Molecular Therapy. Nucleic Acids最新文献_第4页

Intranasal mRNA vaccines: Targeting mucosal immunity through optimized delivery. 鼻内mRNA疫苗：通过优化递送靶向粘膜免疫

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-08 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102654

Achyut Pandey, Sacheen Kumar, Shruti Mishra

引用次数: 0

Opposing impacts of DNA polyplex crosslinking on delivery efficiency and vaccine responses. DNA多聚交联对递送效率和疫苗反应的相反影响。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-08 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102656

Satoshi Uchida

引用次数: 0

Gold nanoparticle-based delivery of Cas13d for targeted RNA virus defense. 基于金纳米颗粒的Cas13d靶向RNA病毒防御

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-08 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102652

Natália Jordana Alves da Silva, Marco Tullio Rodrigues Alves, Flávia Alves França, Pedro Pires Goulart Guimarães

引用次数: 0

Retraction Notice to: MicroRNA-4500 Inhibits Migration, Invasion, and Angiogenesis of Breast Cancer Cells via RRM2-Dependent MAPK Signaling Pathway. MicroRNA-4500通过rrm2依赖性MAPK信号通路抑制乳腺癌细胞的迁移、侵袭和血管生成。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-07 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102658

Shaoying Li, Huifen Mai, Yefeng Zhu, Guofeng Li, Jing Sun, Guisen Li, Bichan Liang, Shaojun Chen

引用次数: 0

Context dependent role of miR-486 promoting neuroregeneration of primary sensory neurons downstream of interleukin-6 signal transducer. miR-486促进白细胞介素-6信号换能器下游初级感觉神经元神经再生的环境依赖性作用。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-06 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102670

Theodora Kalpachidou, Kai Kummer, Valentina Handle, David Zimmermann, Maria Peteinareli, Serena Quarta, Natalia Mach, Laura Castaldi, Paul A Heppenstall, Rainer V Haberberger, Hermona Soreq, Michaela Kress

{"title":"Context dependent role of miR-486 promoting neuroregeneration of primary sensory neurons downstream of interleukin-6 signal transducer.","authors":"Theodora Kalpachidou, Kai Kummer, Valentina Handle, David Zimmermann, Maria Peteinareli, Serena Quarta, Natalia Mach, Laura Castaldi, Paul A Heppenstall, Rainer V Haberberger, Hermona Soreq, Michaela Kress","doi":"10.1016/j.omtn.2025.102670","DOIUrl":"10.1016/j.omtn.2025.102670","url":null,"abstract":"The pro-inflammatory cytokine interleukin-6 (IL-6) via its IL-6 signal transducer (IL6ST/gp130) plays an important role in neuronal survival, neuro-regeneration, and pathological pain. While its critical importance in the nervous system is well established, the underlying molecular mechanisms and the involvement of microRNAs (miRNAs) as critical regulators of biological processes in health and disease are not sufficiently understood. We identified miR-486-5p as the single significantly deregulated miRNA in sensory neurons with a conditional depletion of gp130. In situ hybridization and immunofluorescence in dorsal root ganglia (DRG) localized miR-486 to small diameter neurons, including peptidergic nociceptors. miR-486-/- mice exhibited normal baseline and neuropathic pain-like behaviors and recovered similarly to wild-type (WT) littermate controls in response to sciatic crush injury. On the other hand, DRG neurons derived from mice with a conditional deletion of IL6ST/gp130 in Nav1.8-expressing primary afferent nociceptors (SNS-gp130-/-) show strongly compromised neuro-regeneration, which was significantly rescued by overexpressing miR-486, indicative of a specific role of miR-486 in IL-6/gp130-dependent neuro-regenerative processes. Our findings highlight context-dependent differential expression and roles of miRNAs after nerve injury driving nerve regeneration versus neuropathic pain.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102670"},"PeriodicalIF":6.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961814","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

Nose-to-brain siRNA delivery by PEI/PPI-based nanoparticles reduces α-synuclein expression in a Parkinson's disease mouse model. 在帕金森病小鼠模型中，PEI/ ppi纳米颗粒经鼻至脑siRNA递送降低α-突触核蛋白表达。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-06 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102671

Malte Feja, Isabell Drath, Sandra Weiß, Alexander Ewe, Birthe Gericke, Tiago F Outeiro, Leonidas Stefanis, Achim Aigner, Franziska Richter

