Molecular Therapy最新文献_第10页

Vitronectin regulates lung tissue remodeling and emphysema in chronic obstructive pulmonary disease. 玻璃体连接蛋白调节慢性阻塞性肺疾病的肺组织重塑和肺气肿。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-21 DOI: 10.1016/j.ymthe.2025.01.032

Gang Liu, Alan C Hsu, Silke Geirnaert, Christine Cong, Prema M Nair, Sj Shen, Jacqueline E Marshall, Tatt Jhong Haw, Michael Fricker, Ashleigh M Philp, Nicole G Hansbro, Stelios Pavlidis, Yike Guo, Janette K Burgess, Leandro Castellano, Antonio Ieni, Gaetano Caramori, Brain G G Oliver, K Fan Chung, Ian M Adcock, Darryl A Knight, Francesca Polverino, Ken Bracke, Peter A Wark, Philip M Hansbro

{"title":"Vitronectin regulates lung tissue remodeling and emphysema in chronic obstructive pulmonary disease.","authors":"Gang Liu, Alan C Hsu, Silke Geirnaert, Christine Cong, Prema M Nair, Sj Shen, Jacqueline E Marshall, Tatt Jhong Haw, Michael Fricker, Ashleigh M Philp, Nicole G Hansbro, Stelios Pavlidis, Yike Guo, Janette K Burgess, Leandro Castellano, Antonio Ieni, Gaetano Caramori, Brain G G Oliver, K Fan Chung, Ian M Adcock, Darryl A Knight, Francesca Polverino, Ken Bracke, Peter A Wark, Philip M Hansbro","doi":"10.1016/j.ymthe.2025.01.032","DOIUrl":"10.1016/j.ymthe.2025.01.032","url":null,"abstract":"Vitronectin (VTN) is an important extracellular matrix protein in tissue remodeling, but its role in chronic obstructive pulmonary disease (COPD) is unknown. We show that VTN regulates tissue remodeling through urokinase plasminogen activator (uPA) signaling pathway in COPD. In human COPD airways and bronchoepithelial cells and the airways of mice with cigarette smoke (CS)-induced experimental COPD, VTN protein was not changed, but downstream uPA signaling was altered (increased plasminogen activator inhibitor-1) that induced collagen and airway remodeling. In the parenchyma, VTN levels were decreased, uPA signaling pathway differentially altered and collagen reduced in lung fibroblasts from human and lung parenchyma in experimental COPD. Vtn inhibition with siRNA in mouse fibroblasts altered uPA signaling increased matrix metalloproteinase-12, and reduced collagen, whereas over-expression restored collagen production after CS extract challenge. Vtn-/- and Vtn small interfering RNA-treated mice had exaggerated inflammation, emphysema, and impaired lung function compared with controls with CS-induced COPD. Restoration of VTN in the parenchyma may be a therapeutic option for emphysema and COPD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143007659","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

Treating genetic blood disorders in the era of CRISPR-mediated genome editing. 在crispr介导的基因组编辑时代治疗遗传性血液病。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-01-17 DOI: 10.1016/j.ymthe.2025.01.031

Alhomidi Almotiri,Ahmed Abogosh,Ali Abdelfattah,Dalya Alowaisy,Neil P Rodrigues

引用次数: 0

Transforming Bacterial Pathogens into Wonder Tools in Cancer Immunotherapy. 将细菌病原体转化为癌症免疫治疗的神奇工具。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-01-17 DOI: 10.1016/j.ymthe.2025.01.029

Amal Senevirathne,Khristine Kaith S Lloren,Ram Prasad Aganja,Jun Kwon,John Hwa Lee

{"title":"Transforming Bacterial Pathogens into Wonder Tools in Cancer Immunotherapy.","authors":"Amal Senevirathne,Khristine Kaith S Lloren,Ram Prasad Aganja,Jun Kwon,John Hwa Lee","doi":"10.1016/j.ymthe.2025.01.029","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.029","url":null,"abstract":"Cancer immunotherapy has revolutionized cancer treatment due to its precise, target-specific approach compared to conventional therapies. However, treating solid tumors remains challenging as these tumors are inherently immunosuppressive, and their tumor microenvironment (TME) often limits therapeutic efficacy. Interestingly, certain bacterial species offer a promising alternative by exhibiting an innate ability to target and proliferate within tumor environments. Bacterial structural and functional components can activate innate and adaptive immune responses, creating tumor-suppressive conditions that reduce tumor mass. Additionally, bacteria can deliver effector molecules directly into tumor cells, inducing apoptotic and necrotic cell death. Despite their potential, the use of bacteria in cancer immunotherapy poses risks due to possible toxicities and unpredictable in vivo behavior. Advances in genetic engineering have addressed these concerns by enabling the development of attenuated bacterial strains with enhanced anticancer properties for safer medical applications. This review highlights the role of bacteria in TME modulation, recent strategies to bioengineer bacterial pathogens as therapeutic tools, and the synergistic effects of combining bacteria with other immunotherapies. It also discusses the challenges and prospects of translating this innovative approach into clinical practice, offering a comprehensive overview of bacteria-based cancer immunotherapy's potential to reshape the future of cancer treatment.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"57 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989781","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

