Molecular Therapy最新文献_第9页

Novel insights into the ROCK-JAK-STAT signaling pathway in upper respiratory tract infections and neurodegenerative diseases. 对上呼吸道感染和神经退行性疾病中 ROCK-JAK-STAT 信号通路的新认识

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-07 DOI: 10.1016/j.ymthe.2024.11.011

Jiaxuan Li, Naihui Mao, Ying Wang, Shuli Deng, Keda Chen

引用次数: 0

Proton pump inhibitor attenuates acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis. 质子泵抑制剂可改善酸性微环境，从而提高 MSLN-CAR-T 细胞对实体瘤脑转移的治疗效果。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-07 DOI: 10.1016/j.ymthe.2024.11.010

Xuejia Zhai, Ling Mao, Qingmei Kang, Jie Liu, Yu Zhou, Jun Wang, Xianyan Yang, Di Wang, Junhan Wang, Yao Li, Jiangjie Duan, Tao Zhang, Shuang Lin, Tingting Zhao, Jianjun Li, Min Wu, Shicang Yu

{"title":"Proton pump inhibitor attenuates acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis.","authors":"Xuejia Zhai, Ling Mao, Qingmei Kang, Jie Liu, Yu Zhou, Jun Wang, Xianyan Yang, Di Wang, Junhan Wang, Yao Li, Jiangjie Duan, Tao Zhang, Shuang Lin, Tingting Zhao, Jianjun Li, Min Wu, Shicang Yu","doi":"10.1016/j.ymthe.2024.11.010","DOIUrl":"10.1016/j.ymthe.2024.11.010","url":null,"abstract":"The incidence of brain metastasis (BM) is gradually increasing, and the prognosis and therapeutic effect are poor. The emergence of immunotherapy has brought hope for the development of BM treatments. This study revealed that compared with primary cancers, BMs have a colder and more acidic tumor microenvironment (TME), resulting in reduced protein levels of mesothelin (MSLN), a promising target for chimeric antigen receptor-T (CAR-T) cell therapy for triple-negative breast cancer (TNBC) with BMs. These factors could significantly decrease the efficiency of MSLN-CAR-T cells in TNBC BMs. Pantoprazole (PPZ) administration at the most commonly used dose in the clinic notably increased the pH of the TME, inhibited lysosomal activity, increased the membrane levels of the MSLN protein and improved the killing ability of MSLN-CAR-T cells both in vitro and in vivo. Similar results were obtained in non-small cell lung cancer BMs. Hence, when administered in combination with CAR-T cells, PPZ, which increases the protein levels of target antigens, may constitute a new immunotherapeutic strategy for treating solid tumors with BMs.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604921","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

Entering the playing field: Therapy for multiple sulfatase deficiency. 进入赛场：治疗多重硫酸酯酶缺乏症。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-30 DOI: 10.1016/j.ymthe.2024.10.008

Patricia Dickson

引用次数: 0

Preclinical lentiviral hematopoietic stem cell gene therapy corrects Pompe disease-related muscle and neurological manifestations. 临床前慢病毒载体介导的造血干细胞和祖细胞基因疗法可纠正庞贝病相关的肌肉和神经系统表现。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-17 DOI: 10.1016/j.ymthe.2024.09.024

John K Yoon, Jeffrey W Schindler, Mariana Loperfido, Cristina Baricordi, Mark P DeAndrade, Mary E Jacobs, Christopher Treleaven, Robert N Plasschaert, Aimin Yan, Cecilia N Barese, Yildirim Dogan, Vicky Ping Chen, Claudia Fiorini, Fritz Hull, Luigi Barbarossa, Zeenath Unnisa, Daniel Ivanov, Robert H Kutner, Swaroopa Guda, Christine Oborski, Tim Maiwald, Véronique Michaud, Michael Rothe, Axel Schambach, Richard Pfeifer, Chris Mason, Luca Biasco, Niek P van Til

