Nature biotechnology最新文献_第10页

Base editors model mitochondrial disease 碱基编辑器模拟线粒体疾病

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-03 DOI: 10.1038/s41587-025-02706-9

Patrick Buchholz, Jens Boch

引用次数: 0

A mitochondrial disease model is generated and corrected using engineered base editors in rat zygotes 在大鼠受精卵中使用工程碱基编辑器生成和纠正线粒体疾病模型

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-03 DOI: 10.1038/s41587-025-02684-y

Liang Chen, Changming Luan, Mengjia Hong, Meng Yuan, Hao Huang, Debo Gao, Xinyuan Guo, Zhengxin Chen, Yongmei Li, Lei Yang, Zongyi Yi, Wensheng Wei, Mingyao Liu, Liangcai Gao, Honghui Han, Dali Li

引用次数: 0

Resurrecting a miniature Cas9 ancestor for genome and epigenome editing 复活一个微型Cas9祖先用于基因组和表观基因组编辑

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-03 DOI: 10.1038/s41587-025-02707-8

Gabriel L. Butterfield, Charles A. Gersbach

引用次数: 0

Efficient mitochondrial A-to-G base editors for the generation of mitochondrial disease models 高效线粒体A-to-G碱基编辑器生成线粒体疾病模型

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-03 DOI: 10.1038/s41587-025-02685-x

Liang Chen, Mengjia Hong, Changming Luan, Meng Yuan, Yiming Wang, Xinyuan Guo, Yue Fang, Hao Huang, Xiaohua Dong, Hongyi Gao, Dan Zhang, Xi Chen, Dihao Meng, Molin Huang, Zongyi Yi, Mingyao Liu, Wensheng Wei, Liangcai Gao, Gaojie Song, Xiaoming Zhou, Dali Li

{"title":"Efficient mitochondrial A-to-G base editors for the generation of mitochondrial disease models","authors":"Liang Chen, Mengjia Hong, Changming Luan, Meng Yuan, Yiming Wang, Xinyuan Guo, Yue Fang, Hao Huang, Xiaohua Dong, Hongyi Gao, Dan Zhang, Xi Chen, Dihao Meng, Molin Huang, Zongyi Yi, Mingyao Liu, Wensheng Wei, Liangcai Gao, Gaojie Song, Xiaoming Zhou, Dali Li","doi":"10.1038/s41587-025-02685-x","DOIUrl":"https://doi.org/10.1038/s41587-025-02685-x","url":null,"abstract":"Existing A-to-G base editors for mitochondrial DNA (mtDNA) are limited by low efficiency. We used directed evolution to discover variants of the TadA-8e base editors that have substantially increased activity and expanded targeting compatibility for both nuclear and mitochondrial adenine base editing, especially in previously unfavored sequence contexts. The engineered mtDNA editors (eTd-mtABEs) showed up to 87% editing efficiency in human cells, with greatly reduced DNA and RNA off-target effects. Strand-selective A-to-G editing was enhanced by an average of 3.2-fold with substitution of DddA to DNA nickases in eTd-mtABE backbones compared to mitochondrial ABEs. In rat cells, editing efficiencies of eTd-mtABEs were up to 145-fold higher compared to split DddA transcription activator-like effector-linked deaminase. We also generated rats with sensorineural hearing loss by installing targeted mutations with frequencies of up to 44% through embryonic injection. The developed eTd-mtABEs are efficient and precise mtDNA-engineering tools for basic research and translational studies.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"42 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Improving gene isoform quantification with miniQuant 用miniQuant改进基因异构体定量

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-03 DOI: 10.1038/s41587-025-02633-9

Haoran Li, Dingjie Wang, Qi Gao, Puwen Tan, Yunhao Wang, Xiaoyu Cai, Aifu Li, Yue Zhao, Andrew L. Thurman, Seyed Amir Malekpour, Ying Zhang, Roberta Sala, Andrea Cipriano, Chia-Lin Wei, Vittorio Sebastiano, Chi Song, Nancy R. Zhang, Kin Fai Au