Enhanced restoration of visual code after targeting ON bipolar cells compared with retinal ganglion cells with optogenetic therapy. 与光基因治疗视网膜神经节细胞相比，靶向双极细胞后视觉密码的恢复增强。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-17 DOI: 10.1016/j.ymthe.2025.01.030

Jessica Rodgers, Steven Hughes, Aghileh S Ebrahimi, Annette E Allen, Riccardo Storchi, Moritz Lindner, Stuart N Peirson, Tudor C Badea, Mark W Hankins, Robert J Lucas

{"title":"Enhanced restoration of visual code after targeting ON bipolar cells compared with retinal ganglion cells with optogenetic therapy.","authors":"Jessica Rodgers, Steven Hughes, Aghileh S Ebrahimi, Annette E Allen, Riccardo Storchi, Moritz Lindner, Stuart N Peirson, Tudor C Badea, Mark W Hankins, Robert J Lucas","doi":"10.1016/j.ymthe.2025.01.030","DOIUrl":"10.1016/j.ymthe.2025.01.030","url":null,"abstract":"Optogenetic therapy is a promising vision restoration method where light-sensitive opsins are introduced to the surviving inner retina following photoreceptor degeneration. The cell type targeted for opsin expression will likely influence the quality of restored vision. However, a like-for-like preclinical comparison of visual responses evoked following equivalent opsin expression in the two major targets, ON bipolar (ON BCs) or retinal ganglion cells (RGCs), is absent. We address this deficit by comparing stimulus-response characteristics at single-unit resolution in the retina and dorsal lateral geniculate nucleus of retinally degenerate mice genetically engineered to express the opsin ReaChR in Grm6- or Brn3c-expressing cells (ON BC vs. RGCs, respectively). For both targeting strategies, we find ReaChR-evoked responses have equivalent sensitivity and can encode contrast across different background irradiances. Compared with ON BCs, targeting RGCs decreased response reproducibility and resulted in more stereotyped responses with reduced diversity in response polarity, contrast sensitivity, and temporal frequency tuning. Recording ReaChR-driven responses in visually intact retinas confirmed that RGC-targeted ReaChR expression disrupts visual feature selectivity of individual RGCs. Our data show that, while both approaches restore visual responses with impressive fidelity, ON BC targeting produces a richer visual code closer to that of wild-type mice.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008782","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

Characterisation of the ocular inflammatory response to AAV reveals divergence by sex and age. 对AAV的眼部炎症反应的特征显示出性别和年龄的差异。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-01-17 DOI: 10.1016/j.ymthe.2025.01.028

Alison J Clare,Philip M Langer,Amy Ward,Ying Kai Chan,Andrew D Dick,David A Copland

{"title":"Characterisation of the ocular inflammatory response to AAV reveals divergence by sex and age.","authors":"Alison J Clare,Philip M Langer,Amy Ward,Ying Kai Chan,Andrew D Dick,David A Copland","doi":"10.1016/j.ymthe.2025.01.028","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.028","url":null,"abstract":"Progress for ocular AAV gene therapy has been hindered by AAV-induced inflammation, limiting dose escalation and long-term efficacy. Broadly, the extent of inflammatory responses alters with age and sex, yet these factors are poorly represented in pre-clinical development of ocular AAV gene therapies. Here, we combined clinical imaging, flow cytometry and bulk-sequencing of sorted microglia to interrogate the longitudinal inflammatory response following intravitreal delivery of AAV2 in young (3-month), middle aged (9-month) and old (18-month) Cx3cr1-creER:R26tdTomato+/- mice of both sexes. Young males and females exhibited a similar dynamic response, with peak inflammation evident at D10-12 and signs of clinical resolution by D28. However, the magnitude of the transcriptional response by microglia and adaptive T cell infiltrate differed between sexes. With age, increased and persistent inflammation were observed in both sexes, though old males maintained their microglia transcriptional AAV response signature. Contrary, females demonstrated greater divergence in their inflammatory response across age, with enriched cellular stress and inflammatory gene expression in older mice, and corresponding signs of retinal degeneration. These findings inform crucial sex and age differences for therapeutic application of ocular gene therapy, highlighting the need to further understand these factors to overcome AAV immunogenicity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"56 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142989777","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 risk of reactivity against healthy tissues: Novel CARs demand testing for overlooked binding properties. 对健康组织的反应性风险：新型car需要检测被忽视的结合特性。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-01-15 DOI: 10.1016/j.ymthe.2024.12.035

