Molecular Therapy最新文献_第7页

Systematic empirical evaluation of individual base editing targets: Validating therapeutic targets in USH2A and comparison of methods. 个体碱基编辑靶点的系统经验评价：验证USH2A治疗靶点及方法比较。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-01-28 DOI: 10.1016/j.ymthe.2025.01.042

Yuki Tachida, Kannan V Manian, Rossano Butcher, Jonathan M Levy, Nachiket Pendse, Erin Hennessey, David R Liu, Eric A Pierce, Qin Liu, Jason Comander

{"title":"Systematic empirical evaluation of individual base editing targets: Validating therapeutic targets in USH2A and comparison of methods.","authors":"Yuki Tachida, Kannan V Manian, Rossano Butcher, Jonathan M Levy, Nachiket Pendse, Erin Hennessey, David R Liu, Eric A Pierce, Qin Liu, Jason Comander","doi":"10.1016/j.ymthe.2025.01.042","DOIUrl":"10.1016/j.ymthe.2025.01.042","url":null,"abstract":"Base editing shows promise for the correction of human mutations at a higher efficiency than other repair methods and is especially attractive for mutations in large genes that are not amenable to gene augmentation therapy. Here, we demonstrate a comprehensive workflow for in vitro screening of potential therapeutic base editing targets for the USH2A gene and empirically validate the efficiency of adenine and cytosine base editor/guide combinations for correcting 35 USH2A mutations. Editing efficiency and bystander edits are compared between different target templates (plasmids vs. transgenes) and assays (next-generation sequencing vs. Sanger), as well as comparisons between unbiased empirical results and computational predictions. Based on these observations, practical assay recommendations are discussed. Finally, a humanized knockin mouse model was created with the best-performing target, the nonsense mutation c.11864G>A p.(Trp3955∗). Split-intein AAV9 delivery of editing reagents resulted in the restoration of USH2A protein and a correction rate of 65% ± 3% at the mutant base pair and of 52% ± 3% excluding bystander amino acid changes. This efficiency is higher than that seen in a retinal gene editing program testing in a clinical trial. These results demonstrate the effectiveness of this overall strategy to identify and test base editing reagents with the potential for human therapeutic applications.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1466-1484"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Four Decades of Adenovirus Gene Transfer Vectors: History and Current Use. 腺病毒基因转移载体的四十年：历史和当前使用情况。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.062

Neil R Hackett, Ronald G Crystal

引用次数: 0

The deubiquitinase USP28 maintains the expression of PPARγ and its inactivation protects mice from diet-induced MASH and hepatocarcinoma. 去泛素酶USP28维持PPARγ的表达，其失活保护小鼠免受饮食诱导的MASH和肝癌。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-03 DOI: 10.1016/j.ymthe.2025.01.046

Changzhou Cai, Hangqi Luo, Jin Peng, Xinghua Zhen, Xiang Shen, Xiaomei Xi, Jianrong Zhu, Yanfei Fang, Xiaoli Chen, Jiewei Wang, Chaohui Yu, Pumin Zhang, Chengfu Xu

{"title":"The deubiquitinase USP28 maintains the expression of PPARγ and its inactivation protects mice from diet-induced MASH and hepatocarcinoma.","authors":"Changzhou Cai, Hangqi Luo, Jin Peng, Xinghua Zhen, Xiang Shen, Xiaomei Xi, Jianrong Zhu, Yanfei Fang, Xiaoli Chen, Jiewei Wang, Chaohui Yu, Pumin Zhang, Chengfu Xu","doi":"10.1016/j.ymthe.2025.01.046","DOIUrl":"10.1016/j.ymthe.2025.01.046","url":null,"abstract":"Metabolic dysfunction-associated steatohepatitis (MASH), a progressive form of metabolic dysfunction-associated fatty liver disease (MAFLD), is a leading cause of liver disease worldwide and can progress to cirrhosis and cancer. Despite its prevalence, the pathogenesis of MASH remains poorly understood, and there is only one U.S. Food and Drug Administration-approved treatment, highlighting the need for new therapeutic strategies. Peroxisome proliferator-activated receptor (PPAR)γ is activated in the liver under high-fat or obese conditions, promoting lipid storage and contributing to MASH progression. We found that USP28 expression is elevated in the livers of MAFLD/MASH patients. Through dietary induction, including a methionine-choline deficient (MCD) diet and a western diet (WD) combined with carbon tetrachloride (CCl4) injections, we established two severe mouse models of MASH to explore the role of USP28. Mechanistically, the hepatic deubiquitinase (DUB) USP28 directly binds to PPARγ, preventing its ubiquitination and subsequent degradation, thereby maintaining the integrity of the PPARγ signaling pathway. In the absence of Usp28 or if the DUB is inhibited, PPARγ is downregulated, and the PPAR signaling pathway is inhibited, enhancing cellular defenses against excess fat. Both genetic and pharmacological inactivation of Usp28 significantly reduced MASH severity induced by the MCD diet or WD-CCl4 regimen, as well as WD-CCl4-induced hepatocellular carcinoma in mice.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1825-1841"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143190046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience. s-KL治疗对野生型小鼠的长期影响：延长寿命、身体健康和神经恢复力。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-22 DOI: 10.1016/j.ymthe.2025.02.030