{"title":"Improving gene isoform quantification with miniQuant","authors":"Haoran Li, Dingjie Wang, Qi Gao, Puwen Tan, Yunhao Wang, Xiaoyu Cai, Aifu Li, Yue Zhao, Andrew L. Thurman, Seyed Amir Malekpour, Ying Zhang, Roberta Sala, Andrea Cipriano, Chia-Lin Wei, Vittorio Sebastiano, Chi Song, Nancy R. Zhang, Kin Fai Au","doi":"10.1038/s41587-025-02633-9","DOIUrl":"https://doi.org/10.1038/s41587-025-02633-9","url":null,"abstract":"RNA sequencing has been widely applied for gene isoform quantification, but limitations exist in quantifying isoforms of complex genes accurately, especially for short reads. Here we identify genes that are difficult to quantify accurately with short reads and illustrate the information benefit of using long reads to quantify these regions. We present miniQuant, which ranks genes with quantification errors caused by the ambiguity of read alignments and integrates the complementary strengths of long reads and short reads with optimal combination in a gene- and data-specific manner to achieve more accurate quantification. These results are supported by rigorous mathematical proofs, validated with a wide range of simulation data, experimental validations and more than 17,000 public datasets from GTEx, TCGA and ENCODE consortia. We demonstrate miniQuant can uncover isoform switches during the differentiation of human embryonic stem cells to pharyngeal endoderm and primordial germ cell-like cells.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"99 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144201479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Powering new therapeutics with precision mitochondrial editing 通过精确的线粒体编辑为新疗法提供动力

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-03 DOI: 10.1038/s41587-025-02693-x

引用次数: 0

Merck’s anti-RSV antibody expands protection for infants 默克公司的抗rsv抗体扩大了对婴儿的保护

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-02 DOI: 10.1038/s41587-025-02713-w

引用次数: 0

Dual SORT LNPs for multi-organ base editing 用于多器官碱基编辑的双排序LNPs

IF 46.9 1区生物学

Nature biotechnology Pub Date : 2025-06-02 DOI: 10.1038/s41587-025-02675-z

Minjeong Kim, Eunice S. Song, Joseph C. Chen, Sumanta Chatterjee, Yehui Sun, Sang M. Lee, Shiying Wu, Priyanka Patel, Zeru Tian, Ariel Kantor, Brandon A. Wustman, David J. Lockhart, Daniel J. Siegwart

{"title":"Dual SORT LNPs for multi-organ base editing","authors":"Minjeong Kim, Eunice S. Song, Joseph C. Chen, Sumanta Chatterjee, Yehui Sun, Sang M. Lee, Shiying Wu, Priyanka Patel, Zeru Tian, Ariel Kantor, Brandon A. Wustman, David J. Lockhart, Daniel J. Siegwart","doi":"10.1038/s41587-025-02675-z","DOIUrl":"https://doi.org/10.1038/s41587-025-02675-z","url":null,"abstract":"Alpha-1 antitrypsin (A1AT) deficiency (AATD) is caused by a mutation in the SERPINA1 gene (PiZ allele), where misfolded A1AT liver accumulation leads to liver damage, and A1AT deficiency in the lungs results in emphysema due to unregulated neutrophil elastase activity. Base editing offers a potential cure for A1AT; however, effective treatment is hindered by the absence of dual-target delivery systems that can target key tissues. We developed Dual Selective ORgan-Targeting lipid nanoparticles (SORT LNPs) to deliver base editors to the liver and lungs. Dual SORT LNPs correct the PiZ mutation, achieving 40% correction editing in liver cells and 10% in lung AT2 cells. The liver maintains stable editing for 32 weeks, reducing Z-A1AT levels by over 80% and restoring a normal liver phenotype. In parallel, 89% neutrophil elastase inhibition is achieved in lung bronchoalveolar lavage fluid. Taken together, Dual SORT LNP therapy offers a promising approach for long-lasting genome correction for multi-organ diseases such as AATD.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":"25 1","pages":""},"PeriodicalIF":46.9,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants. 大规模发现染色质失调是由同源基因融合和其他蛋白质编码变异引起的。

IF 33.1 1区生物学

Nature biotechnology Pub Date : 2025-06-01 Epub Date: 2024-07-24 DOI: 10.1038/s41587-024-02347-4

