Molecular Therapy. Nucleic Acids最新文献

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Optimizing C14120-based lipid nanoparticles for mRNA delivery: Editorial commentary. 优化c14120为基础的脂质纳米颗粒mRNA递送:编辑评论。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-25 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102945
Vincent Fung, Caroline Argenti, Maggie Magaw, Owen S Fenton
{"title":"Optimizing C14120-based lipid nanoparticles for mRNA delivery: Editorial commentary.","authors":"Vincent Fung, Caroline Argenti, Maggie Magaw, Owen S Fenton","doi":"10.1016/j.omtn.2026.102945","DOIUrl":"10.1016/j.omtn.2026.102945","url":null,"abstract":"","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102945"},"PeriodicalIF":6.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13226814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157440","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 self-amplifying RNA vector based on rubella virus for mRNA therapeutics and vaccine applications. 基于风疹病毒的mRNA治疗和疫苗应用的自扩增RNA载体。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-25 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102967
Miao Jing, Michelle Cheok Yien Law, Cao Dai Phung, Yu He, Yaw Bia Tan, Minh T N Le, Dahai Luo
{"title":"A self-amplifying RNA vector based on rubella virus for mRNA therapeutics and vaccine applications.","authors":"Miao Jing, Michelle Cheok Yien Law, Cao Dai Phung, Yu He, Yaw Bia Tan, Minh T N Le, Dahai Luo","doi":"10.1016/j.omtn.2026.102967","DOIUrl":"10.1016/j.omtn.2026.102967","url":null,"abstract":"<p><p>Significant efforts have been made in the burgeoning field of RNA therapies since the COVID-19 pandemic. Self-amplifying RNA (saRNA)-based therapies are considered more promising than conventional messenger RNA due to their lower concentration requirements, long-lasting effects, and self-adjuvanticity. Here, we developed a novel saRNA vector, based on the rubella virus ([RuV], based on the RA27/3 vaccine strain) as an alternative virus-derived replicon that demonstrates effective expression in multiple cell lines and induces immune response. As it is derived from a commonly used vaccine, it potentially offers a better safety profile with reduced risk of adverse events compared with current alphavirus-derived saRNAs. We further optimized this RuV saRNA by screening the capsid region, the nonstructural polyprotein p200 codon, and the 3' untranslated region. This RuV saRNA has great potential to be used as a vaccine vector and in other applications in RNA therapeutics.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102967"},"PeriodicalIF":6.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13264025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252163","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
Rational design of hammerhead ribozymes as CD93 silencing tools for vascular diseases. 锤头核酶作为血管疾病CD93沉默工具的合理设计。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-25 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102968
Cosimo Damiano Perrone, Luisa Raucci, Sara Papini, Gian Marco Tosi, Federico Galvagni, Massimo Olivucci, Danny Incarnato, Maurizio Orlandini
{"title":"Rational design of hammerhead ribozymes as CD93 silencing tools for vascular diseases.","authors":"Cosimo Damiano Perrone, Luisa Raucci, Sara Papini, Gian Marco Tosi, Federico Galvagni, Massimo Olivucci, Danny Incarnato, Maurizio Orlandini","doi":"10.1016/j.omtn.2026.102968","DOIUrl":"10.1016/j.omtn.2026.102968","url":null,"abstract":"<p><p>While targeting angiogenesis represents a key therapeutic strategy in several pathological contexts, it comes with significant challenges associated with therapeutic efficacy and drug resistance. Therefore, developing novel, more effective and durable therapeutic modalities is paramount. We have previously reported that antibody-mediated inhibition of CD93, a vascular endothelial cell surface glycoprotein, can inhibit angiogenesis. Here, we describe a novel strategy to efficiently inhibit CD93 expression in cells, based on the targeted degradation of CD93 mRNA using <i>trans-</i>acting hammerhead ribozymes. To pinpoint single-stranded regions in CD93 mRNA that are amenable to ribozyme targeting in living cells, we performed RNA secondary structure mapping via targeted DMS-MaPseq analysis. Next, since exogenous hammerhead ribozymes are easily degraded and lose catalytic activity when expressed in living cells, we developed a novel scaffold RNA based on short stems from the 3' UTR of histone mRNAs to stabilize the active ribozyme structure and promote the CD93 cleavage under physiological conditions. Ectopic expression of these engineered ribozymes in primary endothelial cells resulted in efficient inhibition of CD93 expression, cell migration, and formation of tube-like structures in functional assays. Collectively, our data provides the proof-of-concept for the use of ribozyme-based therapeutics for the treatment of neovascular pathologies.