype, in particular through targeting selective inflammatory pathways or modulating cell-intrinsic metabolism, may be translated into antifibrogenic therapies.
{"title":"Immunoregulation of Liver Fibrosis: New Opportunities for Antifibrotic Therapy","authors":"Helene Gilgenkrantz, Rola Al Sayegh, Sophie Lotersztajn","doi":"10.1146/annurev-pharmtox-020524-012013","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-020524-012013","url":null,"abstract":"Liver fibrosis develops in response to chronic liver injury and is characterized by a sustained inflammatory response that leads to excessive collagen deposition by myofibroblasts. The fibrogenic response is governed by the release of inflammatory mediators from innate, adaptive, and innate-like lymphoid cells and from nonprofessional immune cells (i.e., epithelial cells, hepatic myofibroblasts, and liver sinusoidal endothelial cells). Upon removal of the underlying cause, liver fibrosis can resolve via activation of specific immune cell subsets. Despite major advances in the understanding of fibrosis pathogenesis, there is still no approved antifibrotic therapy. This review summarizes our current knowledge of the immune cell landscape and the inflammatory mechanisms underlying liver fibrosis progression and regression. We discuss how reprogramming immune cell phenotype, in particular through targeting selective inflammatory pathways or modulating cell-intrinsic metabolism, may be translated into antifibrogenic therapies.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"62 1","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142225518","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}
Pub Date : 2024-09-11DOI: 10.1146/annurev-pharmtox-061124-102218
Carolina Alves Costa Silva, Marine Fidelle, Andrew A. Almonte, Lisa Derosa, Laurence Zitvogel
Carcinogenesis is associated with the emergence of protracted intestinal dysbiosis and metabolic changes. Increasing evidence shows that gut microbiota–related biomarkers and microbiota-centered interventions are promising strategies to overcome resistance to immunotherapy. However, current standard methods for evaluating gut microbiota composition are cost- and time-consuming. The development of routine diagnostic tools for intestinal barrier alterations and dysbiosis constitutes a critical unmet medical need that can guide routine treatment and microbiota-centered intervention decisions in patients with cancer. In this review, we explore the influence of gut microbiota on cancer immunotherapy and highlight gut-associated biomarkers that have the potential to be transformed into simple diagnostic tools, thus guiding standard treatment decisions in the field of immuno-oncology. Mechanistic insights toward leveraging the complex relationship between cancer immunosurveillance, gut microbiota, and metabolism open exciting opportunities for developing novel biomarkers in immuno-oncology.
{"title":"Gut Microbiota–Related Biomarkers in Immuno-Oncology","authors":"Carolina Alves Costa Silva, Marine Fidelle, Andrew A. Almonte, Lisa Derosa, Laurence Zitvogel","doi":"10.1146/annurev-pharmtox-061124-102218","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-061124-102218","url":null,"abstract":"Carcinogenesis is associated with the emergence of protracted intestinal dysbiosis and metabolic changes. Increasing evidence shows that gut microbiota–related biomarkers and microbiota-centered interventions are promising strategies to overcome resistance to immunotherapy. However, current standard methods for evaluating gut microbiota composition are cost- and time-consuming. The development of routine diagnostic tools for intestinal barrier alterations and dysbiosis constitutes a critical unmet medical need that can guide routine treatment and microbiota-centered intervention decisions in patients with cancer. In this review, we explore the influence of gut microbiota on cancer immunotherapy and highlight gut-associated biomarkers that have the potential to be transformed into simple diagnostic tools, thus guiding standard treatment decisions in the field of immuno-oncology. Mechanistic insights toward leveraging the complex relationship between cancer immunosurveillance, gut microbiota, and metabolism open exciting opportunities for developing novel biomarkers in immuno-oncology.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"31 1","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142225517","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}
Pub Date : 2024-09-11DOI: 10.1146/annurev-pharmtox-022124-022000
Marina Cavazzana, Alice Corsia, Megane Brusson, Annarita Miccio, Michaela Semeraro
Sickle cell disease (SCD) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin molecules and thus distortion (sickling) of the red blood cells. SCD causes chronic pain and organ damage and shortens life expectancy. Gene therapy emerges as a potentially curative approach for people with SCD who lack a matched sibling donor for hematopoietic stem cell transplantation. Here, we review recent progress in gene therapy for SCD and focus on innovative technologies that target the genetic roots of the disease. We also review the challenges associated with gene therapy, including oncogenic risks, and the need for refined delivery methods. Despite these hurdles, the rapidly evolving landscape of gene therapy for SCD raises hope for a paradigm shift in the treatment of this debilitating disease. As research progresses, a deeper understanding of the molecular mechanisms involved and continuous improvements in gene-editing technologies promise to bring gene therapy for SCD closer to mainstream clinical application, offering a transformative, curative option for patients with this genetic disorder.
