Molecular Therapy最新文献_第6页

Host RNA N⁶-methyladenosine and incoming DNA N⁶-methyldeoxyadenosine modifications cooperatively elevate the condensation potential of DNA to activate immune surveillance. 宿主 RNA 的 N6-甲基腺苷和传入 DNA 的 N6-甲基脱氧腺苷修饰共同提高了 DNA 的缩合潜力，从而激活了免疫监视。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.027

Na Wang, Qiaoling Liu, Bo Wang, Zhuo Yang, Siru Li, Ran Li, Xinyuan Liang, Jiayu Fan, Hui Wang, Zhen Sun, Ling Dong, Yueru Hou, Shengnan Wang, Chengli Song, Yang Wang, Chunshan Quan, Qingkai Yang, Lina Wang

{"title":"Host RNA N6-methyladenosine and incoming DNA N6-methyldeoxyadenosine modifications cooperatively elevate the condensation potential of DNA to activate immune surveillance.","authors":"Na Wang, Qiaoling Liu, Bo Wang, Zhuo Yang, Siru Li, Ran Li, Xinyuan Liang, Jiayu Fan, Hui Wang, Zhen Sun, Ling Dong, Yueru Hou, Shengnan Wang, Chengli Song, Yang Wang, Chunshan Quan, Qingkai Yang, Lina Wang","doi":"10.1016/j.ymthe.2024.10.027","DOIUrl":"10.1016/j.ymthe.2024.10.027","url":null,"abstract":"Self-non-self discrimination is fundamental to life, thereby even microbes can apply DNA modifications to recognize non-self DNA. However, mammalian cytosolic DNA sensors indiscriminately bind DNA, necessitating specific mechanism(s) for self-non-self discrimination. Here, we show that mammalian RNA N6-methyladenosine (m6A) and incoming DNA N6-methyldeoxyadenosine (6mdA) cooperatively elevate the condensation potential of DNA to activate immunosurveillance. RNA m6A modification was found to enhance the activation of cyclic guanosine monophosphate-AMP synthase (cGAS) via increasing DNA phase separation. And 6mdA further increased the phase separation potential of DNA. Consistently, host RNA m6A and incoming DNA 6mdA modifications cooperatively elevated the incoming DNA condensation and cGAS activation. Moreover, we developed a prodrug, QKY-613. QKY-613 promoted a discriminative incorporation of 6mdA into viral DNAs to elevate host immune surveillance, and decreased mortality in virus-infected aged mice. Our results link nucleic acid modification diversity with immune surveillance via phase separation, which might be targeted for therapeutic intervention.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4418-4434"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

AAVrh.10 delivery of novel APOE2-Christchurch variant suppresses amyloid and Tau pathology in Alzheimer's disease mice. AAVrh.10输送新型APOE2-Christchurch变体可抑制阿尔茨海默病小鼠的淀粉样蛋白和Tau病理学。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-06 DOI: 10.1016/j.ymthe.2024.11.003

Caner Günaydin, Dolan Sondhi, Stephen M Kaminsky, Hailey C Lephart, Philip L Leopold, Neil R Hackett, Richie Khanna, Ronald G Crystal

{"title":"AAVrh.10 delivery of novel APOE2-Christchurch variant suppresses amyloid and Tau pathology in Alzheimer's disease mice.","authors":"Caner Günaydin, Dolan Sondhi, Stephen M Kaminsky, Hailey C Lephart, Philip L Leopold, Neil R Hackett, Richie Khanna, Ronald G Crystal","doi":"10.1016/j.ymthe.2024.11.003","DOIUrl":"10.1016/j.ymthe.2024.11.003","url":null,"abstract":"Gene therapy to treat hereditary disorders conventionally delivers the normal allele to compensate for loss-of-function mutations. More effective gene therapy may be achieved using a gain-of-function variant. We tested the hypothesis that AAVrh.10-mediated CNS delivery of the human APOE2 allele with the Christchurch mutation (R136S) (E2Ch) will provide superior protection against APOE4-associated Alzheimer's disease (AD) in mice compared to the unmodified APOE2 allele (E2). The vectors were assessed in two mouse strains with humanized APOE4: APP.PSEN1/TRE4 \"amyloid mice\" and P301S/TRE4, \"tau mice.\" Both the E2Ch and E2 vectors prevented Aβ42 and Aβ40 accumulation and decreased β-amyloid aggregates in amyloid mice, but only the E2Ch vector suppressed tau tangles in tau mice. Microglial activation and reactive astrocytes were significantly suppressed by both vectors in amyloid mice but only the E2Ch vector mediated significant suppression of Iba1 and glial fibrillary acidic protein (GFAP) in tau mice. In four behavioral assays, the E2 and E2Ch vectors had similar benefits in amyloid mice, but E2Ch outperformed E2 in tau mice. In summary, while E2 is effective in suppressing amyloid pathology, the novel E2 variant E2Ch more effectively treats both the amyloid and tau pathology of murine AD in APOE4 background, supporting the development of AAVrh.10APOE2Ch as a therapy for APOE4-associated AD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4303-4318"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Engineered extracellular vesicles for combinatorial TNBC therapy: SR-SIM-guided design achieves substantial drug dosage reduction. 用于 TNBC 组合疗法的工程细胞外囊泡：SR-SIM引导的设计实现了药物剂量的大幅降低