{"title":"Nose-to-brain siRNA delivery by PEI/PPI-based nanoparticles reduces α-synuclein expression in a Parkinson's disease mouse model.","authors":"Malte Feja, Isabell Drath, Sandra Weiß, Alexander Ewe, Birthe Gericke, Tiago F Outeiro, Leonidas Stefanis, Achim Aigner, Franziska Richter","doi":"10.1016/j.omtn.2025.102671","DOIUrl":"10.1016/j.omtn.2025.102671","url":null,"abstract":"Potential strategies to develop new treatments for Parkinson's disease (PD) aim at targeting disease-associated proteins like alpha-synuclein (aSyn), which accumulates in neurons of PD patients and contributes to neuronal degeneration. A promising new approach is the therapeutic use of small interfering RNAs (siRNAs) for aSyn knockdown, but is challenging due to siRNA instability, poor delivery, and inefficient uptake. Therefore, we developed a nanoparticle-based approach for intranasal delivery of siRNAs, circumventing the blood-brain barrier and enhancing the potential of siRNAs for clinical application. Tyrosine-modified polyethylenimines (PEIs), or polypropylenimine dendrimers (PPIs), were complexed with siRNA targeting the aSyn-encoding gene SNCA (siSNCA) and combined with liposomes. Nanoparticles efficiently transfected SH-SY5Y cells with low cytotoxicity and significantly reduced SNCA mRNA levels. In Thy1-aSyn mice, intranasally administered labeled nanoparticles distributed extensively across the brain, including the olfactory bulb, substantia nigra, and prefrontal cortex. After only 4 days of treatment, siSNCA-loaded nanoparticles significantly reduced aSyn protein and SNCA mRNA levels in the brain. Mice showed neither overt adverse behavioral effects nor increased reactive microglia. These findings highlight the potential of nanoparticle-mediated intranasal siRNA delivery as a promising, non-invasive approach to reduce aSyn levels in the brain, offering a novel therapeutic strategy for Parkinson's disease.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102671"},"PeriodicalIF":6.1,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12447568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113736","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

A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health. 一种组合寡核苷酸疗法改善营养不良蛋白恢复和营养不良蛋白缺乏的肌肉健康。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-05 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102665

Young Jae Moon, Ravi Hindupur, Iteoluwakishi H Gamu, Nikki M McCormack, Fatima Shaikh, James S Novak, Jyoti K Jaiswal

{"title":"A combinatorial oligonucleotide therapy to improve dystrophin restoration and dystrophin-deficient muscle health.","authors":"Young Jae Moon, Ravi Hindupur, Iteoluwakishi H Gamu, Nikki M McCormack, Fatima Shaikh, James S Novak, Jyoti K Jaiswal","doi":"10.1016/j.omtn.2025.102665","DOIUrl":"10.1016/j.omtn.2025.102665","url":null,"abstract":"Despite the proven safety of dystrophin-targeting phosphorodiamidate morpholino oligomer (PMO) therapy, poor delivery of the PMOs limit the efficacy of this dystrophin restoring gene therapy for Duchenne muscular dystrophy (DMD). Limited myogenesis and excessive fibrosis in DMD are pathological features that contribute to the poor efficacy of PMOs. We show that the severe DMD mouse model (D2-mdx) not only replicates these pathological features of DMD but also mirrors the resulting PMO-mediated dystrophin restoration deficit. High transforming growth factor β (TGF-β) activity, which is a common feature of DMD patient and D2-mdx muscles, limits myogenesis and causes fibrosis. We developed a TGF-β-targeting PO (TPMO), which when used acutely, lowered macrophage TGF-β activity and signaling in the dystrophic muscle, enhanced muscle regeneration, and enhanced dystrophin restoration when used in combination with dystrophin exon skipping PMO (DPMO). Chronic use of this combination PMO therapy in D2-mdx mice reduced muscle fibrosis and muscle loss, allowed dystrophin restoration in skeletal muscle and heart, and led to an overall enhancement of skeletal muscle function. This approach leverages the safety of PMO-based therapy and represents the first combination PMO treatment for DMD that simultaneously enhances dystrophin restoration, reduces fibrosis, and alleviates myogenic deficits to ultimately improve health and function of dystrophic muscles.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102665"},"PeriodicalIF":6.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961870","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

Development of conditional-siRNA programmable riboswitch for targeting adverse cardiac remodeling. 靶向不良心脏重构的条件sirna可编程核糖开关的开发。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-05 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102667

Priyanka Gokulnath, Ane M Salvador, Caleb Graham, Si-Ping Han, Guoping Li, Ramaswamy Kannappan, Christopher Azzam, Michail Spanos, Lisa Scherer, Palaniappan Sethu, John Rossi, William A Goddard, Saumya Das

{"title":"Development of conditional-siRNA programmable riboswitch for targeting adverse cardiac remodeling.","authors":"Priyanka Gokulnath, Ane M Salvador, Caleb Graham, Si-Ping Han, Guoping Li, Ramaswamy Kannappan, Christopher Azzam, Michail Spanos, Lisa Scherer, Palaniappan Sethu, John Rossi, William A Goddard, Saumya Das","doi":"10.1016/j.omtn.2025.102667","DOIUrl":"10.1016/j.omtn.2025.102667","url":null,"abstract":"Heart failure (HF) remains a significant healthcare burden, with an unmet need for novel therapies to target the preceding pathological hypertrophy in HF patients. Here we report the development of novel conditional-siRNA (Cond-siRNA) constructs that are selectively activated by disease-specific RNA biomarkers to enable cell-specific inhibition of a target disease-causing RNA. We designed a Cond-siRNA that can be activated by Nppa mRNA, upregulated specifically in cardiomyocytes (CMs) under pathological stress, to silence the key pro-hypertrophic gene calcineurin (CaN) A-a by the effector small interfering RNA (siRNA). In both neonatal rat ventricular myocytes (NRVMs) and H9c2 CMs, Cond-siRNA showed minimal baseline activity but selectively silenced CaN upon Nppa mRNA induction by phenylephrine (PE) stress in cell culture models and pressure overload (PO) in a heart-on-a-chip model. In NRVMs, Cond-siRNA reduced CaN mRNA only after PE or PO, but not with vehicle, confirming Nppa-specific activation. This specificity was further validated as Cond-siRNA did not affect CaN in cardiac fibroblasts or T cells lacking Nppa. Reduced CaN protein levels and NFATc1 nuclear translocation correlated with decreased NRVM hypertrophy after PE treatment, confirming Cond-siRNA's efficacy. This study offers proof-of-concept for Cond-siRNA as a targeted therapy to mitigate hypertrophic progression, paving the way for novel HF treatments.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102667"},"PeriodicalIF":6.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12375242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961864","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