{"title":"Treating Sickle Cell Disease: Gene Therapy Approaches","authors":"Marina Cavazzana, Alice Corsia, Megane Brusson, Annarita Miccio, Michaela Semeraro","doi":"10.1146/annurev-pharmtox-022124-022000","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-022124-022000","url":null,"abstract":"Sickle cell disease (SCD) is a hereditary blood disorder characterized by the presence of abnormal hemoglobin molecules and thus distortion (sickling) of the red blood cells. SCD causes chronic pain and organ damage and shortens life expectancy. Gene therapy emerges as a potentially curative approach for people with SCD who lack a matched sibling donor for hematopoietic stem cell transplantation. Here, we review recent progress in gene therapy for SCD and focus on innovative technologies that target the genetic roots of the disease. We also review the challenges associated with gene therapy, including oncogenic risks, and the need for refined delivery methods. Despite these hurdles, the rapidly evolving landscape of gene therapy for SCD raises hope for a paradigm shift in the treatment of this debilitating disease. As research progresses, a deeper understanding of the molecular mechanisms involved and continuous improvements in gene-editing technologies promise to bring gene therapy for SCD closer to mainstream clinical application, offering a transformative, curative option for patients with this genetic disorder.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"90 1","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199106","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}
Pub Date : 2024-09-11DOI: 10.1146/annurev-pharmtox-061324-011832
Qingtong Zhou, Guanyi Li, Kaini Hang, Jie Li, Dehua Yang, Ming-Wei Wang
Obesity and type 2 diabetes mellitus (T2DM) impact more than 2.5 billion adults worldwide, necessitating innovative therapeutic approaches. Unimolecular polypharmacology, which involves designing single molecules to target multiple receptors or pathways simultaneously, has revolutionized treatment strategies. Blockbuster drugs such as tirzepatide and retatrutide have shown unprecedented success in managing obesity and T2DM, demonstrating superior efficacy compared to conventional single agonists. Tirzepatide, in particular, has garnered tremendous attention for its remarkable effectiveness in promoting weight loss and improving glycemic control, while offering additional cardiovascular and renal benefits. Despite their promises, such therapeutic agents also face challenges that include gastrointestinal side effects, patient compliance issues, and body weight rebound after cessation of the treatment. Nonetheless, the development of these therapies marks a significant leap forward, underscoring the transformative potential of unimolecular polypharmacology in addressing metabolic diseases and paving the way for future innovations in personalized medicine.
{"title":"Weight Loss Blockbuster Development: A Role for Unimolecular Polypharmacology","authors":"Qingtong Zhou, Guanyi Li, Kaini Hang, Jie Li, Dehua Yang, Ming-Wei Wang","doi":"10.1146/annurev-pharmtox-061324-011832","DOIUrl":"https://doi.org/10.1146/annurev-pharmtox-061324-011832","url":null,"abstract":"Obesity and type 2 diabetes mellitus (T2DM) impact more than 2.5 billion adults worldwide, necessitating innovative therapeutic approaches. Unimolecular polypharmacology, which involves designing single molecules to target multiple receptors or pathways simultaneously, has revolutionized treatment strategies. Blockbuster drugs such as tirzepatide and retatrutide have shown unprecedented success in managing obesity and T2DM, demonstrating superior efficacy compared to conventional single agonists. Tirzepatide, in particular, has garnered tremendous attention for its remarkable effectiveness in promoting weight loss and improving glycemic control, while offering additional cardiovascular and renal benefits. Despite their promises, such therapeutic agents also face challenges that include gastrointestinal side effects, patient compliance issues, and body weight rebound after cessation of the treatment. Nonetheless, the development of these therapies marks a significant leap forward, underscoring the transformative potential of unimolecular polypharmacology in addressing metabolic diseases and paving the way for future innovations in personalized medicine.","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":"42 1","pages":""},"PeriodicalIF":12.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142225516","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}
Pub Date : 2024-01-24Epub Date: 2023-09-18DOI: 10.1146/annurev-pathol-042420-092719
Christopher A Febres-Aldana, Rachel Fanaroff, Michael Offin, Marjorie G Zauderer, Jennifer L Sauter, Soo-Ryum Yang, Marc Ladanyi
Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.
{"title":"Diffuse Pleural Mesothelioma: Advances in Molecular Pathogenesis, Diagnosis, and Treatment.","authors":"Christopher A Febres-Aldana, Rachel Fanaroff, Michael Offin, Marjorie G Zauderer, Jennifer L Sauter, Soo-Ryum Yang, Marc Ladanyi","doi":"10.1146/annurev-pathol-042420-092719","DOIUrl":"10.1146/annurev-pathol-042420-092719","url":null,"abstract":"<p><p>Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.</p>","PeriodicalId":8057,"journal":{"name":"Annual review of pharmacology and toxicology","volume":" ","pages":"11-42"},"PeriodicalIF":12.5,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10673542","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}
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