Max Frenkel, James E Corban, Margaux L A Hujoel, Zachary Morris, Srivatsan Raman

{"title":"Large-scale discovery of chromatin dysregulation induced by oncofusions and other protein-coding variants.","authors":"Max Frenkel, James E Corban, Margaux L A Hujoel, Zachary Morris, Srivatsan Raman","doi":"10.1038/s41587-024-02347-4","DOIUrl":"10.1038/s41587-024-02347-4","url":null,"abstract":"Population-scale databases have expanded to millions of protein-coding variants, yet insight into their mechanistic consequences has lagged. Here we present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin regulation. A pooled variant library is expressed in a disease-agnostic cell line, and single-cell assay for transposase-accessible chromatin resolves each variant's effect on the chromatin landscape. Using PROD-ATAC, we characterized the effects of more than 100 oncofusions (cancer-causing chimeric proteins) and controls and revealed that chromatin remodeling is common to fusions spanning an enormous range of fusion frequencies. Furthermore, fusion-induced dysregulation can be context agnostic, as observed mechanisms often overlapped with cancer and cell-type-specific prior knowledge. We also showed that gain-of-function activity is common among oncofusions. This work begins to outline a global map of fusion-induced chromatin alterations. We suggest that there might be convergent mechanisms among disparate oncofusions and shared modes of dysregulation among fusions present in tumors at different frequencies. PROD-ATAC is generalizable to any set of protein-coding variants.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":"996-1010"},"PeriodicalIF":33.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141760014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancing siRNA efficacy in vivo with extended nucleic acid backbones. 利用扩展核酸骨架增强 siRNA 在体内的功效。

IF 33.1 1区生物学

Nature biotechnology Pub Date : 2025-06-01 Epub Date: 2024-08-01 DOI: 10.1038/s41587-024-02336-7

Ken Yamada, Vignesh N Hariharan, Jillian Caiazzi, Rachael Miller, Chantal M Ferguson, Ellen Sapp, Hassan H Fakih, Qi Tang, Nozomi Yamada, Raymond C Furgal, Joseph D Paquette, Annabelle Biscans, Brianna M Bramato, Nicholas McHugh, Ashley Summers, Clemens Lochmann, Bruno M D C Godinho, Samuel Hildebrand, Samuel O Jackson, Dimas Echeverria, Matthew R Hassler, Julia F Alterman, Marian DiFiglia, Neil Aronin, Anastasia Khvorova

{"title":"Enhancing siRNA efficacy in vivo with extended nucleic acid backbones.","authors":"Ken Yamada, Vignesh N Hariharan, Jillian Caiazzi, Rachael Miller, Chantal M Ferguson, Ellen Sapp, Hassan H Fakih, Qi Tang, Nozomi Yamada, Raymond C Furgal, Joseph D Paquette, Annabelle Biscans, Brianna M Bramato, Nicholas McHugh, Ashley Summers, Clemens Lochmann, Bruno M D C Godinho, Samuel Hildebrand, Samuel O Jackson, Dimas Echeverria, Matthew R Hassler, Julia F Alterman, Marian DiFiglia, Neil Aronin, Anastasia Khvorova","doi":"10.1038/s41587-024-02336-7","DOIUrl":"10.1038/s41587-024-02336-7","url":null,"abstract":"Therapeutic small interfering RNA (siRNA) requires sugar and backbone modifications to inhibit nuclease degradation. However, metabolic stabilization by phosphorothioate (PS), the only backbone chemistry used clinically, may be insufficient for targeting extrahepatic tissues. To improve oligonucleotide stabilization, we report the discovery, synthesis and characterization of extended nucleic acid (exNA) consisting of a methylene insertion between the 5'-C and 5'-OH of a nucleoside. exNA incorporation is compatible with common oligonucleotide synthetic protocols and the PS backbone, provides stabilization against 3' and 5' exonucleases and is tolerated at multiple oligonucleotide positions. A combined exNA-PS backbone enhances resistance to 3' exonuclease by ~32-fold over the conventional PS backbone and by >1,000-fold over the natural phosphodiester backbone, improving tissue exposure, tissue accumulation and efficacy in mice, both systemically and in the brain. The improved efficacy and durability imparted by exNA may enable therapeutic interventions in extrahepatic tissues, both with siRNA and with other oligonucleotides such as CRISPR guide RNA, antisense oligonucleotides, mRNA and tRNA.","PeriodicalId":19084,"journal":{"name":"Nature biotechnology","volume":" ","pages":"904-913"},"PeriodicalIF":33.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0