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102968"},"PeriodicalIF":6.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13264038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252389","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
Cell type-stratified immunogenetic framework reveals immune drivers and therapeutic targets in kidney stone disease. 细胞类型分层免疫遗传学框架揭示肾结石疾病的免疫驱动因素和治疗靶点。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-25 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102964
Dianjie Zeng, Lingfei Zhu, Jiachen Liu, Xiaorui Qiu, Leyi Chen, Chenming Wei, Yinhuai Wang, Zebin Deng
{"title":"Cell type-stratified immunogenetic framework reveals immune drivers and therapeutic targets in kidney stone disease.","authors":"Dianjie Zeng, Lingfei Zhu, Jiachen Liu, Xiaorui Qiu, Leyi Chen, Chenming Wei, Yinhuai Wang, Zebin Deng","doi":"10.1016/j.omtn.2026.102964","DOIUrl":"10.1016/j.omtn.2026.102964","url":null,"abstract":"<p><p>Despite growing recognition of immune involvement in kidney stone disease (KSD), its immunogenetic basis remains unclear. We applied a cell type-stratified immunogenetic framework, integrating single-cell <i>cis</i>-expression quantitative trait loci (<i>cis</i>-eQTL) data from the OneK1K immune atlas, to identify gene-cell type associations across four anatomical KSD subtypes. This approach revealed 80 colocalized gene-cell type pairs with strong genetic support. Natural killer (NK) cells and CD4<sup>+</sup> naive/central memory T cells emerged as major contributors to disease risk, with consistent associations observed for <i>BCR</i>-NK cells and <i>RGS14</i>-CD4<sup>+</sup>/CD8<sup>+</sup> T cells across all KSD subtypes. Functional and network analyses highlighted roles for MHC class II antigen presentation and T cell activation, implicating adaptive immunity in pathogenesis. Prioritized genes showed pleiotropic links to renal function, inflammation, and mineral metabolism-for example, <i>RGS14</i> was associated with improved eGFR and reduced urinary citrate; <i>GPX1</i> with impaired renal function and elevated CRP; <i>HCG25</i> and <i>DGKD</i> with higher calcium and uric acid. Clinical complication mapping further implicated these targets in osteoporosis, hypertension, and systemic inflammation. A multi-domain prioritization identified seven top targets-<i>RGS14</i>, <i>BCR</i>, <i>PRR3</i>, <i>HIST1H2BG</i>, <i>SLC44A4</i>, <i>POU5F1</i>, and <i>CTSS</i>-as clinically actionable. These insights may inform future strategies for risk stratification, early detection, and immune-targeted intervention in KSD.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102964"},"PeriodicalIF":6.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13264055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252150","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
Developing a pan cancer therapy based on DISE-inducing short RNAs. 开发一种基于诱导疾病的短rna的泛癌症治疗。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-25 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102963
Andrea E Murmann, Mehrnoosh Ebadi, Monal Patel, Alexander Ewe, Sergio Barajas, Shiyu Xiao, Min Jun Ko, Sanghee Lee, Wenjie Cai, Bidur Paudel, Limin Sun, Elizabeth T Bartom, Masha Kocherginsky, Yan Liu, Dong-Hyun Kim, Achim Aigner, Marcus E Peter
