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

Cell-targeted gene modification by delivery of CRISPR-Cas9 ribonucleoprotein complexes in pseudotyped lentivirus-derived nanoparticles 通过在伪型慢病毒衍生纳米颗粒中递送 CRISPR-Cas9 核糖核蛋白复合物实现细胞靶向基因修饰

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-31 DOI: 10.1016/j.omtn.2024.102318

Ian Helstrup Nielsen, Anne Bruun Rovsing, Jacob Hørlück Janns, Emil Aagaard Thomsen, Albert Ruzo, Andreas Bøggild, Frederikke Nedergaard, Charlotte Thornild Møller, Thomas Boesen, Søren Egedal Degn, Jagesh V. Shah, Jacob Giehm Mikkelsen

{"title":"Cell-targeted gene modification by delivery of CRISPR-Cas9 ribonucleoprotein complexes in pseudotyped lentivirus-derived nanoparticles","authors":"Ian Helstrup Nielsen, Anne Bruun Rovsing, Jacob Hørlück Janns, Emil Aagaard Thomsen, Albert Ruzo, Andreas Bøggild, Frederikke Nedergaard, Charlotte Thornild Møller, Thomas Boesen, Søren Egedal Degn, Jagesh V. Shah, Jacob Giehm Mikkelsen","doi":"10.1016/j.omtn.2024.102318","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102318","url":null,"abstract":"To fully utilize the potential of CRISPR-Cas9-mediated genome editing, time-restricted and targeted delivery is crucial. By modulating the pseudotype of engineered lentivirus-derived nanoparticles (LVNPs), we demonstrate efficient cell-targeted delivery of Cas9/single guide RNA (sgRNA) ribonucleoprotein (RNP) complexes, supporting gene modification in a defined subset of cells in mixed cell populations. LVNPs pseudotyped with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein resulted in angiotensin-converting enzyme 2 (ACE2)-dependent insertion or deletion (indel) formation in an ACE2/ACE2 population of cells, whereas Nipah virus glycoprotein pseudotyping resulted in Ephrin-B2/B3-specific gene knockout. Additionally, LVNPs pseudotyped with Edmonston strain measles virus glycoproteins (MV-H/F) delivered Cas9/sgRNA RNPs to CD46 cells with and without additional expression of SLAM (signaling lymphocytic activation molecule; CD150). However, an engineered SLAM-specific measles virus pseudotype (measles virus-hemagglutinin/fusion [MV-H/F]-SLAM) efficiently targeted LVNPs to SLAM cells. Lentiviral vectors (LVs) pseudotyped with MV-H/F-SLAM efficiently transduced >80% of interleukin (IL)-4/IL-21-stimulated primary B cells cultured on CD40 ligand (CD40L)-expressing feeder cells. Notably, LVNPs pseudotyped with MV-H/F and MV-H/F-SLAM reached indel rates of >80% and >60% in stimulated primary B cells, respectively. Collectively, our findings demonstrate the modularity of LVNP-directed delivery of ready-to-function Cas9/sgRNA complexes. Using a panel of different pseudotypes, we provide evidence that LVNPs can be engineered to induce effective indel formation in a subpopulation of cells defined by the expression of surface receptors.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"29 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222584","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

How well does the adaptive feature representation learning approach identify human mRNA N4-acetylcytidine sites? 自适应特征表征学习法识别人类 mRNA N4-乙酰胞嘧啶位点的效果如何？

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-29 DOI: 10.1016/j.omtn.2024.102300

Rahul Kumar, Yanfeng Wang, Sandeep Kumar Dhanda

引用次数: 0

Advancing gene editing by engineering miniature CRISPR-Cas Un1Cas12f1 通过微型 CRISPR-Cas Un1Cas12f1 工程推进基因编辑工作

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-29 DOI: 10.1016/j.omtn.2024.102302

