Molecular Therapy最新文献_第5页

The past, present, and future of RNA vaccines. RNA疫苗的过去、现在和未来。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-02-19 DOI: 10.1016/j.ymthe.2025.02.016

John S Tregoning, Niek N Sanders

引用次数: 0

ABI and generative biology: A new paradigm for gene therapy, genome engineering, and engineered cell therapy. ABI 和生成生物学：基因治疗、基因组工程和工程细胞疗法的新范例。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-21 DOI: 10.1016/j.ymthe.2025.02.021

Adrian Woolfson

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 : 2025-05-07 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.062

Neil R Hackett, Ronald G Crystal

引用次数: 0

The road toward 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 : 2025-05-07 Epub Date: 2025-04-02 DOI: 10.1016/j.ymthe.2025.03.065

Niclas E Bengtsson, Hichem Tasfaout, Jeffrey S Chamberlain

{"title":"The road toward 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":"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 the design of effective DMD gene therapies. Included is a summary of efforts to deliver micro-, mini-, and full-length dystrophins to muscles. Finally, we 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":"2035-2051"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","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

A synthetic opsin restores vision in patients with severe retinal degeneration. 一种人工合成的视蛋白能恢复严重视网膜变性患者的视力。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-05-07 Epub Date: 2025-03-21 DOI: 10.1016/j.ymthe.2025.03.031

Samarendra K Mohanty, Santosh Mahapatra, Subrata Batabyal, Michael Carlson, Gayatri Kanungo, Ananta Ayyagari, Kissaou Tchedre, Joel A Franco, Michael Singer, Samuel B Barone, Sai Chavala, Vinit B Mahajan

{"title":"A synthetic opsin restores vision in patients with severe retinal degeneration.","authors":"Samarendra K Mohanty, Santosh Mahapatra, Subrata Batabyal, Michael Carlson, Gayatri Kanungo, Ananta Ayyagari, Kissaou Tchedre, Joel A Franco, Michael Singer, Samuel B Barone, Sai Chavala, Vinit B Mahajan","doi":"10.1016/j.ymthe.2025.03.031","DOIUrl":"10.1016/j.ymthe.2025.03.031","url":null,"abstract":"Inherited retinal degenerations are the leading cause of blindness worldwide, and, in advanced stages, cell loss makes gene replacement ineffective. Optogenetics offers a therapeutic opportunity to restore vision by photo-sensitizing remaining retinal neurons. However, current opsins are kinetically slow, partially activated in ambient light, unresponsive to different light colors, and target low-resolution retinal cell circuits. To overcome these limits, we engineered a synthopsin made of three selectively mutated non-mammalian proteins to achieve a broadband multi-characteristic opsin. The synthopsin was packaged into an optimized AAV2 gene-therapy vector that targets human retinal bipolar cells. In an investigator-initiated, open-label study, four blind retinitis pigmentosa patients with ABCA4 variants received a single intravitreal gene-therapy injection. Noninvasive imaging confirmed retinal gene expression via a fluorescent reporter protein. Patients showed improvement in vision, shape discrimination, and mobility through 52 weeks. There were no significant safety issues despite what is likely one of the most synthetic, non-mammalian proteins ever expressed in a human. This is the first report of a gene monotherapy that can restore vision in blind patients in a mutation-independent manner utilizing an optogenetics technology platform.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2279-2290"},"PeriodicalIF":12.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692708","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

Therapeutic mRNA vaccine applications in oncology. 治疗性mRNA疫苗在肿瘤学中的应用。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-06 DOI: 10.1016/j.ymthe.2025.04.044

Leighton Elliott,Timothy Foster,Paul Castillo,Hector Mendez-Gomez,Elias J Sayour

引用次数: 0

Understanding the Role of NOTCH2 Mutation in Centronuclear Myopathy. 了解NOTCH2突变在核中性肌病中的作用。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-06 DOI: 10.1016/j.ymthe.2025.04.041

Youxi Lin,Hang Zhou,Wenjun Hu,Bo Gao,Tongzhou Liang,Jincheng Qiu,Pengfei Li,Yichen Que,Chipiu Wong,Xianjian Qiu,Zhihuai Deng,Huihong Shi,Song Liu,Jianan Chen,Nianchun Liao,Qihui Chen,Xiaojuan Li,Anjing Liang,Wenjie Gao,Dongsheng Huang

