Expert Opinion on Therapeutic Targets最新文献

Established and emerging roles of protein kinases in regulating primary sensory neurons in injury-and inflammation-associated pain. 蛋白激酶在损伤和炎症相关疼痛中调节初级感觉神经元的既定和新兴角色。

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-04-08 DOI: 10.1080/14728222.2025.2489540

David Zimmermann, Michaela Kress, Istvan Nagy

{"title":"Established and emerging roles of protein kinases in regulating primary sensory neurons in injury-and inflammation-associated pain.","authors":"David Zimmermann, Michaela Kress, Istvan Nagy","doi":"10.1080/14728222.2025.2489540","DOIUrl":"https://doi.org/10.1080/14728222.2025.2489540","url":null,"abstract":"Introduction: Recent seminal neuroscience research has significantly increased our knowledge on cellular and molecular responses of various cells in the pain pathway to peripheral nerve injuries and inflammatory processes. Transcriptomic and epigenetic analysis of primary sensory neurons (PSNs) in animal models of peripheral injuries revealed new insights into altered gene expression profiles and epigenetic modifications, which, via increasing spinal nociceptive input, lead to the development of pain. Among the various classes of molecules involved in driving differential gene expression, protein kinases, the enzymes that catalyze the phosphorylation of molecules, are emerging to control histone modification and chromatin remodeling needed for the alteration in transcriptional activity.Areas covered: Here, we focused on how protein kinases contribute to transcriptomic changes and pathways of induced reprogramming within PSNs upon peripheral nerve injury and inflammation. We conducted systematic literature search across multiple databases, including PubMed, NIH ClinicalTrials.gov portal and GEOData from 1980-2024 and compared protein kinase expression frequencies between publicly available RNA sequencing datasets of PSNs and investigated differences in protein kinase expression levels after peripheral nerve injury.Expert opinion: Novel findings support a new concept that protein kinases constitute regulatory hubs of reprogramming of PSNs, which offers novel analgesic approaches.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders. 恢复FXR表达作为肝癌和其他肝脏疾病的新治疗策略。

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-04-01 DOI: 10.1080/14728222.2025.2487465

Sosmitha Girisa, Babu Santha Aswani, Mukesh Kumar Manickasamy, Mangala Hegde, Mohammed S Alqahtani, Mohamed Abbas, Gautam Sethi, Ajaikumar B Kunnumakkara

{"title":"Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders.","authors":"Sosmitha Girisa, Babu Santha Aswani, Mukesh Kumar Manickasamy, Mangala Hegde, Mohammed S Alqahtani, Mohamed Abbas, Gautam Sethi, Ajaikumar B Kunnumakkara","doi":"10.1080/14728222.2025.2487465","DOIUrl":"https://doi.org/10.1080/14728222.2025.2487465","url":null,"abstract":"Introduction: Liver cancer is a leading cause of cancer-associated mortality and is often linked to preexisting liver conditions. Emerging research demonstrates FXR dysregulation, particularly its reduced expression, in the pathogenesis of liver diseases, including inflammation, fibrosis, cholestatic disorders, metabolic dysregulation, and liver cancer. Therefore, this review explores the role of FXR and its agonists in mitigating these conditions.Areas covered: This article summarizes FXR's involvement in liver disorders, primarily emphasizing on hepatic neoplasms, and examines the potential of FXR agonists in restoring FXR activity in liver diseases, thereby preventing their progression to liver cancer. The information presented is drawn from existing preclinical and clinical studies specific to each liver disorder, sourced from PubMed.Expert opinion: It is well established that FXR expression is downregulated in liver disorders, contributing to disease progression. Notably, FXR agonists have demonstrated therapeutic potential in ameliorating liver diseases, including hepatocellular carcinoma. We believe that activating or restoring FXR expression with agonists offers significant promise for the treatment of liver cancer and other liver conditions. Therefore, FXR modulation by agonists, particularly in combination with other therapeutic agents, could lead to more targeted treatments, improving efficacy while reducing side effects.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":""},"PeriodicalIF":4.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Can we develop effective direct or indirect inhibitors of transcription factors? On the clinical evolution of protein degraders for multiple myeloma therapy. 我们能开发有效的转录因子直接或间接抑制剂吗？蛋白降解物治疗多发性骨髓瘤的临床进展。

