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Pilocytic Astrocytoma in a Child with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec. Mol. Ther. (IF 12.1) Pub Date : 2025-02-15 Dorothea Holzwarth,Gabriele Calaminus,Johannes Friese,Thomas Sejersen,Hildegard Büning,Philipp John-Neek,Antonella Lucía Bastone,Michael Rothe,Keith Mansfield,Silvana Libertini,Valerie Dubost,Brent Kuzmiski,Iulian Alecu,Ivan Labik,Janbernd Kirschner
Spinal muscular atrophy (SMA) is a severe neuromuscular disease, leading to progressive muscle weakness and potentially early mortality if untreated. Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (rAAV9)-based gene therapy that has demonstrated improvements in survival and motor function for SMA patients. Here, we present a case of a patient diagnosed with a grade 1 pilocytic
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Targeting BCL11B in CAR-engineered lymphoid progenitors drives NK-like cell development with prolonged anti-leukemic activity. Mol. Ther. (IF 12.1) Pub Date : 2025-02-15 Franziska Baatz,Arnab Ghosh,Jessica Herbst,Saskia Polten,Johann Meyer,Manuel Rhiel,Tobias Maetzig,Robert Geffers,Michael Rothe,Antonella Lucia Bastone,Philipp John-Neek,Jörg Frühauf,Britta Eiz-Vesper,Agnes Bonifacius,Christine S Falk,Constantin V Kaisenberg,Toni Cathomen,Axel Schambach,Marcel R M van den Brink,Michael Hust,Martin G Sauer
Chimeric antigen receptor (CAR)-induced suppression of the transcription factor B cell CLL/lymphoma 11B (BCL11B) propagates CAR-induced killer (CARiK) cell development from lymphoid progenitors. Here, we show that CRISPR/Cas9-mediated Bcl11b knockout in human and murine early lymphoid progenitors distinctively modulates this process either alone or in combination with a CAR. Upon adoptive transfer
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Immunological responses and clinical outcomes in pet dogs with osteosarcoma receiving standard of care therapy and a recombinant Listeria vaccine expressing HER2/neu. Mol. Ther. (IF 12.1) Pub Date : 2025-02-15 Nicola J Mason,Laura Selmic,Audrey Ruple,C A London,L Barber,K Weishaar,J A Perry,J Mahoney,B Flesner,J N Bryan,J L Willcox,J H Burton,D M Vail,W C Kisseberth,C E Balkman,A L McCleary-Wheeler,K M Curran,H Leeper,J P Woods,A J Mutsaers,M L Higginbotham,R M Wouda,H Wilson-Robles,N Dervisis,C Saba,V S MacDonald-Dickinson,P R Hess,A Cherukuri,A Rotolo,J A Beck,S Patkar,C Mazcko,A K LeBlanc
A clinical trial in dogs with spontaneous osteosarcoma was performed to assess a recombinant Listeria expressing a chimeric human HER2/neu (ADXS31-164c) as an adjunctive vaccine strategy to prevent metastatic disease and determine immunological correlates of clinical outcome. 118 dogs with appendicular osteosarcoma were recruited into a 1-arm, multicenter, prospective trial of standard of care (SOC)
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Modulating the PD-1-FABP5 Axis in ILC2s to Regulate Adipose Tissue Metabolism in Obesity. Mol. Ther. (IF 12.1) Pub Date : 2025-02-12 Jongho Ham,Jaemoon Koh,Jungeun Kim,Joo-Youn Cho,TaeSoo Kim,Doo Hyun Chung,Yong-Soo Bae,Hye Young Kim
Obesity is closely linked to metabolic dysregulation and chronic inflammation, which significantly impact immune cell functions in adipose tissue. Type 2 innate lymphoid cells (ILC2s) have emerged as key regulators of energy homeostasis, positioning them as promising targets for obesity management. However, the mechanisms governing ILC2 activity and their therapeutic potential in obesity are not fully
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Multiple-omics Analysis Reveals Dedifferentiation-Immunosuppression Loop Formed by Malignant Cell and Macrophage in Intrahepatic cholangiocarcinoma. Mol. Ther. (IF 12.1) Pub Date : 2025-02-12 Jian Ruan,Qiong Li,Yuzhi Jin,Jie Yin,Chanqi Ye,Fei Cheng,Shuaishuai Xu,Ruyin Chen,Chuan Liu,Xiaoxiang Rong,Ming Jiang,Wenguang Fu,Dayong Zheng,Jinzhang Chen,Xuanwen Bao,Houhong Wang,Jianpeng Sheng,Peng Zhao