{"title":"Understanding the Role of NOTCH2 Mutation in Centronuclear Myopathy.","authors":"Youxi Lin,Hang Zhou,Wenjun Hu,Bo Gao,Tongzhou Liang,Jincheng Qiu,Pengfei Li,Yichen Que,Chipiu Wong,Xianjian Qiu,Zhihuai Deng,Huihong Shi,Song Liu,Jianan Chen,Nianchun Liao,Qihui Chen,Xiaojuan Li,Anjing Liang,Wenjie Gao,Dongsheng Huang","doi":"10.1016/j.ymthe.2025.04.041","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.041","url":null,"abstract":"NOTCH2 is a widely expressed protein that plays a crucial role in the normal development and function of various tissues, including skeletal muscle. This study focused on a pedigree with centronuclear myopathy, primarily characterized by muscle weakness and centralized nuclei, and identified the autosomal recessive NOTCH2 I1689F mutation through whole exome sequencing. Using a homologous mutant mouse model, several defects were identified that elucidate the muscle phenotype. These defects include a reduction in Pax7 expressing, proliferating myoblasts and the functional consequences of this reduction. In vitro studies demonstrated that the Notch2 mutation impaired proliferation and causing premature differentiation of myogenic progenitor cells. Mechanistically, the Notch2 mutation resulted in decreased the production of the Notch2 intracellular domain from γ-secretase S3 cleavage, which affected the function of Pax7+ cells through the Notch2-Hey1-MyoD axis. Overall, our findings reveal impaired muscle regeneration in mice with the Notch2 mutation, contributing to the understanding of centronuclear myopathy by identifying a previously unreported gene and mutation site of NOTCH2.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"23 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921048","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

SARS-CoV-2 N protein induces hypokalemia in acute kidney injury mice via ENaC-dependent mechanism. sars - cov - 2n蛋白通过enact依赖机制诱导急性肾损伤小鼠低钾血症

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-06 DOI: 10.1016/j.ymthe.2025.04.043

Dan-Dan Zhang,Yang Liu,Wenbiao Wang,Wenjing Wu,Junzhe Chen,Lin Wan,Liumei Wu,Xiao-Ru Huang,Hui-Yao Lan,Xueqing Yu

{"title":"SARS-CoV-2 N protein induces hypokalemia in acute kidney injury mice via ENaC-dependent mechanism.","authors":"Dan-Dan Zhang,Yang Liu,Wenbiao Wang,Wenjing Wu,Junzhe Chen,Lin Wan,Liumei Wu,Xiao-Ru Huang,Hui-Yao Lan,Xueqing Yu","doi":"10.1016/j.ymthe.2025.04.043","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.043","url":null,"abstract":"Hypokalemia is a prevalent complication of COVID-19 patients with acute kidney injury (AKI), however, mechanisms have yet to be fully understood. By single-nucleus RNA sequencing, we found that COVID-19 patients with AKI were associated with a marked upregulation of the epithelial sodium channel (ENaC) in the renal tubular epithelial cells (TECs). By using a mouse model of AKI induced by kidney-specifically overexpressing SARS-CoV-2 N protein, we detected that overexpression of renal SARS-CoV-2 N protein could induce hypokalemia and AKI, which was associated with upregulation of ENaC, ROMK and BK proteins. Functionally, patch-clamp study revealed that overexpression of SARS-CoV-2 N protein largely increased the ENaC current in the TECs. Mechanically, we uncovered that kidney-specifically overexpressing SARS-CoV-2 N protein could activate ENaC to cause hypokalemia and AKI directly by binding to the ENaCα and ENaCγ subunits and indirectly by activating the p38 MAPK pathway. Importantly, treatment with an ENaC specific inhibitor could protect against SARS-CoV-2 N-induced hypokalemia and AKI, revealing a regulatory role and therapeutic target of ENaC in SARS-CoV-2 N-induced hypokalemia and AKI. In conclusion, hypokalemia in COVID-19 AKI is induced by SARS-CoV-2 N protein via the ENaC-dependent mechanism. Targeting ENaC may offer a novel therapy for COVID-19 patients with AKI.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"96 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921049","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

Current Clinical Applications of AAV-mediated Gene Therapy. aav介导基因治疗的临床应用现状。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-05 DOI: 10.1016/j.ymthe.2025.04.045

Barry J Byrne,Kevin M Flanigan,Susan E Matesanz,Richard S Finkel,Megan A Waldrop,Eleonora S D'Ambrosio,Nicholas E Johnson,Barbara K Smith,Carsten Bönnemann,Sean Carrig,Joseph W Rossano,Barry Greenberg,Laura Lalaguna,Enrique Lara-Pezzi,Sub Subramony,Manuela Corti,Claudia Mercado-Rodriguez,Carmen Leon-Astudillo,Rebecca Ahrens-Nicklas,Diana Bharucha-Goebel,Guangping Gao,Dominic J Gessler,Wuh-Liang Hwu,Yin-Hsiu Chien,Ni-Chung Lee,Sanford L Boye,Shannon E Boye,Lindsey A George