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-03-01 Epub Date: 2025-03-28 DOI: 10.1080/14728222.2025.2482557

Rajeshwari Meli, Osman Aksoy, Sonia Vallet, Dea Slade, Klaus Podar

{"title":"Can we develop effective direct or indirect inhibitors of transcription factors? On the clinical evolution of protein degraders for multiple myeloma therapy.","authors":"Rajeshwari Meli, Osman Aksoy, Sonia Vallet, Dea Slade, Klaus Podar","doi":"10.1080/14728222.2025.2482557","DOIUrl":"10.1080/14728222.2025.2482557","url":null,"abstract":"Introduction: Transcription factors (TFs) are master regulators of cellular function and orchestrate diverse signaling pathways and processes. Acting as convergence points of signaling pathways, they integrate extracellular stimuli with intracellular responses to regulate cell functions. Dysregulation of TFs drives tumorigenesis including proliferation, drug resistance, and immune evasion of multiple myeloma (MM), the second most-common hematologic malignancy.Areas covered: The discovery that IMiDs are molecular glue degraders, which reprogram the E3-ligase cereblon (CRBN) to ubiquitinate and degrade IKZF1 and IKZF3, two otherwise un-druggable crucial TFs in MM, gave rise to the widespread interest in proximity-induced protein-degradation as an exciting novel therapeutic strategy. This review summarizes our up-to-date knowledge on the pre/clinical development of IMiD-related, more potent CRBN E3-Ligase Modulatory Drugs (CELMoDs), directed PROteolysis TArgeting Chimeras (PROTACs) and degronomids as well as on promising future avenues in the field of targeted protein-degradation (TPD).Expert opinion: TPD is an emerging field to treat cancer, including MM. CELMoDs are already reshaping the treatment landscape of MM. Preclinical data on PROTACs are promising. Nevertheless, a deeper understanding of TF biology as well as further advancements in screening methodologies and chemoproteomics are crucial to further spur the transformative potential of targeted TF degradation in MM.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"101-115"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Can targeting the FGF23-αKlotho signaling system delay phosphate-driven organ damage? 靶向FGF23-αKlotho信号系统能否延缓磷酸盐驱动的器官损伤？

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-03-01 Epub Date: 2025-03-28 DOI: 10.1080/14728222.2025.2482552

Mohammed S Razzaque, Moosa Mohammadi

{"title":"Can targeting the FGF23-αKlotho signaling system delay phosphate-driven organ damage?","authors":"Mohammed S Razzaque, Moosa Mohammadi","doi":"10.1080/14728222.2025.2482552","DOIUrl":"10.1080/14728222.2025.2482552","url":null,"abstract":"Introduction: Inexorable high serum phosphate levels in chronic kidney disease (CKD) patients deteriorate the functionality of the musculoskeletal, renal, and cardiovascular systems, thereby contributing to increased morbidity and mortality. Higher phosphate balance has also been correlated with increased mortality rates in individuals with normal renal function, independent of other comorbidities. Clinical and epidemiological studies of CKD patients and healthy subjects, alongside evidence of accelerated aging in murine models induced by excessive phosphate loading, indicate that phosphate toxicity is a driver of premature aging and age-related organ damage.Area covered: This article briefly discusses the causes and consequences of phosphate toxicity in the context of organ damage and aging while also elaborating on the therapeutic potential of the fibroblast growth factor 23 (FGF23) hormone signaling system in alleviating phosphate toxicity in patients with normal kidney function and CKD.Expert opinion: Human age-associated disorders may be delayed through dietary programs or pharmacological interventions capable of modulating the activity of FGF23 signaling to reduce the systemic phosphate burden.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"93-100"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143729439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MDA-9/Syntenin as a therapeutic cancer metastasis target: current molecular and preclinical understanding. MDA-9/Syntenin作为治疗癌症转移的靶点：目前的分子和临床前认识。

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-03-01 Epub Date: 2025-03-09 DOI: 10.1080/14728222.2025.2472042