Joan Roig-Soriano, Ángel Edo, Sergi Verdés, Carlos Martín-Alonso, Cristina Sánchez-de-Diego, Laura Rodriguez-Estevez, Antonio L Serrano, Carmela R Abraham, Assumpció Bosch, Francesc Ventura, Bryen A Jordan, Pura Muñoz-Cánoves, Miguel Chillón

{"title":"Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience.","authors":"Joan Roig-Soriano, Ángel Edo, Sergi Verdés, Carlos Martín-Alonso, Cristina Sánchez-de-Diego, Laura Rodriguez-Estevez, Antonio L Serrano, Carmela R Abraham, Assumpció Bosch, Francesc Ventura, Bryen A Jordan, Pura Muñoz-Cánoves, Miguel Chillón","doi":"10.1016/j.ymthe.2025.02.030","DOIUrl":"10.1016/j.ymthe.2025.02.030","url":null,"abstract":"Aging is a major risk factor for pathologies including sarcopenia, osteoporosis, and cognitive decline, which bring suffering, disability, and elevated economic and social costs. Therefore, new therapies are needed to achieve healthy aging. The protein Klotho (KL) has emerged as a promising anti-aging molecule due to its pleiotropic actions modulating insulin, insulin-like growth factor-1, and Wnt signaling pathways and reducing inflammatory and oxidative stress. Here, we explored the anti-aging potential of the secreted isoform of this protein on the non-pathological aging progression of wild-type mice. The delivery of an adeno-associated virus serotype 9 (AAV9) coding for secreted KL (s-KL) efficiently increased the concentration of s-KL in serum, resulting in a 20% increase in lifespan. Notably, KL treatment improved physical fitness, related to a reduction in muscle fibrosis and an increase in muscular regenerative capacity. KL treatment also improved bone microstructural parameters associated with osteoporosis. Finally, s-KL-treated mice exhibited increased cellular markers of adult neurogenesis and immune response, with transcriptomic analysis revealing induced phagocytosis and immune cell activity in the aged hippocampus. These results show the potential of elevating s-KL expression to simultaneously reduce the age-associated degeneration in multiple organs, increasing both life and health span.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1449-1465"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

An engineered β-globin homology donor reveals insights into β-globin expression and betters HDR. 工程β-珠蛋白同源供体揭示了β-珠蛋白表达和更好的HDR。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-03-22 DOI: 10.1016/j.ymthe.2025.03.007

Mengna Chi, Punam Malik

引用次数: 0

A VSV-based oral rabies vaccine was sentineled by Peyer's patches and induced a timely and durable immune response. 以 VSV 为基础的狂犬病口服疫苗通过佩耶氏斑块发出哨音，并诱导出及时而持久的免疫反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-28 DOI: 10.1016/j.ymthe.2025.02.038

Shen Wang, Zhenshan Wang, Weiqi Wang, Hongyu Sun, Na Feng, Yongkun Zhao, Jianzhong Wang, Tiecheng Wang, Xianzhu Xia, Feihu Yan

{"title":"A VSV-based oral rabies vaccine was sentineled by Peyer's patches and induced a timely and durable immune response.","authors":"Shen Wang, Zhenshan Wang, Weiqi Wang, Hongyu Sun, Na Feng, Yongkun Zhao, Jianzhong Wang, Tiecheng Wang, Xianzhu Xia, Feihu Yan","doi":"10.1016/j.ymthe.2025.02.038","DOIUrl":"10.1016/j.ymthe.2025.02.038","url":null,"abstract":"The global eradication of canine-mediated human rabies remains an ongoing public health priority. While conventional oral rabies vaccines (ORVs) have demonstrated partial success in interrupting zoonotic transmission, current formulations necessitate improvements in both immunogenic profiles and mechanistic clarity. Herein, we present a recombinant vesicular stomatitis virus (VSV)-vectored vaccine candidate (rVSVΔG-ERA-G) engineered to express the glycoprotein of the rabies virus (RABV) ERA strain, substituting the native VSV glycoprotein. Preclinical evaluation across multiple mammalian species (Mus musculus, Canis lupus familiaris, Felis catus, Vulpes lagopus, and Nyctereutes procyonoides) revealed rapid seroconversion and sustained neutralizing antibody responses. Challenge experiments demonstrated 100% survival efficacy in pre-exposure prophylaxis models, with partial protection observed in post-exposure scenarios. Safety assessments confirmed significant attenuation of neurotropism and absence of horizontal transmission or environmental shedding. Furthermore, evidence showed that rVSVΔG-ERA-G is recognized by Peyer's patches (PPs), where a cascade activation of immune cells occurred. From another perspective, the absence of functional microfold cells in PPs hampered the initiation and progression of immune responses. This proof-of-concept study establishes rVSVΔG-ERA-G as an ORV candidate with enhanced biosafety and cross-species immunogenicity. The elucidation of M cell-dependent mucosal priming mechanisms provides a rational framework for optimizing the targeted delivery of ORVs.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1701-1719"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