{"title":"Preclinical lentiviral hematopoietic stem cell gene therapy corrects Pompe disease-related muscle and neurological manifestations.","authors":"John K Yoon, Jeffrey W Schindler, Mariana Loperfido, Cristina Baricordi, Mark P DeAndrade, Mary E Jacobs, Christopher Treleaven, Robert N Plasschaert, Aimin Yan, Cecilia N Barese, Yildirim Dogan, Vicky Ping Chen, Claudia Fiorini, Fritz Hull, Luigi Barbarossa, Zeenath Unnisa, Daniel Ivanov, Robert H Kutner, Swaroopa Guda, Christine Oborski, Tim Maiwald, Véronique Michaud, Michael Rothe, Axel Schambach, Richard Pfeifer, Chris Mason, Luca Biasco, Niek P van Til","doi":"10.1016/j.ymthe.2024.09.024","DOIUrl":"10.1016/j.ymthe.2024.09.024","url":null,"abstract":"Pompe disease, a rare genetic neuromuscular disorder, is caused by a deficiency of acid alpha-glucosidase (GAA), leading to an accumulation of glycogen in lysosomes, and resulting in the progressive development of muscle weakness. The current standard treatment, enzyme replacement therapy (ERT), is not curative and has limitations such as poor penetration into skeletal muscle and both the central and peripheral nervous systems, a risk of immune responses against the recombinant enzyme, and the requirement for high doses and frequent infusions. To overcome these limitations, lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy has been proposed as a next-generation approach for treating Pompe disease. This study demonstrates the potential of lentiviral HSPC gene therapy to reverse the pathological effects of Pompe disease in a preclinical mouse model. It includes a comprehensive safety assessment via integration site analysis, along with single-cell RNA sequencing analysis of central nervous tissue samples to gain insights into the underlying mechanisms of phenotype correction.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3847-3864"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291752","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

Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8⁺ T and CAR-T cells. 靶向 ROS 传感 Nrf2 可增强瘤内 CD8+ T 细胞和 CAR-T 细胞的抗肿瘤免疫力。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-08-22 DOI: 10.1016/j.ymthe.2024.08.019

Yuna Jo, Ju A Shim, Jin Woo Jeong, Hyori Kim, So Min Lee, Juhee Jeong, Segi Kim, Sun-Kyoung Im, Donghoon Choi, Byung Ha Lee, Yun Hak Kim, Chi Dae Kim, Chan Hyuk Kim, Changwan Hong

{"title":"Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8+ T and CAR-T cells.","authors":"Yuna Jo, Ju A Shim, Jin Woo Jeong, Hyori Kim, So Min Lee, Juhee Jeong, Segi Kim, Sun-Kyoung Im, Donghoon Choi, Byung Ha Lee, Yun Hak Kim, Chi Dae Kim, Chan Hyuk Kim, Changwan Hong","doi":"10.1016/j.ymthe.2024.08.019","DOIUrl":"10.1016/j.ymthe.2024.08.019","url":null,"abstract":"Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor erythroid 2-related 2 (Nrf2) is the ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8+ T and chimeric antigen receptor (CAR) T cells in the ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using an adoptive transfer model of antigen-specific CD8+ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in the TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in a solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3879-3894"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018093","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

In vivo neuroregenerative gene therapy to treat neurodegenerative disorders. 治疗神经退行性疾病的体内神经再生基因疗法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-24 DOI: 10.1016/j.ymthe.2024.10.005

Gong Chen

引用次数: 0

A chimeric anti-vascularization immunomodulator prevents high-risk corneal transplantation rejection via ex vivo gene therapy. 嵌合抗炎和抗血管免疫调节剂通过体外基因疗法预防高风险角膜移植排斥反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-07 DOI: 10.1016/j.ymthe.2024.09.007

Brian C Gilger, Tomoko Hasegawa, R Bryan Sutton, Jacquelyn J Bower, Chengwen Li, Matthew L Hirsch