Swadesh K Das, Paul B Fisher

{"title":"MDA-9/Syntenin as a therapeutic cancer metastasis target: current molecular and preclinical understanding.","authors":"Swadesh K Das, Paul B Fisher","doi":"10.1080/14728222.2025.2472042","DOIUrl":"10.1080/14728222.2025.2472042","url":null,"abstract":"Introduction: Metastasis is a principal cause of patient morbidity and death from solid cancers with current therapies being inadequate.Areas covered: Detailed genomic analyses document mutational differences between the initial tumor and metastatic clones, posing a challenge to current targeted therapies, which focus predominantly on the phenotype of primary tumors. Considering the diverse signaling cascades and numerous compensatory pathways in metastasis, designing broad-spectrum anti-metastatic therapies remains challenging. Although significant anti-cancer activity is evident in specific patients with advanced cancers and metastases treated with single or combination immunotherapies, there are limitations, i.e. toxicity, immune inhibitory 'cold' tumors and the tumor microenvironment (TME), and intra- and intertumoral heterogeneity. Accordingly, multidisciplinary strategies are required to attack metastases and the TME to obtain optimal therapeutic responses.Expert opinion: To create potent anti-metastatic agents, defining critical genes/proteins and drugs controlling discrete steps in the metastatic cascade are mandatory. Melanoma differentiation-associated gene-9 (MDA-9), Syndecan Binding Protein (SDCBP) or Syntenin (MDA-9/Syntenin) is robustly expressed and serves essential roles in cancer disease progression through protein-protein interactions with additional metastasis-associated molecules and pathways. The importance of MDA-9/Syntenin in the metastatic process is now established and first-in-class inhibitory molecules look promising with some moving toward clinical evaluation.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"75-92"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancer of zeste homolog 2 (EZH2) in endocrine tumors: current knowledge and future directions. 内分泌肿瘤中zeste同源物2增强子（EZH2）的研究现状及未来发展方向

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-03-01 Epub Date: 2025-03-25 DOI: 10.1080/14728222.2025.2482555

Poonam Kumari, Sheenam Garg, Ashutosh Kumar Arya, Jyotdeep Kaur, Naresh Kumar Sachdeva, Uma Nahar Saikia, Divya Dahiya, Sanjay Kumar Bhadada, Sudhaker D Rao

{"title":"Enhancer of zeste homolog 2 (EZH2) in endocrine tumors: current knowledge and future directions.","authors":"Poonam Kumari, Sheenam Garg, Ashutosh Kumar Arya, Jyotdeep Kaur, Naresh Kumar Sachdeva, Uma Nahar Saikia, Divya Dahiya, Sanjay Kumar Bhadada, Sudhaker D Rao","doi":"10.1080/14728222.2025.2482555","DOIUrl":"10.1080/14728222.2025.2482555","url":null,"abstract":"Introduction: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that orchestrates gene expression via epigenetic and non-epigenetic mechanisms. EZH2 performs epigenetic functions by methylating histones and/or non-histone proteins and suppressing or activating target genes. Moreover, non-epigenetic functions involve dysregulation of target genes independent of histone methylation, thereby impacting multiple signaling pathways.Areas covered: EZH2 has emerged as a pivotal player in the initiation of various cancers. EZH2 overexpression facilitated by H3K27me3 is the principal driver. However, the consequent dysregulation of target genes resulting from EZH2 overexpression has emerged as a secondary instigator of tumorigenesis, leading to metastasis and poor prognosis. Further complexity arises from somatic mutations in EZH2 and downstream target genes such as BRAF and RASSF1A. However, understanding its effects on endocrine tumors/cancers remains an underexplored with the potential to significantly enhance clinical outcomes and contribute to human health. Therefore, the present review focuses on the multifaceted functions of EZH2 and its pathophysiological mechanisms in tumor proliferation, with a specific emphasis on endocrine tumors.Expert opinion: Investigating EZH2 mechanisms and targeting with inhibitors and drugs is an active area of research that could offer a promising avenue for treatment and a better understanding of molecular therapeutic interventions.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"159-169"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting PCSK9 beyond the liver: evidence from experimental and clinical studies. 靶向肝脏以外的PCSK9：来自实验和临床研究的证据