Intrahepatic cholangiocarcinoma (ICC) is known for its diverse cell types and resistance to standard treatments, highlighting the importance of understanding its tumor microenvironment (TME) for improved prognostic accuracy and therapeutic innovation. Our study used a multi-omics approach to analyze the ICC TME in both human and mouse samples, linking survival outcomes to the complex cellular interactions
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Dasatinib-Resistant Universal CAR-T cells Proliferate in the Presence of Host Immune Cells and Exhibit Antitumor Activity. Mol. Ther. (IF 12.1) Pub Date : 2025-02-11 Yuhang Cheng,Jiayuan Zhang,Wei Mu,Shanwei Ye,Jiali Cheng,Li Zhu,Gaoxiang Wang,Yang Cao,Dengju Li,Guang Hu,Liang Huang,Jue Wang,Jianfeng Zhou
The universal chimeric antigen receptor T-cell (UCAR-T) immunotherapy derived from healthy donors holds great promise in pan-cancer treatment. However, UCAR-T cell therapy faces a challenge in the rapid elimination of allogeneic cells by the host immune system. To address this, we introduced a T316I mutation in the leukocyte-specific protein tyrosine kinase (LCK) locus in CAR-T cells using the cytosine
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Y4 RNA fragment mitigates myocardial ischemia-reperfusion injury in heart transplantation through SNRNP200-mediated enhancement of IL-10 pre-mRNA splicing. Mol. Ther. (IF 12.1) Pub Date : 2025-02-11 Chuanghong Lu,Zhongyuan Meng,Senhu Tang,Heng Wei,Yaoshi Hu,Dexin Chen,Dezhao Liu,Hong Wen,Kun Dong,Na Na,Feng Huang,Zhiyu Zeng
Myocardial ischemia-reperfusion injury (MIRI) inevitably occurs during heart transplantation, highlighting the imperative for effective therapeutic interventions. A Y4 RNA fragment (YF1) was applied to treat a syngeneic mouse model of heart transplantation, with heart subjected to cold ischemia-reperfusion (CIR). Cardiomyocytes and macrophages were treated with YF1, and a cellular cold hypoxia-reoxygenation
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A BPTF-specific PROTAC degrader enhances NK cell-based cancer immunotherapy. Mol. Ther. (IF 12.1) Pub Date : 2025-02-11 Yunjia Li,Lin Bai,Hao Liang,Peidong Yan,Hao Chen,Zhuoxian Cao,Yiqing Shen,Zhongyv Wang,Mei Huang,Bin He,Quan Hao,Yide Mei,Haiming Wei,Chen Ding,Jing Jin,Yi Wang
Natural killer (NK) cell-based immunotherapy shows promise in cancer treatment, but its efficacy remains limited, necessitating the development of novel strategies. In this study, we demonstrate that the epigenetic factor BPTF (bromodomain PHD-finger containing transcription factor) hinders hepatocellular carcinoma (HCC) recognition by NK cells through its PHD finger's interpretation of H3K4me3. We
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Overcoming Immunotherapy Resistance in Hepatocellular Carcinoma by Targeting Myeloid IL-8/ CXCR2 Signaling. Mol. Ther. (IF 12.1) Pub Date : 2025-02-05 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
Durable response 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
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Mesenchymal stromal cell therapy: progress to date and future outlook. Mol. Ther. (IF 12.1) Pub Date : 2025-02-05 Wen Lu,Julie Allickson
In clinical trials, mesenchymal stromal/stem cells (MSC) have consistently demonstrated safety. However, demonstration of efficacy has been inconsistent and many MSC trials have failed to meet their efficacy endpoint. This disappointing reality is reflected by the limited number MSC therapies approved by regulatory agencies, despite the large number of MSC trials registered on clinicaltrials.gov. Notably