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-05 DOI: 10.1016/j.ymthe.2024.09.034

Abhjeet S Bhullar, Kai Jin, Haizhu Shi, Austen Jones, Dalton Hironaka, Gaofeng Xiong, Ren Xu, Peixuan Guo, Daniel W Binzel, Dan Shu

{"title":"Engineered extracellular vesicles for combinatorial TNBC therapy: SR-SIM-guided design achieves substantial drug dosage reduction.","authors":"Abhjeet S Bhullar, Kai Jin, Haizhu Shi, Austen Jones, Dalton Hironaka, Gaofeng Xiong, Ren Xu, Peixuan Guo, Daniel W Binzel, Dan Shu","doi":"10.1016/j.ymthe.2024.09.034","DOIUrl":"10.1016/j.ymthe.2024.09.034","url":null,"abstract":"Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles (EVs) serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, EVs were engineered with RNA nanotechnology to develop TNBC tumor inhibitors. Using super resolved-structured illumination microscopy, EVs were optimized for precise Survivin small interfering RNA (siRNA) conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity toward TNBC cells. Conventional treatments typically employ chemotherapy drugs gemcitabine (GEM) and paclitaxel (PTX) at dosages on the order of mg/kg respectively, per injection (intravenous) in mice. In contrast, engineered EVs encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 μg/kg for GEM or 5.6 μg/kg for PTX, in combination with 21.5 μg/kg survivin-siRNA in mice. The result is a substantial decrease in the chemotherapeutic dose required, by orders of magnitude, compared with standard regimens. In vivo and in vitro evaluations in a TNBC orthotopic xenograft mouse model demonstrated the efficacy of this decreased dosage strategy, indicating the potential for decreased chemotherapy-associated toxicity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4467-4481"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice. 通过体内碱基编辑将 G-Makassar 变体引入造血干细胞，治疗小鼠镰状细胞病。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.018

Chang Li, Aphrodite Georgakopoulou, Kiriaki Paschoudi, Anna K Anderson, Lishan Huang, Sucheol Gil, Maria Giannaki, Efthymia Vlachaki, Gregory A Newby, David R Liu, Evangelia Yannaki, Hans-Peter Kiem, André Lieber

{"title":"Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.","authors":"Chang Li, Aphrodite Georgakopoulou, Kiriaki Paschoudi, Anna K Anderson, Lishan Huang, Sucheol Gil, Maria Giannaki, Efthymia Vlachaki, Gregory A Newby, David R Liu, Evangelia Yannaki, Hans-Peter Kiem, André Lieber","doi":"10.1016/j.ymthe.2024.10.018","DOIUrl":"10.1016/j.ymthe.2024.10.018","url":null,"abstract":"Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements in the derived red blood cells. After ex vivo transduction of HSCs from an SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without any noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires a single non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach holds potential for scalable applications in resource-limiting regions where SCD is prevalent.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4353-4371"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Nucleic acid modifications in self-nonself discrimination. 自我非我辨别中的核酸修饰

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.008

Qian Jing, Yang Meng, Junhong Han

引用次数: 0

Second gene therapy for hemophilia B approved: More answers or questions?

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-29 DOI: 10.1016/j.ymthe.2024.11.026

Radoslaw Kaczmarek, Glenn F Pierce

引用次数: 0

When promising therapies are out of reach: Ethical responsibilities of stakeholders in gene therapy trials for rare disorders.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-27 DOI: 10.1016/j.ymthe.2024.11.019

Rami M Major, Zollie Yavarow

引用次数: 0

Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-27 DOI: 10.1016/j.ymthe.2024.11.031

Yanhong Jiang, Shuanghong Chen, Shenlin Hsiao, Haokun Zhang, Da Xie, Zi Jun Wang, Wendan Ren, Mingyao Liu, Jiaoyang Liao, Yuxuan Wu