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-03-01 Epub Date: 2025-03-30 DOI: 10.1080/14728222.2025.2482545

Lorenzo Da Dalt, Andrea Baragetti, Giuseppe Danilo Norata

{"title":"Targeting PCSK9 beyond the liver: evidence from experimental and clinical studies.","authors":"Lorenzo Da Dalt, Andrea Baragetti, Giuseppe Danilo Norata","doi":"10.1080/14728222.2025.2482545","DOIUrl":"10.1080/14728222.2025.2482545","url":null,"abstract":"Introduction: PCSK9 has been widely studied as a target for lipid-lowering as its inhibition increases LDLR recycling on the surface of hepatocytes, which promotes the catabolism of LDL particles. PCSK9 can be synthesized in extra-hepatic tissues, including in the brain, the pancreas, and the heart, and in immune cells. It is of interest to understand whether the extra-hepatic effects observed when PCSK9 is genetically inhibited by naturally occurring mutations are also recapitulated by pharmacology.Area covered: Genetics studies reported an increased risk of developing new-onset diabetes, ectopic adiposity, and reduced immune-inflammatory responses with PCSK9 deficiency. However, these aspects were not observed in clinical trials and data from real-world medicine with monoclonal antibodies (mAbs) and gene silencing approaches targeting PCSK9.Expert opinion: It is possible that the biological adaptations occurring when PCSK9 is inhibited lifelong, as in the case of genetic studies, could explain the discrepancy with the data obtained by clinical studies testing the pharmacological inhibition of PCSK9. Also, PCSK9 mAbs have been in use for 12 years; thus, probably, in this time window, a pharmacological reduction of circulating PCSK9 up to 80-90% does not lead to changes other than the impressive reduction in LDL-C and in CVD events.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"137-157"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sirtuins as therapeutic targets in diabetes. Sirtuins作为糖尿病的治疗靶点。

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-03-01 Epub Date: 2025-03-31 DOI: 10.1080/14728222.2025.2482563

Kajetan Kielbowski, Aleksandra Wiktoria Bratborska, Estera Bakinowska, Andrzej Pawlik

{"title":"Sirtuins as therapeutic targets in diabetes.","authors":"Kajetan Kielbowski, Aleksandra Wiktoria Bratborska, Estera Bakinowska, Andrzej Pawlik","doi":"10.1080/14728222.2025.2482563","DOIUrl":"10.1080/14728222.2025.2482563","url":null,"abstract":"Introduction: Sirtuins (SIRTs) are NAD+-dependent deacetylases that mediate post-translational modifications of proteins. Seven members of the SIRT family have been identified in mammals. Importantly, SIRTs interact with numerous metabolic and inflammatory pathways. Thus, researchers have investigated their role in metabolic and inflammatory disorders.Areas covered: In this review, we comprehensively discuss the involvement of SIRTs in the processes of pancreatic β-cell dysfunction, glucose tolerance, insulin secretion, lipid metabolism, and adipocyte functions. In addition, we describe the current evidence regarding modulation of the expression and activity of SIRTs in diabetes, diabetic complications, and obesity.Expert opinion: The development of specific SIRT activators and inhibitors that exhibit high selectivity toward specific SIRT isoforms remains a major challenge. This involves the need to elucidate the physiological pathways involving SIRTs, as well as their important role in the development of metabolic disorders. Molecular modeling techniques will be helpful to develop new compounds that modulate the activity of SIRTs, which may contribute to the preparation of new drugs that selectively target specific SIRTs. SIRTs hold promise as potential targets in metabolic disease, but there is much to learn about specific modulators and the final answers will await clinical trials.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"117-135"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potential role of indole-3-propionic acid in tuberculosis: current perspectives and future prospects. 吲哚-3-丙酸在结核病中的潜在作用：目前的观点和未来的展望。

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-03-01 Epub Date: 2025-03-31 DOI: 10.1080/14728222.2025.2482548