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Converting TCR-based chimeric antigen receptor STAR into dual-specific targeting receptor for cancer immunotherapy. Mol. Ther. (IF 12.1) Pub Date : 2025-02-05 Li Yu,Zhixiao Zhou,Hanyang Yu,Yue Liu,Daosheng Huang,Jiasheng Wang,Xin Lin
Chimeric Antigen Receptor (CAR) T cell therapy has achieved great success in treating hematopoietic malignancies, however, post-therapy relapse remains a challenge. Traditionally, multi-specific CAR engineering requires precise arrangement of single-chain variable fragments (scFvs), which can lead to aggregation issues when assembled linearly. In this study, we developed a novel chimeric receptor,
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Development of RelB-Targeting Small Molecule Inhibitors of Non-canonical NF-κB Signaling with Antitumor Efficacy. Mol. Ther. (IF 12.1) Pub Date : 2025-02-04 Cuifeng Li,Shuqi Wei,Donglin Sun,Zhuo Yang,Qi Wang,Han Lin,Haohao Zhang,Yiming Hu,Dandan Liu,Deji Ye,Yu Tao,Zhanjie Liu,Zhijian Xu,Bo Li,Lingling Li,Jie Zhang,Xi Chen,Ningxia Xie,Yufang Shi,Sanhong Liu,Yongzhong Liu,Yuhang Jiang,Weiliang Zhu,Xiaoren Zhang
Dysfunction of the non-canonical NF-κB signaling pathway has been causally associated with numbers of cancers and autoimmune diseases. However, specific inhibitors for this signaling pathway remain to be developed. Here we showed that structure-based cell-based screening yielded a potent and specific small molecule targeting RelB to inhibit non-canonical NF-κB signaling pathway, while had no inhibitory
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FKBP5 Inhibition Ameliorates Neurodegeneration and Motor Dysfunction in the Neuromelanin-SNCA Mouse Model of Parkinson's Disease. Mol. Ther. (IF 12.1) Pub Date : 2025-02-03 M Garcia-Gomara,N Legarra-Marcos,M Serena,E Rojas-de-Miguel,M Espelosin,I Marcilla,A Perez-Mediavilla,M R Luquin,J L Lanciego,M A Burrel,M Cuadrado-Tejedor,A Garcia-Osta
Parkinson's disease (PD) is characterized by the loss of neuromelanin (NM)-containing dopaminergic neurons (DA) in the substantia nigra pars compacta (SNpc) and the buildup of α-synuclein inclusions, called Lewy bodies. To investigate the roles of NM and α-syn in DA neuron degeneration, we modeled PD by inducing NM accumulation in a humanized α-syn mouse model (Snca-;PAC-Tg-SNCAWT) via the expression
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The Deubiquitinase USP28 Maintains the Expression of PPARγ and Its Inactivation Protects Mice from Diet-Induced MASH and Hepatocarcinoma. Mol. Ther. (IF 12.1) Pub Date : 2025-02-03 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
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 FDA-approved treatment, highlighting the need for new therapeutic strategies
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Targeting the TRIM21-PD-1 axis potentiates immune checkpoint blockade and CAR T cell therapy. Mol. Ther. (IF 12.1) Pub Date : 2025-02-03 Jie Shi,Zijian Zhang,Hsin-Yi Chen,Yingmeng Yao,Shanwen Ke,Kechun Yu,Jiangzhou Shi,Xiangling Xiao,Chuan He,Bolin Xiang,Yishuang Sun,Minling Gao,Xixin Xing,Haisheng Yu,Xiyong Wang,Wei-Chien Yuan,Bugi Ratno Budiarto,Shih-Yu Chen,Tongcun Zhang,Yu-Ru Lee,Haichuan Zhu,Jinfang Zhang
Dysregulation of T cells is a major limitation for the clinical success of T-cell based cancer immunotherapies, such as immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapy. Understanding the underlying mechanisms for regulating T cell functions can facilitate designing therapeutic strategies to improve immunotherapies. Here, we report that TRIM21 impairs CD8+ T cell activation
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Surface-modified extracellular vesicles take their chance in the big PCSK9 inhibitors’ race Mol. Ther. (IF 12.1) Pub Date : 2025-01-30 Soumaya Ben-Aicha, Costanza Emanueli