引用次数: 0

Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9. 将工程细胞外囊泡作为溶酶体降解 PCSK9 的纳米海绵。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-26 DOI: 10.1016/j.ymthe.2024.11.034

Chen Wang, Xueying Zhou, Te Bu, Shuang Liang, Zhenzhen Hao, Mi Qu, Yang Liu, Mengying Wei, Changyang Xing, Guodong Yang, Lijun Yuan

{"title":"Engineered extracellular vesicles as nanosponges for lysosomal degradation of PCSK9.","authors":"Chen Wang, Xueying Zhou, Te Bu, Shuang Liang, Zhenzhen Hao, Mi Qu, Yang Liu, Mengying Wei, Changyang Xing, Guodong Yang, Lijun Yuan","doi":"10.1016/j.ymthe.2024.11.034","DOIUrl":"10.1016/j.ymthe.2024.11.034","url":null,"abstract":"Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the degradation of the low-density lipoprotein receptor (LDLR), and PCSK9 inhibition emerges as an attractive strategy for atherosclerosis management. In this study, extracellular vesicles (EVs) were engineered to nanosponges, which could efficiently adsorb and deliver PCSK9 into lysosomes for degradation. Briefly, nanosponges were engineered by modifying EVs with EGF-A/PTGFRN fusion protein (PCSK9 binding domain EGF-A from the mutant LDLR with higher affinity was fused to the C terminus of prostaglandin F2 receptor negative regulator). The modification endowed the EVs with hundreds of EGF-As displayed on the surface, and thus the capacity to adsorb PCSK9 efficiently. The adsorbed PCSK9 would thus be delivered into lysosomes for degradation when the nanosponges were endocytosed by liver cells, thus releasing endogenous LDLR from degradation. In the ApoE-/- mouse model, tail vein-injected nanosponges were able to degrade PCSK9, increase LDLR expression, lower the LDL-C level, and thus alleviate atherosclerosis. In summary, here we not only develop a novel strategy for PCSK9 inhibition but we also propose a universal method for adsorption and degradation of circulating proteins for disease management.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739992","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

Amelioration of metabolic and behavioral defects through base editing in the Pah^R408W phenylketonuria mouse model. 通过碱基编辑改善 PahR408W 苯丙酮尿症小鼠模型的代谢和行为缺陷。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-26 DOI: 10.1016/j.ymthe.2024.11.032

Shuming Yin, Liangcai Gao, Xiaoyue Sun, Mei Zhang, Hongyi Gao, Xiaoqing Chen, Dan Zhang, Xinyu Ming, Lei Yang, Yaqiang Hu, Xi Chen, Meizhen Liu, Xia Zhan, Yuting Guan, Liren Wang, Lianshu Han, Ping Zhu, Dali Li

{"title":"Amelioration of metabolic and behavioral defects through base editing in the PahR408W phenylketonuria mouse model.","authors":"Shuming Yin, Liangcai Gao, Xiaoyue Sun, Mei Zhang, Hongyi Gao, Xiaoqing Chen, Dan Zhang, Xinyu Ming, Lei Yang, Yaqiang Hu, Xi Chen, Meizhen Liu, Xia Zhan, Yuting Guan, Liren Wang, Lianshu Han, Ping Zhu, Dali Li","doi":"10.1016/j.ymthe.2024.11.032","DOIUrl":"10.1016/j.ymthe.2024.11.032","url":null,"abstract":"Phenylketonuria (PKU) is a liver metabolic disorder mainly caused by a deficiency of the hepatic phenylalanine hydroxylase (PAH) enzyme activity, often leading to severe brain function impairment in patients if untreated or if treatment is delayed. In this study, we utilized dual-AAV8 vectors to deliver a near PAM-less adenine base editor variant, known as ABE8e-SpRY, to treat the PahR408W PKU mouse model carrying a frequent R408W mutation in the Pah gene. Our findings revealed that a single intravenous injection in adult mice and a single intraperitoneal injection in neonatal mice resulted in 19.1%-34.6% A-to-G editing efficiency at the pathogenic mutation site with minimal bystander edits. Furthermore, the dual-AAV8-treated mice exhibited reduced blood Phe levels to below the therapeutic threshold of 360 μmol L-1 and restored weight and fur color to normal levels. Importantly, the brain function of the mice was restored after the treatment, particularly when administered during the neonatal stage, as levels of monoamine neurotransmitters and metabolites in the brain returned to normal and near-normal levels. Our study demonstrated that ABE8e-SpRY-based base editing could effectively correct the point mutation in the PahR408W PKU mouse model, indicating potential clinical applications for PKU and other genetic diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730716","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