{"title":"Developing a pan cancer therapy based on DISE-inducing short RNAs.","authors":"Andrea E Murmann, Mehrnoosh Ebadi, Monal Patel, Alexander Ewe, Sergio Barajas, Shiyu Xiao, Min Jun Ko, Sanghee Lee, Wenjie Cai, Bidur Paudel, Limin Sun, Elizabeth T Bartom, Masha Kocherginsky, Yan Liu, Dong-Hyun Kim, Achim Aigner, Marcus E Peter","doi":"10.1016/j.omtn.2026.102963","DOIUrl":"10.1016/j.omtn.2026.102963","url":null,"abstract":"<p><p>RNA interference (RNAi) regulates gene expression through small RNAs that act via Argonaute-containing RNA-induced silencing complexes (RISCs). We previously found that short RNAs with G-rich 6mer seeds (e.g., GGGGGC and G5C) can kill cells by targeting C-rich 3' UTR seed matches in essential survival genes (SGs), a mechanism termed death induced by survival gene elimination (DISE). To assess therapeutic potential, we systemically delivered two DISE-inducing sRNAs, sG5C and sCAG (based on CAG trinucleotide repeats), using lipopolyplexes (LPPs) composed of low-molecular-weight polyethyleneimines and lipids. In mouse ovarian and prostate cancer models and a rat hepatocellular carcinoma model, LPP-delivered small RNAs (sRNAs) markedly reduced or eliminated tumors without harming normal tissues. Predicted SG targets were engaged in tumors. Transcriptomic analyses across 10 major human cancers showed that many sG5C-targeted SGs are consistently upregulated in tumors and increase with stage, revealing a therapeutic window. These results support LPP-delivered DISE-inducing sRNAs as a promising pan-cancer therapy.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102963"},"PeriodicalIF":6.5,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265466","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
Fine-scale structural information substantially improves mRNA therapeutic stability prediction. 精细结构信息大大提高了mRNA治疗稳定性的预测。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-21 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102960
Soon Yi, Sara E Ali, Yashrajsinh Jadeja, J Wade Davis, Mihir Metkar
{"title":"Fine-scale structural information substantially improves mRNA therapeutic stability prediction.","authors":"Soon Yi, Sara E Ali, Yashrajsinh Jadeja, J Wade Davis, Mihir Metkar","doi":"10.1016/j.omtn.2026.102960","DOIUrl":"10.1016/j.omtn.2026.102960","url":null,"abstract":"<p><p>The success of COVID-19 mRNA vaccines has made the in-solution stability optimization of mRNAs a key objective. However, we still lack a complete understanding of sequence metrics that influence mRNA in-solution stability. RNA secondary structure plays a critical role in protecting against hydrolysis, the primary degradation pathway under storage conditions. Yet, the structural metrics that best guide stability-focused mRNA design remain incompletely defined. Global metrics like minimum free energy and average unpaired probability have improved mRNA stability but fail to capture local structural variation relevant to RNA degradation. We demonstrate that base-pairing log odds (LO) provide fine-scale, orthogonal insight that complements global metrics and improves stability modeling. Further, by combining local and global features into a parsimonious four-feature regression model, dubbed stability regression analysis using nucleotide-derived features (STRAND), we achieve a greater than 2-fold reduction in prediction error compared to existing machine learning and deep learning approaches and demonstrate robust generalization across diverse transcript contexts. This compact and interpretable model provides an accurate and reliable framework for predicting mRNA in-solution stability.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102960"},"PeriodicalIF":6.5,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13264031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252344","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
Comprehensive assessment of on- and off-target mutagenesis via lipid nanoparticle delivery of CRISPR-Cas9 genome editing. 通过脂质纳米颗粒递送CRISPR-Cas9基因组编辑的靶向和脱靶诱变的综合评估。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-20 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102958
Youichi Naoe, Naoko Fujimoto, Yukimasa Makita, Dongyang Li, Naoto Inukai, Akitsu Hotta
{"title":"Comprehensive assessment of on- and off-target mutagenesis via lipid nanoparticle delivery of CRISPR-Cas9 genome editing.","authors":"Youichi Naoe, Naoko Fujimoto, Yukimasa Makita, Dongyang Li, Naoto Inukai, Akitsu Hotta","doi":"10.1016/j.omtn.2026.102958","DOIUrl":"10.1016/j.omtn.2026.102958","url":null,"abstract":"<p><p>Ensuring the safety of CRISPR-Cas9 genome editing requires comprehensive assessment of off-target mutagenesis, particularly for therapeutic applications under regulatory review. DNA-free lipid nanoparticle (LNP) delivery is expected to minimize insertional risks compared to adeno-associated virus (AAV) vectors, but experimental validation has been limited. Here, on-target amplicon sequencing in mouse muscle demonstrated insertions largely derived from host genomic