Targeting a pathogenic cryptic exon that drives HLRCC to induce exon skipping. 靶向致病隐外显子，驱动HLRCC诱导外显子跳变。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-05 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102668

Siddhardha S Maligireddy, Mariana D Mandler, Judith C Lunger, Madeline Yuen, Sneha Kulkarni, Alexendar R Perez, Christina M Fitzsimmons, Daniel R Crooks, Raj Chari, W Marston Linehan, Pedro J Batista

{"title":"Targeting a pathogenic cryptic exon that drives HLRCC to induce exon skipping.","authors":"Siddhardha S Maligireddy, Mariana D Mandler, Judith C Lunger, Madeline Yuen, Sneha Kulkarni, Alexendar R Perez, Christina M Fitzsimmons, Daniel R Crooks, Raj Chari, W Marston Linehan, Pedro J Batista","doi":"10.1016/j.omtn.2025.102668","DOIUrl":"10.1016/j.omtn.2025.102668","url":null,"abstract":"Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant cancer predisposition syndrome driven by the loss of fumarate hydratase (FH) activity. Recently, we identified a pathogenic variant in intron 9 of the FH gene that disrupts splicing by creating a novel splice acceptor site, resulting in the aberrant inclusion of a cryptic exon. Inclusion of the cryptic exon introduces a premature termination codon, leading to loss of FH activity. To restore FH expression, we sought to identify strategies to drive exclusion of the cryptic exon from the mature mRNA. To this end, we generated a minigene GFP reporter system that recapitulates the splicing defect observed in patients. We employed CRISPR-Cas9-mediated genome editing and antisense oligonucleotides (ASOs) to modulate splicing and demonstrated that both strategies can successfully promote skipping of the cryptic exon in a reporter cell line. Furthermore, we were able to show that ASOs can be used to shift the balance between the FH mRNA isoforms originated from the reference and the variant allele in patient-derived fibroblasts using ASOs. These findings support the potential for splicing modulation as a therapeutic approach for HLRCC-associated non-coding loss-of-function mutations in FH.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102668"},"PeriodicalIF":6.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961738","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

Advancing gene editing therapeutics: Clinical trials and innovative delivery systems across diverse diseases. 推进基因编辑治疗：跨多种疾病的临床试验和创新递送系统。

IF 6.1 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2025-08-05 eCollection Date: 2025-09-09 DOI: 10.1016/j.omtn.2025.102666

Mozhghan Raigani, Zohre Eftekhari, Ahmad Adeli, Fatemeh Kazemi-Lomedasht

{"title":"Advancing gene editing therapeutics: Clinical trials and innovative delivery systems across diverse diseases.","authors":"Mozhghan Raigani, Zohre Eftekhari, Ahmad Adeli, Fatemeh Kazemi-Lomedasht","doi":"10.1016/j.omtn.2025.102666","DOIUrl":"10.1016/j.omtn.2025.102666","url":null,"abstract":"Gene editing is a groundbreaking therapeutic approach that can potentially treat a broad spectrum of genetic and acquired diseases. This review highlights recent clinical trials employing advanced gene editing technologies such as CRISPR-Cas9, zinc-finger nucleases (ZFNs), and base editors across multiple disease areas including metabolic disorders, autoimmune diseases, muscular dystrophies, and inherited eye disorders. Central to the success of these therapies is the development of efficient and safe delivery systems, including lipid nanoparticles (LNPs), viral vectors (adenoviral and lentiviral), electroporation techniques, and virus-like particles (VLPs), which facilitate precise editing of target cells in vivo or ex vivo. These delivery platforms have enabled promising early-phase clinical trials demonstrating feasibility, safety, and durable gene modification in patient populations. For example, LNPs have been pivotal in delivering mRNA editors for liver-targeted metabolic diseases. At the same time, viral vectors have been used for ex vivo modification of T cells and hematopoietic stem cells in autoimmune and infectious diseases. Despite encouraging results, challenges remain in optimizing delivery specificity, minimizing off-target effects, and ensuring long-term safety and efficacy. Ongoing and upcoming trials continue to refine these delivery technologies and expand the therapeutic reach of gene editing.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"36 3","pages":"102666"},"PeriodicalIF":6.1,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12395446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961901","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