Astrid Holzinger,Florian Weber,Hinrich Abken

引用次数: 0

Pancreatic cancer-derived extracellular vesicles enhance chemoresistance by delivering KRAS^G12D protein to cancer-associated fibroblasts. 胰腺癌来源的细胞外囊泡通过向癌症相关成纤维细胞传递KRASG12D蛋白来重塑肿瘤微环境并增强化疗耐药。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-14 DOI: 10.1016/j.ymthe.2025.01.023

Xinyuan Liu, Jiaqi Yang, Sicong Huang, Yifan Hong, Yupeng Zhu, Jianing Wang, Yi Wang, Tingbo Liang, Xueli Bai

{"title":"Pancreatic cancer-derived extracellular vesicles enhance chemoresistance by delivering KRASG12D protein to cancer-associated fibroblasts.","authors":"Xinyuan Liu, Jiaqi Yang, Sicong Huang, Yifan Hong, Yupeng Zhu, Jianing Wang, Yi Wang, Tingbo Liang, Xueli Bai","doi":"10.1016/j.ymthe.2025.01.023","DOIUrl":"10.1016/j.ymthe.2025.01.023","url":null,"abstract":"KRAS mutations are instrumental in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the efficacy of direct targeting of KRAS mutations to inhibit tumor development remains doubtful. It is therefore necessary to gain a deeper insight into the mechanism in which KRAS mutations influence the effectiveness of clinical treatments. In this study, KRASG12D protein was detected in cancer-associated fibroblasts (CAFs) from clinical samples of PDAC. In vitro experiments demonstrated that KRASG12D protein in CAFs was not expressed from its own mutant gene but was derived from the ingestion of tumor cell-derived extracellular vesicles (EVs). The presence of KRASG12D protein in CAFs resulted in enhanced proliferation and migration. Furthermore, KRASG12D-containing CAFs were observed to promote tumor chemoresistance to gemcitabine treatment both in vitro and in vivo. Application of a KRAS mutation-specific inhibitor, MRTX1133, has been demonstrated to reverse chemoresistance in PDAC. Moreover, clinical data suggest that patients with KRAS mutations have poorer prognosis following adjuvant chemotherapy. These findings elucidate the mechanism by which oncogenic KRAS mutations promote cancer chemoresistance and remodel tumor environment in a non-autonomous manner, suggesting a novel strategy for targeting KRAS mutations to enhance chemosensitivity in PDAC.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984070","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

Genetically Reprogrammed Exosomes for Immunotherapy of Acute Myeloid Leukemia. 基因重编程外泌体用于急性髓系白血病的免疫治疗。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-01-14 DOI: 10.1016/j.ymthe.2025.01.025

Lei Zhang,Guoyun Kao,Yuanteng Zhao,Zeyu Zhang,Hyo Sun Kim,Xiaojing Shi,Qinqin Cheng,Tianling Hou,Heinz-Josef Lenz,Yong Zhang

引用次数: 0

Virus-free CRISPR knockin of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells. 无病毒的CRISPR敲入嵌合抗原受体到KLRC1中，产生有效的gd2特异性自然杀伤细胞。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-14 DOI: 10.1016/j.ymthe.2025.01.024

Keerthana Shankar, Isabelle Zingler-Hoslet, Diana M Tabima, Seth Zima, Lei Shi, Kirstan Gimse, Matthew H Forsberg, Varun Katta, Sage Z Davis, Daniel Maldonado, Brittany E Russell, Muhammed Murtaza, Shengdar Q Tsai, Jose M Ayuso, Christian M Capitini, Krishanu Saha