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Systematic empirical evaluation of individual base editing targets: Validating therapeutic targets in USH2A and comparison of methods Mol. Ther. (IF 12.1) Pub Date : 2025-01-28 Yuki Tachida, Kannan V. Manian, Rossano Butcher, Jonathan M. Levy, Nachiket Pendse, Erin Hennessey, David R. Liu, Eric A. Pierce, Qin Liu, Jason Comander
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
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Rescue from Stx2-Producing E. coli-Associated Encephalopathy by Intravenous Injection of Muse Cells in NOD-SCID Mice Mol. Ther. (IF 12.1) Pub Date : 2025-01-28 Ryo Ozuru, Shohei Wakao, Takahiro Tsuji, Naoya Ohara, Takashi Matsuba, Muhammad Y. Amran, Junko Isobe, Morio Iino, Naoki Nishida, Sari Matsumoto, Kimiharu Iwadate, Noriko Konishi, Kaori Yasuda, Kosuke Tashiro, Misato Hida, Arisato Yadoiwa, Shinsuke Kato, Eijiro Yamashita, Sohkichi Matsumoto, Yoichi Kurozawa, Mari Dezawa, Jun Fujii
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Centrosome protein TAX1BP mediates STING-dependent immune response and potentiates anti-PD-1 efficacy in hepatocellular carcinoma Mol. Ther. (IF 12.1) Pub Date : 2025-01-28 Qingmei Zhang, Wing-Lim Chan, Sin-Yee Fung, Li Pang, Tao Ding, Jia Ming Nickolas Teo, Yuan Zhou, Chung Ming Alex Wu, Kam-Leung Siu, Jiacheng Bi, Guang Sheng Ling, Dong-Yan Jin, Kwan Man, Yick Pang Ching
Centrosome aberrations are a common feature in human cancer cells. Our previous studies demonstrated that the centrosomal protein Tax1 binding protein 2 (TAX1BP2) inhibits centrosome overduplication and is underexpressed in hepatocellular carcinoma (HCC). Here, we report that Intratumoral TAX1BP2 promotes tumor lymphocyte infiltration and enhances the efficacy of anti-PD-1 therapy. Clinically, we discovered
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PBAE-PEG-based lipid nanoparticles for lung cell-specific gene delivery Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Bingxin Liu, Yamato Sajiki, Nicole Littlefield, Yongan Hu, William D. Stuart, Anusha Sridharan, Xuemei Cui, Matthew E. Siefert, Koichi Araki, Assem G. Ziady, Donglu Shi, Jeffery A. Whitsett, Yutaka Maeda
Exemplified by successful use in COVID-19 vaccination, delivery of modified mRNA encapsulated in lipid nanoparticles (LNPs) provides a framework for treating various genetic and acquired disorders. However, LNPs that can deliver mRNA into specific lung cell types have not yet been established. Here, we sought to determine whether poly(β-amino ester)s (PBAE) or PEGylated PBAE (PBAE-PEG) in combination
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A comprehensive atlas of AAV tropism in the mouse Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Christopher J. Walkey, Kathy J. Snow, Jote Bulcha, Aaron R. Cox, Alexa E. Martinez, M. Cecilia Ljungberg, Denise G. Lanza, Marco De Giorgi, Marcel A. Chuecos, Michele Alves-Bezerra, Carlos Flores Suarez, Sean M. Hartig, Susan G. Hilsenbeck, Chih-Wei Hsu, Ethan Saville, Yaned Gaitan, Jeff Duryea Jr., Seth Hannigan, Mary E. Dickinson, Oleg Mirochnitchenko, Dan Wang, Cathleen M. Lutz, Jason D. Heaney
Gene therapy with adeno-associated virus (AAV) vectors requires knowledge of their tropism within the body. Here we analyze the tropism of 10 naturally occurring AAV serotypes (AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10, and AAVrh74) following systemic delivery into male and female mice. A transgene-expressing ZsGreen and Cre recombinase was used to identify transduction in a cell-dependent
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CDK1-loaded extracellular vesicles promote cell cycle to reverse impaired wound healing in diabetic obese mice Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Wooil Choi, Dong Jun Park, Robert A. Dorschner, Keita Nakatsutsumi, Michelle Yi, Brian P. Eliceiri
