Molecular Therapy. Nucleic Acids最新文献_第3页

Simple improvements in vector design afford substantial gains in AAV delivery of aggregation-slowing Aβ variants 载体设计的简单改进就能大幅提高 AAV 释放聚集减缓型 Aβ 变体的能力

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-26 DOI: 10.1016/j.omtn.2024.102314

Ella Borgenheimer, Cameron Trueblood, Bryan L. Nguyen, William R. Lagor, Joanna L. Jankowsky

{"title":"Simple improvements in vector design afford substantial gains in AAV delivery of aggregation-slowing Aβ variants","authors":"Ella Borgenheimer, Cameron Trueblood, Bryan L. Nguyen, William R. Lagor, Joanna L. Jankowsky","doi":"10.1016/j.omtn.2024.102314","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102314","url":null,"abstract":"Adeno-associated virus (AAV) gene therapy for neurological disease has gained traction due to stunning advances in capsid evolution for CNS targeting. With AAV brain delivery now in focus, conventional improvements in viral expression vectors offer a complementary route for optimizing gene delivery. We previously introduced a novel AAV gene therapy to slow amyloid aggregation in the brain based on neuronal release of an Aβ sequence variant that inhibited fibrilization of wild-type Aβ. Here we explore three coding elements of the virally delivered DNA plasmid in an effort to maximize the production of therapeutic peptide in the brain. We demonstrate that simply replacing the Gaussia luciferase signal peptide with the mouse immunoglobulin heavy chain signal peptide increased release of variant Aβ by ∼5-fold. Sequence modifications within the expressed minigene further increased peptide release by promoting γ-secretase cleavage. Addition of a cytosolic fusion tag compatible with γ-secretase interaction allowed viral transduction to be tracked by immunostaining, independent from the variant Aβ peptide. Collectively these construct modifications increased neuronal production of therapeutic peptide by 10-fold upon intracranial AAV injection of neonatal mice. These findings demonstrate that modest changes in expression vector design can yield substantial gains in AAV efficiency for therapeutic applications.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222593","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

Topical DNA aptamer therapeutics for the skin 用于皮肤的局部 DNA 类似物疗法

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-23 DOI: 10.1016/j.omtn.2024.102299

Simon C.C. Shiu, Andrew B. Kinghorn, Julian A. Tanner

引用次数: 0

Unveiling the inflammatory potential of endogenous sncRNAs: Insights from infections to autoimmune diseases 揭示内源性 sncRNA 的炎症潜能：从感染到自身免疫性疾病的启示

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-23 DOI: 10.1016/j.omtn.2024.102297

Taisuke Kanaji, Xiang-Lei Yang

引用次数: 0

Network biology approach unveils transcriptomic alterations triggered by particle radiation 网络生物学方法揭示粒子辐射引发的转录组变化

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-21 DOI: 10.1016/j.omtn.2024.102294

Zhi-Ping Liu, Tong Wang

引用次数: 0

PLA-PEG as an alternative to PEGylated lipids for nanoparticle-based DNA vaccination against SARS-CoV-2 聚乳酸-聚乙二醇（PLA-PEG）作为聚乙二醇化脂类的替代品，用于基于纳米粒子的 SARS-CoV-2 DNA 疫苗接种

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-21 DOI: 10.1016/j.omtn.2024.102293

Walison Nunes da Silva, Pedro Henrique Dias Moura Prazeres, Pedro Pires Goulart Guimarães

引用次数: 0

Advancements and challenges in mRNA and ribonucleoprotein-based therapies: From delivery systems to clinical applications 基于 mRNA 和核糖核蛋白疗法的进展与挑战：从输送系统到临床应用

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-19 DOI: 10.1016/j.omtn.2024.102313

Zohre Eftekhari, Horieh Zohrabi, Akbar Oghalaie, Tahereh Ebrahimi, Fatemeh Sadat Shariati, Mahdi Behdani, Fatemeh Kazemi-Lomedasht