{"title":"Virus-free CRISPR knockin of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells.","authors":"Keerthana Shankar, Isabelle Zingler-Hoslet, Diana M Tabima, Seth Zima, Lei Shi, Kirstan Gimse, Matthew H Forsberg, Varun Katta, Sage Z Davis, Daniel Maldonado, Brittany E Russell, Muhammed Murtaza, Shengdar Q Tsai, Jose M Ayuso, Christian M Capitini, Krishanu Saha","doi":"10.1016/j.ymthe.2025.01.024","DOIUrl":"10.1016/j.ymthe.2025.01.024","url":null,"abstract":"Natural killer (NK) cells are an appealing off-the-shelf, allogeneic cellular therapy due to their cytotoxic profile. However, their activity against solid tumors remains suboptimal in part due to the upregulation of NK-inhibitory ligands, such as HLA-E, within the tumor microenvironment. Here, we utilize CRISPR-Cas9 to disrupt the KLRC1 gene (encoding the HLA-E-binding NKG2A receptor) and perform non-viral insertion of a GD2-targeting chimeric antigen receptor (CAR) within NK cells isolated from human peripheral blood. Genome editing with CRISPR-Cas9 ribonucleoprotein complexes yields efficient genomic disruption of the KLRC1 gene with 98% knockout efficiency and specific knockin of the GD2 CAR transgene as high as 23%, with minimal off-target activity as shown by CHANGE-seq, in-out PCR, amplicon sequencing, and long-read whole-genome sequencing. KLRC1-GD2 CAR NK cells display high viability and proliferation, as well as precise cellular targeting and potency against GD2+ human tumor cells. Notably, KLRC1-GD2 CAR NK cells overcome HLA-E-based inhibition in vitro against HLA-E-expressing, GD2+ melanoma cells. Using a single-step, virus-free genome editing workflow, this study demonstrates the feasibility of precisely disrupting inhibitory signaling within NK cells via CRISPR-Cas9 while expressing a CAR to generate potent allogeneic cell therapies against HLA-E+ solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008787","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

Depletion of alloreactive B cells by drug-resistant chimeric alloantigen receptor T cells to prevent transplant rejection. 用耐药嵌合同种异体抗原受体T细胞消耗同种异体反应性B细胞以防止移植排斥反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-11 DOI: 10.1016/j.ymthe.2025.01.009

Anna Christina Dragon, Agnes Bonifacius, Stefan Lienenklaus, Murielle Verboom, Jan-Phillipp Gerhards, Fabio Ius, Christian Hinze, Michael Hudecek, Constanca Figueiredo, Rainer Blasczyk, Britta Eiz-Vesper

{"title":"Depletion of alloreactive B cells by drug-resistant chimeric alloantigen receptor T cells to prevent transplant rejection.","authors":"Anna Christina Dragon, Agnes Bonifacius, Stefan Lienenklaus, Murielle Verboom, Jan-Phillipp Gerhards, Fabio Ius, Christian Hinze, Michael Hudecek, Constanca Figueiredo, Rainer Blasczyk, Britta Eiz-Vesper","doi":"10.1016/j.ymthe.2025.01.009","DOIUrl":"10.1016/j.ymthe.2025.01.009","url":null,"abstract":"Antibody-mediated rejection (AMR) remains a major complication after solid organ transplantation (SOT). Current treatment options are inefficient and result in drastic impairment of the general immunity. To selectively eliminate responsible alloreactive B cells characterized by anti-donor-HLA B cell receptors (BCRs), we generated T cells overcoming rejection by antibodies (CORA-Ts) engineered with a novel chimeric receptor comprising a truncated donor-HLA molecule as antigen recognition domain. As proof-of-concept, CORA receptors based on HLA-A∗02 were developed. In co-cultures with anti-HLA-A∗02 B cell lines, CORA-Ts were specifically activated, released pro-inflammatory mediators, and exhibited strong cytotoxicity resulting in an effective reduction of anti-HLA-A∗02 antibody release. Significant reduction of growth of an anti-HLA-A∗02 B cell line could be confirmed using an in vivo mouse model. Modification of the CORA receptor effectively abrogated T cell binding, thereby avoiding T cell sensitization. Additionally, using CRISPR-Cas9-mediated knockout of the FKBP12 gene, CORA-Ts were able to resist immunosuppressive treatment with tacrolimus, thereby allowing high efficiency in transplant patients. Our results demonstrate that CORA-Ts are able to specifically eliminate alloreactive, anti-HLA B cells, thus selectively preventing anti-HLA antibody release even under immunosuppressive conditions. This suggests CORA-Ts as potent approach to combat AMR and improve long-term graft survival in SOT patients while preserving their overall B cell immunity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971638","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