Small extracellular vesicles (sEVs) mediate intercellular signaling to coordinate the proliferation of cell types that promote re-epithelialization of skin following injury. Cyclin-dependent kinase 1 (CDK1) drives cell division and is a key regulator of entry to the cell cycle. To understand the potential of sEV-mediated delivery of CDK1 to reverse impaired wound healing, we generated CDK1-loaded sEVs
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Tissue nanotransfection-based endothelial PLCγ2-targeted epigenetic gene editing in vivo rescues perfusion and diabetic ischemic wound healing Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Sumit S. Verma, Chandan K. Sen, Rajneesh Srivastava, Surya C. Gnyawali, Parul Katiyar, Ajay K. Sahi, Manishekhar Kumar, Yashika Rustagi, Sheng Liu, Diksha Pandey, Ahmed S. Abouhashem, Leila N.W. Fehme, Sedat Kacar, Sujit K. Mohanty, Julie Faden-McCormack, Michael P. Murphy, Sashwati Roy, Jun Wan, Mervin C. Yoder, Kanhaiya Singh
Diabetic wounds are complicated by underlying peripheral vasculopathy. Reliance on vascular endothelial growth factor (VEGF) therapy to improve perfusion makes logical sense, yet clinical study outcomes on rescuing diabetic wound vascularization have yielded disappointing results. Our previous work has identified that low endothelial phospholipase Cγ2 (PLCγ2) expression hinders the therapeutic effect
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Pharmacological blocking of microfibrillar-associated protein 4 reduces retinal neoangiogenesis and vascular leakage Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Anders Schlosser, Bartosz Pilecki, Claire Allen, Andrew V. Benest, Amy P. Lynch, Jing Hua, Nikita Ved, Zoe Blackley, Thomas L. Andersen, Dorle Hennig, Jonas H. Graversen, Sören Möller, Sofie Skallerup, Maria Ormhøj, Clemens Lange, Hansjürgen T. Agostini, Jakob Grauslund, Steffen Heegaard, Ivanka Dacheva, Michael Koss, Wenzheng Hu, Bibiana Iglesias, Matthew S. Lawrence, Hans Christian Beck, Lasse Bach
Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αVβ3/5/6 ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell types in close proximity to vascular endothelial
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Engineering resilient CAR T cells for immunosuppressive environment Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Malak Khalifeh, Huda Salman
Chimeric antigen receptor (CAR) T cell therapy has revolutionized cancer treatment and is now being explored for other diseases, such as autoimmune disorders. While the tumor microenvironment (TME) in cancer is often immunosuppressive, in autoimmune diseases, the environment is typically inflammatory. Both environments can negatively impact CAR T cell survival: the former through direct suppression
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GITRL enhances cytotoxicity and persistence of CAR-T cells in cancer therapy Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Binghe Tan, Chuntian Tu, Hao Xiong, Yongqian Xu, Xiujuan Shi, Xiaolin Zhang, Ruijie Yang, Na Zhang, Boxu Lin, Mingyao Liu, Juliang Qin, Bing Du
Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in treating hematological malignancies. However, its clinical efficacy in solid tumors is less satisfactory, partially due to poor in vivo expansion and the limited persistence of CAR-T cells. Here, we demonstrated that the overexpression of glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein
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TRAF1 promotes osteoclastogenesis by enhancing metabolic adaptation to oxidative phosphorylation in an AKT-dependent manner Mol. Ther. (IF 12.1) Pub Date : 2025-01-25 Honglei Kang, Renpeng Peng, Yiming Dong, Fuben Liao, Meipeng Zhu, Pengju Wang, Shi-an Hu, Peixuan Hu, Jia Wang, Zheming Liu, Kehan Song, Feng Li
Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a crucial signaling adaptor involved in multiple cellular events. However, its role in regulating osteoclastogenesis and energy metabolism remains unclear. Here, we report that TRAF1 promotes osteoclastogenesis and oxidative phosphorylation (OXPHOS). Employing RNA sequencing, we found that TRAF1 is markedly upregulated during osteoclastogenesis
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Gene therapy in China: From a clinician's perspective. Mol. Ther. (IF 12.1) Pub Date : 2025-01-24 Xiaole Wang,Jing Peng
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A path toward developing a universal mucosal influenza vaccine: An upside-down influenza HA vaccine based on extracellular vesicles Mol. Ther. (IF 12.1) Pub Date : 2025-01-24 Sajjad Nejabat, Zahra Adloo, Navid Nezafat
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A promising advance using oncolytic adenovirus to locally block tumorigenic TNF signaling Mol. Ther. (IF 12.1) Pub Date : 2025-01-23 Yalei Zhang, Peng Wang
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Transforming TGF-β suppression into IL-15 stimulation: Advancing engineered CAR-T therapy for solid tumors Mol. Ther. (IF 12.1) Pub Date : 2025-01-23 Hyungseok Seo
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RNA and epigenetic editing: The new frontier in gene and cell therapy Mol. Ther. (IF 12.1) Pub Date : 2025-01-21 Federico Avila-Moreno, Paloma H. Giangrande
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Promotion or inhibition? This is a question in gene editing Mol. Ther. (IF 12.1) Pub Date : 2025-01-21 Li-Kuang Tsai, Renzhi Han, Dongshan Yang, Y. Eugene Chen, Jifeng Zhang, Jie Xu
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Orchestrating cytosolic access: The partnership of cationic lytic peptide L17E and potassium channel KCa3.1 Mol. Ther. (IF 12.1) Pub Date : 2025-01-21 Keykavous Parang
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Low-inflammatory lipid nanoparticles facilitate safe mRNA vaccination against influenza virus infection Mol. Ther. (IF 12.1) Pub Date : 2025-01-21 Yuehua Xu, Guangxi Zhai, Da-Peng Yang, Gang Chen
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SHIV fights back to evade destruction by eCD4-Ig but not without suffering debilitating wounds Mol. Ther. (IF 12.1) Pub Date : 2025-01-21 Eric J. Arts
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Vitronectin regulates lung tissue remodeling and emphysema in chronic obstructive pulmonary disease Mol. Ther. (IF 12.1) Pub Date : 2025-01-21 Gang Liu, Alan C. Hsu, Silke Geirnaert, Christine Cong, Prema M. Nair, Sj Sijie Shen, Jacqueline 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. Oliver, K. Fan Chung, Ian M. Adcock, Darryl A. Knight, Francesca Polverino, Ken Bracke, Peter A. Wark, Philip M. Hansbro
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
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Enhanced restoration of visual code after targeting ON bipolar cells compared with retinal ganglion cells with optogenetic therapy Mol. Ther. (IF 12.1) Pub Date : 2025-01-17 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
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
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Treating genetic blood disorders in the era of CRISPR-mediated genome editing Mol. Ther. (IF 12.1) Pub Date : 2025-01-17 Alhomidi Almotiri, Ahmed Abogosh, Ali Abdelfattah, Dalya Alowaisy, Neil P. Rodrigues
In the setting of monogenic disease, advances made in genome editing technologies can, in principle, be deployed as a therapeutic strategy to precisely correct a specific gene mutation in an affected cell type and restore functionality. Using the β-hemoglobinopathies and hemophilia as exemplars, we review recent experimental breakthroughs using CRISPR-derived genome editing technology that have translated