D-STAR: The Gemini Guardians redefining dual-targeting of immune cell therapy. D-STAR：双子守护者重新定义免疫细胞治疗的双重靶向。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-03-19 DOI: 10.1016/j.ymthe.2025.03.011

Yuwei Huang, Haopeng Wang

引用次数: 0

Converting TCR-based chimeric antigen receptor STAR into dual-specific targeting receptor for cancer immunotherapy. 将基于tcr的嵌合抗原受体STAR转化为肿瘤免疫治疗的双特异性靶向受体。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-05 DOI: 10.1016/j.ymthe.2025.02.001

Li Yu, Zhixiao Zhou, Hanyang Yu, Yue Liu, Daosheng Huang, Jiasheng Wang, Xin Lin

引用次数: 0

Overcoming immunotherapy resistance in hepatocellular carcinoma by targeting myeloid IL-8/CXCR2 signaling. 靶向髓细胞IL-8/ CXCR2信号通路克服肝癌免疫治疗耐药

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 Epub Date: 2025-02-05 DOI: 10.1016/j.ymthe.2025.02.002

Tsz Tung Kwong, Zhewen Xiong, Yiling Zhang, Haoran Wu, Jianquan Cao, Patrick Pak-Chun Wong, Xiaoyu Liu, Jing Wang, Chi Hang Wong, Gary Man-Kit Tse, Joseph Jao-Yiu Sung, Jingying Zhou, Alfred Sze-Lok Cheng, Stephen Lam Chan

{"title":"Overcoming immunotherapy resistance in hepatocellular carcinoma by targeting myeloid IL-8/CXCR2 signaling.","authors":"Tsz Tung Kwong, Zhewen Xiong, Yiling Zhang, Haoran Wu, Jianquan Cao, Patrick Pak-Chun Wong, Xiaoyu Liu, Jing Wang, Chi Hang Wong, Gary Man-Kit Tse, Joseph Jao-Yiu Sung, Jingying Zhou, Alfred Sze-Lok Cheng, Stephen Lam Chan","doi":"10.1016/j.ymthe.2025.02.002","DOIUrl":"10.1016/j.ymthe.2025.02.002","url":null,"abstract":"Durable responses to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) are limited to a minority of patients, yet reliable biomarkers are still lacking. Inflammatory cytokines such as interleukin-8 (IL-8) are associated with HCC progression, and IL-8 is known as the chemoattractant for immunosuppressive myeloid cells. Therefore, we aim to elucidate the ICB resistance mechanisms mediated by the activation of the IL-8/CXCR2 pathway. Single-cell RNA sequencing (scRNA-seq) was performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a phase 2 clinical trial cohort. Our data revealed that IL-8 and its receptor, CXCR2, mainly derived from immunosuppressive myeloid-derived suppressor cells (MDSCs). In particular, the high circulating IL-8 level was strongly associated with poor ICB response. This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist. Suppression of the IL-8/CXCR2 pathway significantly abrogated MDSC trafficking and immunosuppressive activity, which sensitized the anti-PD-L1 blockade to reduce tumor growth and prolong survival. The association between myeloid IL-8 and ICB therapeutic outcomes also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response but it also provides a proof of concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"1659-1673"},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 road towards AAV-mediated gene therapy of Duchenne muscular dystrophy. aav介导的杜氏肌营养不良症基因治疗之路。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.065

Niclas E Bengtsson, Hichem Tasfaout, Jeffrey S Chamberlain

{"title":"The road towards AAV-mediated gene therapy of Duchenne muscular dystrophy.","authors":"Niclas E Bengtsson, Hichem Tasfaout, Jeffrey S Chamberlain","doi":"10.1016/j.ymthe.2025.03.065","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.03.065","url":null,"abstract":"Forty years after the dystrophin gene was cloned, significant progress has been made in developing gene therapy approaches for Duchenne muscular dystrophy (DMD). The disorder has presented numerous challenges, including the enormous size of the gene (2.2 MB), the need to target muscles body wide, and immunogenic issues against both vectors and dystrophin. Among human genetic disorders, DMD is relatively common and the genetics are complicated since one-third of all cases arise from a spontaneous new mutation, resulting in thousands of independent lesions throughout the locus. Many approaches have been pursued in the goal of finding an effective therapy, including exon skipping, nonsense codon suppression, upregulation of surrogate genes, gene replacement and gene editing. Here we focus specifically on methods using AAV vectors, as these approaches have been tested in numerous clinical trials and are able to target muscles systemically. We discuss early advances to understand the structure of dystrophin, which are crucial for design of effective DMD gene therapies. Included is a summary of efforts to deliver micro-, mini- and full-length dystrophins to muscles. Finally, we also review current approaches to adapt gene editing to the enormous DMD gene with prospects for improved therapies using all these methods.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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