{"title":"A chimeric anti-vascularization immunomodulator prevents high-risk corneal transplantation rejection via ex vivo gene therapy.","authors":"Brian C Gilger, Tomoko Hasegawa, R Bryan Sutton, Jacquelyn J Bower, Chengwen Li, Matthew L Hirsch","doi":"10.1016/j.ymthe.2024.09.007","DOIUrl":"10.1016/j.ymthe.2024.09.007","url":null,"abstract":"Corneal blindness affects more than 5 million individuals, with over 180,000 corneal transplantations (CTs) performed annually. In high-risk CTs, almost all grafts are rejected within 10 years. Here, we investigated adeno-associated virus (AAV) ex vivo gene therapy to establish immune tolerance in the corneal allograft to prevent high-risk CT rejection. Our previous work has demonstrated that HLA-G contributes to ocular immune privilege by inhibiting both immune cells and neovascularization; however, homodimerization is a rate-limiting step for optimal HLA-G function. Therefore, a chimeric protein called single-chain immunomodulator (scIM), was engineered to mimic the native activity of the secreted HLA-G dimer complex and eliminate the need for homodimerization. In a murine corneal burn model, AAV8-scIM significantly reduced corneal vascularization and fibrosis. Next, ex vivo AAV8-scIM gene delivery to corneal allografts was evaluated in a high-risk CT rejection rabbit model. All scIM-treated corneas were well tolerated and transparent after 42 days, while 83% of vehicle-treated corneas were rejected. Histologically, AAV-scIM-treated corneas were devoid of immune cell infiltration and vascularization, with minimal fibrosis at the host-graft interface. The data collectively demonstrate that scIM gene therapy prevents corneal neovascularization, reduces trauma-induced corneal fibrosis, and prevents allogeneic CT rejection in a high-risk large animal model.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4006-4020"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154617","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

Biologics-based technologies for highly efficient and targeted RNA delivery. 基于生物制剂的高效定向 RNA 输送技术。

IF 2.9 1区医学

Molecular Therapy Pub Date : 2024-11-06 DOI: 10.1016/j.ymthe.2024.11.004

Anastasiya Kostyusheva, Sergey Brezgin, Natalia Ponomareva, Anastasiia Frolova, Alexander Lunin, Ekaterina Bayurova, Andrey Tikhonov, Olga Slatinskaya, Polina Demina, Artyom Kachanov, Gulalek Babayeva, Irina Khan, Dmitry Khochenkov, Yulia Khochenkova, Darina Sokolova, Denis Silachev, Georgy Maksimov, Evgeny Khaydukov, Vadim S Pokrovsky, Andrey A Zamyatnin, Alessandro Parodi, Ilya Gordeychuk, Vladimir Chulanov, Dmitry Kostyushev

{"title":"Biologics-based technologies for highly efficient and targeted RNA delivery.","authors":"Anastasiya Kostyusheva, Sergey Brezgin, Natalia Ponomareva, Anastasiia Frolova, Alexander Lunin, Ekaterina Bayurova, Andrey Tikhonov, Olga Slatinskaya, Polina Demina, Artyom Kachanov, Gulalek Babayeva, Irina Khan, Dmitry Khochenkov, Yulia Khochenkova, Darina Sokolova, Denis Silachev, Georgy Maksimov, Evgeny Khaydukov, Vadim S Pokrovsky, Andrey A Zamyatnin, Alessandro Parodi, Ilya Gordeychuk, Vladimir Chulanov, Dmitry Kostyushev","doi":"10.1016/j.ymthe.2024.11.004","DOIUrl":"10.1016/j.ymthe.2024.11.004","url":null,"abstract":"The demand for RNA-based therapeutics is increasing globally. However, their use is hampered by the lack of safe and effective delivery vehicles. Here, we developed technologies for highly efficient delivery of RNA cargo into programmable extracellular vesicle-mimetic nanovesicles (EMNVs) by fabricating hybrid EMNV-liposomes (Hybs). Tissue targeting is endowed by highly efficient genetic platforms based on truncated CD63 (ΔCD63) or PTGFRN proteins. For the first time we reveal their efficiency in functionalizing EMNVs, resulting in >10-fold enhancement of nanoparticle internalization in vitro and >2-fold in vivo. RNA delivery using Hybs demonstrated efficiency of >85% in human and mouse cell lines. Comparative analysis of EMNVs and Hyb lysosome colocalization and stability suggested that Hybs enter the lysosomal compartment and escape over time, whereas EMNVs primarily avoid it. Finally, we used these technologies to generate liver-targeting Hybs loaded with therapeutic small interfering RNA and demonstrated the robust efficiency of this system in vitro and in vivo. These technologies can be adapted for manufacturing a wide range of next-generation vehicles for highly efficient, safe delivery of RNA into desired organs and tissues for therapeutic and prophylactic applications.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604742","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 CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion. CD25×TIGIT 双特异性抗体通过选择性消耗瘤内 Treg 细胞诱导抗肿瘤活性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-07 DOI: 10.1016/j.ymthe.2024.09.010