{"title":"Current Clinical Applications of AAV-mediated Gene Therapy.","authors":"Barry J Byrne,Kevin M Flanigan,Susan E Matesanz,Richard S Finkel,Megan A Waldrop,Eleonora S D'Ambrosio,Nicholas E Johnson,Barbara K Smith,Carsten Bönnemann,Sean Carrig,Joseph W Rossano,Barry Greenberg,Laura Lalaguna,Enrique Lara-Pezzi,Sub Subramony,Manuela Corti,Claudia Mercado-Rodriguez,Carmen Leon-Astudillo,Rebecca Ahrens-Nicklas,Diana Bharucha-Goebel,Guangping Gao,Dominic J Gessler,Wuh-Liang Hwu,Yin-Hsiu Chien,Ni-Chung Lee,Sanford L Boye,Shannon E Boye,Lindsey A George","doi":"10.1016/j.ymthe.2025.04.045","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.045","url":null,"abstract":"Currently, there are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population. Even among the 5% of patients with genetic disease that have treatment options, these therapeutics rarely address the underlying cause of disease but rather focus on managing or modifying symptoms and typically require recurrent, lifelong therapy. A therapeutic approach to genetic disease that in vivo delivers a functional copy of the aberrant gene is an intuitive solution that has thus far taken three decades to reduce to clinical practice, predominantly using adeno-associated viral (AAV) vectors. Among available viral and non-viral gene delivery approaches, AAV vectors remain the most efficient means for in vivo delivery of DNA to the nucleus. AAV vectors now constitute a bone fide novel therapeutic drug class comprised of 7 U.S. Food and Drug approved products with over tenfold more in clinical development for an expanding number of disease indications and an identified list of problems to overcome for widespread clinical application. Here, we review current progress in clinical AAV gene therapy, including for neuromuscular disorders, hemophilia, primary cardiovascular disorders or disorders with cardiovascular manifestations, lysosomal storage disorders, mucopolysaccharide disorders, primary central nervous systemic disorders, and ocular disorders.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"47 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915080","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

Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia. 锁定CBL TKBD的天然构象为突变型CBL依赖性白血病提供了新的治疗机会。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-05-05 DOI: 10.1016/j.ymthe.2025.04.042

Syed Feroj Ahmed,Jayanthi Anand,Wei Zhang,Lori Buetow,Loveena Rishi,Louise Mitchell,Jonathan Bohlen,Sergio Lilla,Gary J Sibbet,Colin Nixon,Amrita Patel,Karolina A Majorek,Sara Zanivan,Jacinta C Bustamante,Sachdev S Sidhu,Karen Blyth,Danny T Huang

{"title":"Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia.","authors":"Syed Feroj Ahmed,Jayanthi Anand,Wei Zhang,Lori Buetow,Loveena Rishi,Louise Mitchell,Jonathan Bohlen,Sergio Lilla,Gary J Sibbet,Colin Nixon,Amrita Patel,Karolina A Majorek,Sara Zanivan,Jacinta C Bustamante,Sachdev S Sidhu,Karen Blyth,Danny T Huang","doi":"10.1016/j.ymthe.2025.04.042","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.042","url":null,"abstract":"Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase critical for negatively regulating receptor protein tyrosine kinases (RTKs). Deleterious CBL mutants lose E3 activity, but act as adaptors that gain function to cause myeloproliferative neoplasms. Currently, there is no targeted treatment available for patients with CBL mutant-dependent disorders. By combining phage-display technology and structure-based optimization, we discovered CBLock, a nanomolar affinity peptide inhibitor, that binds the substrate-binding site of CBL's tyrosine kinase binding domain (TKBD). CBLock disrupts the interaction between CBL mutants and RTKs, thereby impairing RTK-mediated priming of adaptor function of CBL mutants and downstream signaling. Notably, CBLock binds TKBD without inducing conformational changes, thereby preserving its ligand-free native conformation. In contrast, when CBL binds RTK substrates, TKBD undergoes a conformational change. Maintaining the native CBL TKBD conformation was crucial for CBLock to inhibit proliferation, induce cell cycle arrest, and promote apoptosis in leukemia cells harboring CBL mutations. In a mouse xenograft model of acute myeloid leukemia (AML), CBLock reduced tumor burden and improved survival rate. Moreover, CBLock inhibited the proliferation of cells derived from patients with CBL mutations. Therefore, inhibiting CBL TKBD in its native state presents a promising therapeutic opportunity in targeting mutant CBL-dependent leukemia.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"20 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915081","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