Tejaswini Baral, Aieshel Serafin Johnson, Mazhuvancherry Kesavan Unnikrishnan, Mohan K Manu, Kavitha Saravu, Chandrashekar Udyavara Kudru, Suhaj Abdulsalim, Jitendra Singh, Chiranjay Mukhopadhyay, Mahadev Rao, Sonal Sekhar Miraj

{"title":"Potential role of indole-3-propionic acid in tuberculosis: current perspectives and future prospects.","authors":"Tejaswini Baral, Aieshel Serafin Johnson, Mazhuvancherry Kesavan Unnikrishnan, Mohan K Manu, Kavitha Saravu, Chandrashekar Udyavara Kudru, Suhaj Abdulsalim, Jitendra Singh, Chiranjay Mukhopadhyay, Mahadev Rao, Sonal Sekhar Miraj","doi":"10.1080/14728222.2025.2482548","DOIUrl":"10.1080/14728222.2025.2482548","url":null,"abstract":"Introduction: Indole-3-propionic acid (IPA), a tryptophan catabolite derived from gut bacterial metabolism, has been identified as a functional link between the gut microbiome and tuberculosis.Area covered: IPA has gained ample attention over the past two decades on account of its multiple physiological roles, besides being both detectable and quantifiable. IPA is well studied across different health conditions, including cardiovascular and neurological conditions. IPA blocks tryptophan synthesis in Mycobacterium by binding to the allosteric tryptophan-binding site of TrpE, thereby threatening Mycobacterium survival due to tryptophan deficit.Expert opinion: Characterizing IPA would enable its use as a tool to investigate the pathophysiology of tuberculosis. Integrating 'OMICS' techniques (through next-generation sequencing) along with targeted microbial metabolomics may help explore the possible association of serum IPA levels with TB in patients. This will aid in identifying IPA-producing gut microbes and selecting probiotic strains as a microbiome-targeting adjunct therapy, eventually enhancing our understanding of the molecular dynamics of the pathophysiology of tuberculosis in the context of the microbiome.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"171-178"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic targeting of the polyglutamine androgen receptor in Spinal and Bulbar Muscular Atrophy. 多谷氨酰胺雄激素受体治疗脊髓和球性肌萎缩的靶向性研究。

IF 4.6 2区医学

Expert Opinion on Therapeutic Targets Pub Date : 2025-01-01 Epub Date: 2025-02-10 DOI: 10.1080/14728222.2025.2464173

Agamjot Sangotra, Andrew P Lieberman

{"title":"Therapeutic targeting of the polyglutamine androgen receptor in Spinal and Bulbar Muscular Atrophy.","authors":"Agamjot Sangotra, Andrew P Lieberman","doi":"10.1080/14728222.2025.2464173","DOIUrl":"10.1080/14728222.2025.2464173","url":null,"abstract":"Introduction: Spinal and Bulbar Muscular Atrophy (SBMA) is a slowly progressive, X-linked, and sex-limited degenerative disorder affecting lower motor neurons and skeletal muscle which lacks disease-modifying therapies. This disease is caused by a CAG/polyglutamine (polyQ) tract expansion in the androgen receptor (AR) gene, and its pathogenesis is driven by toxic gain-of-function mechanisms. Affected men develop proximal limb and bulbar muscle weakness along with signs of partial androgen insensitivity.Areas covered: Toxicity of the polyQ AR is mediated by protein misfolding and nuclear translocation that follow ligand binding, resulting in the disruption of downstream homeostatic mechanisms. This review highlights what is known about disease pathogenesis and how this has been leveraged to test potential therapeutic approaches. The focus is on strategies that alleviate polyQ AR toxicity in SBMA, including those that alter AR function, diminish the expression of the encoding gene, or promote clearance of the misfolded, mutant protein.Expert opinion: We discuss emerging strategies to mitigate polyQ AR toxicity, including gene editing, RNA targeted therapies, and efforts to harness proteostatic mechanisms. These promising approaches are discussed in the context of challenges for drug discovery efforts that are faced when attempting to treat a rare and slowly progressive neurodegenerative disorder.","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"29-41"},"PeriodicalIF":4.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0