sequences, with no detectable AAV or transgene integration. Benchmarking 13 <i>in silico</i> prediction tools identified Cas-OFFinder as the most sensitive, though precision remained low, and correlation with <i>in vitro</i> CIRCLE-seq data was modest. To strengthen off-target detection, we employed karyotypically normal human iPSCs and developed an \"indel cluster\" method using high-depth whole-genome sequencing, enabling discrimination between clustered genome editing-induced indels and background variants. Integration of <i>in silico</i> predictions, CIRCLE-seq cleavage sites, and <i>in cellulo</i> WGS clusters yielded 11 high-confidence off-target candidates, predominantly associated with one gRNA. While sensitivity was maximized, reproducibility across conditions remained limited, and many candidate sites overlapped repetitive or low-mappability regions. Our multilayered framework demonstrates both the utility and current limitations of off-target risk assessment, providing a practical foundation for the safety evaluation of genome editing therapies.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102958"},"PeriodicalIF":6.5,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265505","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
Comparative immunogenic and structural analysis of virus-like particle and inactivated whole-virion vaccines against enterovirus D68. 抗肠病毒D68的病毒样颗粒疫苗和灭活全病毒粒子疫苗的免疫原性和结构分析。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-20 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102957
Kota Senpuku, Yuta Kunishima, Mika Hirose, Tatsuya Karaki, Kotaro Taniguchi, Chikako Kataoka-Nakamura, Toshiro Hirai, Koubun Yasuda, Etsushi Kuroda, Takayuki Kato, Taiki Ito, Yasuo Yoshioka
{"title":"Comparative immunogenic and structural analysis of virus-like particle and inactivated whole-virion vaccines against enterovirus D68.","authors":"Kota Senpuku, Yuta Kunishima, Mika Hirose, Tatsuya Karaki, Kotaro Taniguchi, Chikako Kataoka-Nakamura, Toshiro Hirai, Koubun Yasuda, Etsushi Kuroda, Takayuki Kato, Taiki Ito, Yasuo Yoshioka","doi":"10.1016/j.omtn.2026.102957","DOIUrl":"10.1016/j.omtn.2026.102957","url":null,"abstract":"<p><p>Enterovirus D68 (EV-D68) primarily causes respiratory illnesses and has been implicated in acute flaccid myelitis. Although virus-like particle (VLP) and traditional inactivated whole-virion (IWV) vaccines have demonstrated efficacy in mice, their immunological differences remain undetermined. Here, we directly compared the immunogenic and structural properties of VLP and IWV vaccines derived from the same EV-D68 strain under identical conditions. Although VLP induced significantly lower levels of EV-D68-specific IgG than IWV, neutralizing antibody titers and protective effects against viral challenge were comparable between the two groups in mice. Passive transfer experiments in neonatal mice further confirmed protection against lethal infection for both vaccine groups. Notably, in contrast to the IWV vaccine, the VLP vaccine elicited antibodies that preferentially recognized a limited subset of epitopes. Cryo-electron microscopy analyses revealed that VLPs structurally resemble the native virus but display distinct features in regions corresponding to epitopes that show differential antibody reactivity between VLP and IWV vaccines. By integrating structural and immunological analyses, we established a mechanistic framework linking capsid architecture to vaccine-induced antibody specificity. These findings suggest that VLP is a promising EV-D68 vaccine antigen with distinct epitope recognition profiles driven by structural characteristics.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102957"},"PeriodicalIF":6.5,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13264187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252341","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
Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells. 通过供体DNA进入人细胞线粒体介导的线粒体基因组微同源编辑。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-19 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102959
Vadim V Maximov, Nikita Shebanov, Natalia Nikitchina, Rachel Rapoport, Yehoshua Maor, Ivan Tarassov, Ophry Pines, Nina Entelis