{"title":"Advancements and challenges in mRNA and ribonucleoprotein-based therapies: From delivery systems to clinical applications","authors":"Zohre Eftekhari, Horieh Zohrabi, Akbar Oghalaie, Tahereh Ebrahimi, Fatemeh Sadat Shariati, Mahdi Behdani, Fatemeh Kazemi-Lomedasht","doi":"10.1016/j.omtn.2024.102313","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102313","url":null,"abstract":"The use of mRNA and ribonucleoproteins (RNPs) as therapeutic agents is a promising strategy for treating diseases such as cancer and infectious diseases. This review provides recent advancements and challenges in mRNA- and RNP-based therapies, focusing on delivery systems such as lipid nanoparticles (LNPs), which ensure efficient delivery to target cells. Strategies such as microfluidic devices are employed to prepare LNPs loaded with mRNA and RNPs, demonstrating effective genome editing and protein expression and . These applications extend to cancer treatment and infectious disease management, with promising results in genome editing for cancer therapy using LNPs encapsulating Cas9 mRNA and single-guide RNA. In addition, tissue-specific targeting strategies offer potential for improved therapeutic outcomes and reduced off-target effects. Despite progress, challenges such as optimizing delivery efficiency and targeting remain. Future research should enhance delivery efficiency, explore tissue-specific targeting, investigate combination therapies, and advance clinical translation. In conclusion, mRNA- and RNP-based therapies offer a promising avenue for treating various diseases and have the potential to revolutionize medicine, providing new hope for patients worldwide.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222596","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

RNA exon editing: Splicing the way to treat human diseases RNA 外显子编辑：剪接治疗人类疾病的方法

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-16 DOI: 10.1016/j.omtn.2024.102311

Akiko Doi, Conor Delaney, David Tanner, Kirk Burkhart, Robert D. Bell

{"title":"RNA exon editing: Splicing the way to treat human diseases","authors":"Akiko Doi, Conor Delaney, David Tanner, Kirk Burkhart, Robert D. Bell","doi":"10.1016/j.omtn.2024.102311","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102311","url":null,"abstract":"RNA exon editing is a therapeutic strategy for correcting disease-causing mutations by inducing -splicing between a synthetic RNA molecule and an endogenous pre-mRNA target, resulting in functionally restored mRNA and protein. This approach enables the replacement of exons at the kilobase scale, addresses multiple mutations with a single therapy, and maintains native gene expression without changes to DNA. For genes larger than 5 kb, RNA exon editors can be delivered in a single vector despite AAV capacity limitations because only mutated exons need to be replaced. While correcting mutations by -splicing has been previously demonstrated, prior attempts were hampered by low efficiency or lack of translation in preclinical models. Advances in synthetic biology, next-generation sequencing, and bioinformatics, with a deeper understanding of mechanisms controlling RNA splicing, have triggered a re-emergence of -splicing and the development of new RNA exon editing molecules for treating human disease, including the first application in a clinical trial (this study was registered at []). Here, we provide an overview of RNA splicing, the history of -splicing, previously reported therapeutic applications, and how modern advances are enabling the discovery of RNA exon editing molecules for genetic targets unable to be addressed by conventional gene therapy and gene editing approaches.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222597","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

Aptamer-decorated nanocarriers for viral adsorption: A special look at COVID-19 用于病毒吸附的色素修饰纳米载体：特别关注 COVID-19

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-15 DOI: 10.1016/j.omtn.2024.102310

Somayeh Handali, Mohsen Rezaei

引用次数: 0

LinQURE: A novel AAV gene silencing platform that supports multi-transcript targeting for complex disorders LinQURE：支持多转录本靶向治疗复杂疾病的新型 AAV 基因沉默平台

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-15 DOI: 10.1016/j.omtn.2024.102307

Irena Bočkaj, Anna Moreno Garcia, Pablo de Miguel Herraiz, Sonay Keskin, Vanessa Zancanella, Şeyda Acar Broekmans, Astrid Vallès, Ying Poi Liu, Melvin Evers, Morgane Wartel