Xin Wei, Linlin Zhao, Fang Yang, Yajing Yang, Huixiang Zhang, Kaixin Du, Xinxin Tian, Ruihua Fan, Guangxu Si, Kailun Wang, Yulu Li, Zhizhong Wei, Miaomiao He, Jianhua Sui

{"title":"A CD25×TIGIT bispecific antibody induces anti-tumor activity through selective intratumoral Treg cell depletion.","authors":"Xin Wei, Linlin Zhao, Fang Yang, Yajing Yang, Huixiang Zhang, Kaixin Du, Xinxin Tian, Ruihua Fan, Guangxu Si, Kailun Wang, Yulu Li, Zhizhong Wei, Miaomiao He, Jianhua Sui","doi":"10.1016/j.ymthe.2024.09.010","DOIUrl":"10.1016/j.ymthe.2024.09.010","url":null,"abstract":"Intratumoral regulatory T cells (Tregs) express high levels of CD25 and TIGIT, which are also recognized as markers of effector T cell (Teff) activation. Targeting these molecules each alone with monoclonal antibodies (mAbs) poses a risk of concurrently depleting both Teffs and peripheral Tregs, thereby compromising the effectiveness and selectivity of intratumoral Treg depletion. Here, leveraging the increased abundance of CD25+ TIGIT+ double-positive Tregs in the solid tumor microenvironment (but not in peripheral tissues), we explore the feasibility of using a CD25×TIGIT bispecific antibody (bsAb) to selectively deplete intratumoral Tregs. We initially constructed a bsAb co-targeting mouse CD25 and TIGIT, NSWm7210, and found that NSWm7210 conferred enhanced intratumoral Treg depletion, Teff activation, and tumor suppression as compared to the parental monotherapies in mouse models. We subsequently constructed a bsAb co-targeting human CD25 and TIGIT (NSWh7216), which preferentially eliminated CD25+ TIGIT+ double-positive cells over single-positive cells in vitro. NSWh7216 exhibited enhanced anti-tumor activity without toxicity of peripheral Tregs in CD25 humanized mice compared to the parental monotherapies. Our study illustrates the use of CD25×TIGIT bsAbs as effective agents against solid tumors based on selective depletion of intratumoral Tregs.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4075-4094"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154616","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

Engineering memory T cells as a platform for long-term enzyme replacement therapy in lysosomal storage disorders. 将记忆 T 细胞工程作为溶酶体贮积症长期酶替代疗法的平台。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-04 DOI: 10.1016/j.ymthe.2024.09.033

Evan W Kleinboehl, Kanut Laoharawee, Jacob D Jensen, Joseph J Peterson, Nicholas J Slipek, Bryce J Wick, Matthew J Johnson, Beau R Webber, Branden S Moriarity

{"title":"Engineering memory T cells as a platform for long-term enzyme replacement therapy in lysosomal storage disorders.","authors":"Evan W Kleinboehl, Kanut Laoharawee, Jacob D Jensen, Joseph J Peterson, Nicholas J Slipek, Bryce J Wick, Matthew J Johnson, Beau R Webber, Branden S Moriarity","doi":"10.1016/j.ymthe.2024.09.033","DOIUrl":"10.1016/j.ymthe.2024.09.033","url":null,"abstract":"Enzymopathy disorders are the result of missing or defective enzymes. Among these enzymopathies, mucopolysaccharidosis type I is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), which ultimately causes toxic buildup of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T (Tm) cells migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm cells as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm cells leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm cells take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS, although only minimal improved cognition was observed. Our study indicates that genetically engineered Tm cells hold great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3865-3878"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375691","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