Weimin Tang

引用次数: 0

Metabolism of tRNAs and rRNAs shape immunoactive signatures in chronic obstructive pulmonary disease and pulmonary infections tRNA 和 rRNA 的代谢形成慢性阻塞性肺病和肺部感染的免疫活性特征

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-29 DOI: 10.1016/j.omtn.2024.102298

Zhenyi Hong, Xavier Bofill-De Ros

引用次数: 0

Breaking bad aggregates: How a DNA aptamer cleans up Parkinson’s disease 打破不良聚集：DNA 合酶如何清除帕金森病

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-29 DOI: 10.1016/j.omtn.2024.102296

Maxim V. Berezovski

引用次数: 0

Stereopure ASOs: An unanticipated increase in selectivity for targeting mutant HTT 立体纯ASOs：针对突变型 HTT 的选择性意外提高

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-28 DOI: 10.1016/j.omtn.2024.102312

Vijay N. Gulumkar, Steven F. Dowdy

引用次数: 0

Targeting heterozygous dominant negative variant of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy 利用 Gapmer ASO 靶向 KCNA2 的杂合显性负变异，治疗耐药性癫痫

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-27 DOI: 10.1016/j.omtn.2024.102316

Hua Huang, Dong Rui Ma, Derrick Wei Shih Chan, Adeline Seow Fen Ngoh, Dejie Yu, Shi Jun Ng, John Jia En Chua, Eng King Tan, Hui-Lin Chin, Denise Li Meng Goh, Tuck Wah Soong

{"title":"Targeting heterozygous dominant negative variant of KCNA2 using Gapmer ASO for the treatment of drug-resistant epilepsy","authors":"Hua Huang, Dong Rui Ma, Derrick Wei Shih Chan, Adeline Seow Fen Ngoh, Dejie Yu, Shi Jun Ng, John Jia En Chua, Eng King Tan, Hui-Lin Chin, Denise Li Meng Goh, Tuck Wah Soong","doi":"10.1016/j.omtn.2024.102316","DOIUrl":"https://doi.org/10.1016/j.omtn.2024.102316","url":null,"abstract":"A missense mutation c.1220C>G of gene was recently identified in an infant with epilepsy. encodes K1.2 subunits that form voltage-gated potassium channels (VGKC) via tetrameric assembly. The mutation results in amino acid change P407R at the highly conserved motif. Functional characterization revealed that mutant K1.2_P407R subunits formed loss-of-function channels and suppressed both K1.2 and K1.1 channel activities. Hetero-tetrameric assembly of the K1.2_P407R subunits with other neuronal voltage-gated potassium channels of Shaker subfamily could lead to general deficit of repolarizing potassium current and potentially underlie the enhanced seizure susceptibility. Indeed, expression of human K1.2_P407R in early postnatal rat cortical neurons or genetically engineered hESC-derived neurons disclosed broadening of action potential duration and early afterdepolarization (EAD), associating with reduced potassium current. We hypothesize that Gapmer antisense oligonucleotides (ASOs) targeted to c.1220C>G mutation will selectively degrade the mutant mRNA while allowing the remaining wild-type (WT) subunits to form functional channels. As a proof of principle, delivery of Gapmer packaged in lipid nanoparticle into cortical neurons selectively suppressed K1.2_P407R over the WT protein expression, reversing the broadening of action potential duration, abrogating the EAD and leading to overall increase in potassium current.","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"43 1","pages":""},"PeriodicalIF":8.8,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142222590","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

The role of RNA modifications in disease-associated macrophages RNA 修饰在疾病相关巨噬细胞中的作用

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-26 DOI: 10.1016/j.omtn.2024.102315

Camille Huart, Mayuk Saibal Gupta, Jo A. Van Ginderachter

引用次数: 0

Less is more: Allele-specific removal of dysfunctional RYR1 channel subunits 少即是多：等位基因特异性清除功能失调的 RYR1 通道亚基

IF 8.8 2区医学

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-26 DOI: 10.1016/j.omtn.2024.102301

Derek Sun, William R. Lagor

引用次数: 0

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":"22 1","pages":""},"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