{"title":"Mitochondrial genome microhomology-mediated editing by donor DNA delivery into mitochondria in human cells.","authors":"Vadim V Maximov, Nikita Shebanov, Natalia Nikitchina, Rachel Rapoport, Yehoshua Maor, Ivan Tarassov, Ophry Pines, Nina Entelis","doi":"10.1016/j.omtn.2026.102959","DOIUrl":"10.1016/j.omtn.2026.102959","url":null,"abstract":"<p><p>Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases, lacking efficient therapies. Direct correction of mtDNA mutations may offer a cure for such diseases. We propose a novel strategy based on double-stranded DNA (dsDNA) oligonucleotide delivery into mitochondria and intrinsic microhomology-mediated end joining (MMEJ) for mtDNA editing. This strategy enables the introduction of multiple predefined nucleotide changes in mtDNA. For this, the presence of MMEJ activity in the human mitochondrial lysates was confirmed. Forty-nine bp DNA oligonucleotide duplexes, fused to an RNA hairpin previously identified as a mitochondrial import signal, were delivered into the mitochondria of cultured human cells. Delivery of these donor dsDNA molecules, homologous to an <i>ND4</i> site of mtDNA and bearing designed nucleotide changes, led to a low but statistically significant introduction of the intended nucleotide changes into mtDNA. Donor dsDNA delivery combined with the CRISPR-mito-AsCas12a system also resulted in a statistically significant number of an expected concomitant change of five nucleotides distributed across a 16 nt <i>ND4</i> site of the mitochondrial genome. The proposed strategy may become an efficient mtDNA editing tool suitable for the correction of near-homoplasmic mutations, such as Leber's hereditary optic neuropathy (LHON)-associated mutations in the <i>ND4</i> gene of mtDNA.</p><p><strong>Video abstract: </strong></p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102959"},"PeriodicalIF":6.5,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13267557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148265468","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
BRPtools: An AutoML-Powered web platform for multiclass disease prediction from bulk blood RNA-seq data. BRPtools:一个自动驱动的网络平台,用于从大量血液RNA-seq数据中预测多类疾病。
IF 6.5 2区 医学
Molecular Therapy. Nucleic Acids Pub Date : 2026-05-19 eCollection Date: 2026-06-16 DOI: 10.1016/j.omtn.2026.102956
Yichen Guo, Fengyuan Yang, Xuelu Zhang, Zhaoyu Zhai, Jianbo Pan
{"title":"BRPtools: An AutoML-Powered web platform for multiclass disease prediction from bulk blood RNA-seq data.","authors":"Yichen Guo, Fengyuan Yang, Xuelu Zhang, Zhaoyu Zhai, Jianbo Pan","doi":"10.1016/j.omtn.2026.102956","DOIUrl":"10.1016/j.omtn.2026.102956","url":null,"abstract":"<p><p>Blood-based transcriptomic profiling provides a minimally invasive approach for disease diagnosis; however, the integration of large-scale, heterogeneous RNA sequencing (RNA-seq) datasets remains challenging. Here, we manually curated and uniformly reprocessed 134 publicly available human RNA-seq datasets (<i>n</i> = 9,872 samples), covering 88 distinct blood-related diseases from whole blood and peripheral blood mononuclear cell data. To enable robust and scalable multiclass prediction, we employed AutoGluon, an ensemble-based AutoML framework that automates model selection and hyperparameter tuning through multilayer stacking. Our models achieved high accuracy across most disease categories (>90%), demonstrating strong generalizability. To support biological interpretation, we also performed differential expression and pathway enrichment analyses, revealing disease-associated signatures enriched in relevant Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways. We implemented these capabilities in BRPtools, a web-based platform featuring two modules: (1) a search module for exploring gene- and disease-level expression profiles and (2) a predict module for disease classification using user-uploaded RNA-seq count matrices. The platform supports diagnostic inference and validation and is designed to be accessible to users without programming experience. BRPtools offers an integrated, interpretable, and user-friendly solution for transcriptome-based disease prediction, supporting applications in biomarker discovery, digital diagnostics, and precision medicine.</p>","PeriodicalId":18821,"journal":{"name":"Molecular Therapy. Nucleic Acids","volume":"37 2","pages":"102956"},"PeriodicalIF":6.5,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13254884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148252191","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
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