{"title":"LinQURE: A novel AAV gene silencing platform that supports multi-transcript targeting for complex disorders","authors":"Irena Bočkaj, Anna Moreno Garcia, Pablo de Miguel Herraiz, Sonay Keskin, Vanessa Zancanella, Şeyda Acar Broekmans, Astrid Vallès, Ying Poi Liu, Melvin Evers, Morgane Wartel","doi":"10.1016/j.omtn.2024.102307","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102307","url":null,"abstract":"Given that numerous genetic disorders, driven by diverse pathogenic mechanisms, may be amenable to recombinant adeno-associated virus (rAAV)-delivered gene therapies, the sustained innovation of rAAV-based therapeutic modalities is crucial. The progression and severity of genetic diseases can be reduced by targeting the toxic transcripts of a defective gene using microRNA (miRNA)-based miQURE technology delivered within an AAV vector. By adapting the delivered cassette, it may be possible to simultaneously regulate the expression profile of multiple genes involved in the pathogenesis of complex genetic diseases. The established miQURE gene silencing strategy was expanded by concatenating several miQURE molecules in a single construct, resulting in the novel linQURE platform. Here, a proof of mechanism is established by demonstrating that linQURE technology enables the concomitant expression of two synthetic miRNAs and , allowing more efficient downregulation of their disease-causing mRNA targets. This approach supports the development of multi-targeting therapeutic strategies, enabling gene therapy products to adapt to more complex multigenic indications, thus expanding the toolbox of readily available gene therapies.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222602","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

Molecular classification of geriatric breast cancer displays distinct senescent subgroups of prognostic significance 老年乳腺癌的分子分类显示出具有预后意义的不同衰老亚群

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-15 DOI: 10.1016/j.omtn.2024.102309

Xia Wu, Mengxin Chen, Kang Liu, Yixin Wu, Yun Feng, Shiting Fu, Huaimeng Xu, Yongqi Zhao, Feilong Lin, Liang Lin, Shihui Ye, Junqiang Lin, Taiping Xiao, Wenhao Li, Meng Lou, Hongyu Lv, Ye Qiu, Ruifan Yu, Wenyan Chen, Mengyuan Li, Xu Feng, Zhongbing Luo, Lu Guo, Hao Ke, Limin Zhao

{"title":"Molecular classification of geriatric breast cancer displays distinct senescent subgroups of prognostic significance","authors":"Xia Wu, Mengxin Chen, Kang Liu, Yixin Wu, Yun Feng, Shiting Fu, Huaimeng Xu, Yongqi Zhao, Feilong Lin, Liang Lin, Shihui Ye, Junqiang Lin, Taiping Xiao, Wenhao Li, Meng Lou, Hongyu Lv, Ye Qiu, Ruifan Yu, Wenyan Chen, Mengyuan Li, Xu Feng, Zhongbing Luo, Lu Guo, Hao Ke, Limin Zhao","doi":"10.1016/j.omtn.2024.102309","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102309","url":null,"abstract":"Breast cancer in the elderly presents distinct biological characteristics and clinical treatment responses compared with cancer in younger patients. Comprehensive Geriatric Assessment is recommended for evaluating treatment efficacy in elderly cancer patients based on physiological classification. However, research on molecular classification in older cancer patients remains insufficient. In this study, we identified two subgroups with distinct senescent clusters among geriatric breast cancer patients through multi-omics analysis. Using various machine learning algorithms, we developed a comprehensive scoring model called “Sene_Signature,” which more accurately distinguished elderly breast cancer patients compared with existing methods and better predicted their prognosis. The Sene_Signature was correlated with tumor immune cell infiltration, as supported by single-cell transcriptomics, RNA sequencing, and pathological data. Furthermore, we observed increased drug responsiveness in patients with a high Sene_Signature to treatments targeting the epidermal growth factor receptor and cell-cycle pathways. We also established a user-friendly web platform to assist investigators in assessing Sene_Signature scores and predicting treatment responses for elderly breast cancer patients. In conclusion, we developed a novel model for evaluating prognosis and therapeutic responses, providing a potential molecular classification that assists in the pre-treatment assessment of geriatric breast cancer.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":null,"pages":null},"PeriodicalIF":8.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227591","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