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Characterization of the ocular inflammatory response to AAV reveals divergence by sex and age Mol. Ther. (IF 12.1) Pub Date : 2025-01-17 Alison J. Clare, Philip M. Langer, Amy Ward, Ying Kai Chan, Andrew D. Dick, David A. Copland
Progress for ocular adeno-associated virus (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
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Transforming bacterial pathogens into wonder tools in cancer immunotherapy Mol. Ther. (IF 12.1) Pub Date : 2025-01-17 Amal Senevirathne, Khristine Kaith S. Lloren, Ram Prasad Aganja, Jun Kwon, John Hwa Lee
Cancer immunotherapy has revolutionized cancer treatment due to its precise, target-specific approach compared with 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
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The risk of reactivity against healthy tissues: Novel CARs demand testing for overlooked binding properties Mol. Ther. (IF 12.1) Pub Date : 2025-01-15 Astrid Holzinger, Florian Weber, Hinrich Abken
A rapidly growing number of chimeric antigen receptors (CARs) is being translated into cell therapy for malignant and autoimmune diseases. While cancer cell-selective CAR targeting is undergoing continuous refinement, specific testing for overlooked recognition of healthy tissues is commonly not performed, which potentially results in underestimating of the risk of severe tissue damage upon CAR T cell
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Virus-free CRISPR knockin of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells Mol. Ther. (IF 12.1) Pub Date : 2025-01-14 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
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
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Genetically reprogrammed exosomes for immunotherapy of acute myeloid leukemia Mol. Ther. (IF 12.1) Pub Date : 2025-01-14 Lei Zhang, Guoyun Kao, Yuanteng Zhao, Zeyu Zhang, Hyo Sun Kim, Xiaojing Shi, Qinqin Cheng, Tianling Hou, Heinz-Josef Lenz, Yong Zhang
Current treatments for acute myeloid leukemia (AML) remain challenging and are characterized by poor clinical outcomes. Exosomes, cell-derived membranous vesicles, have been emerging as a new modality of therapy. Here, we designed and generated genetically reprogrammed exosomes with surface-displayed antibodies and immunoregulatory proteins, namely programmed immune-engaging exosomes (PRIME Exos).
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Pancreatic cancer-derived extracellular vesicles remodel the tumor microenvironment and enhance chemoresistance by delivering KRASG12D protein to cancer-associated fibroblasts Mol. Ther. (IF 12.1) Pub Date : 2025-01-14 Xinyuan Liu, Jiaqi Yang, Sicong Huang, Yifan Hong, Yupeng Zhu, Jianing Wang, Yi Wang, Tingbo Liang, Xueli Bai
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
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A new era of Molecular Therapy: My vision for the future of the journal as the incoming Editor-in-Chief Mol. Ther. (IF 12.1) Pub Date : 2025-01-12 Joseph C. Glorioso
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Depletion of alloreactive B cells by drug-resistant chimeric alloantigen receptor T cells to prevent transplant rejection Mol. Ther. (IF 12.1) Pub Date : 2025-01-11 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
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
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Functional rescue of F508del-CFTR through revertant mutations introduced by CRISPR base editing Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Irene Carrozzo, Giulia Maule, Carmelo Gentile, Alessandro Umbach, Matteo Ciciani, Daniela Guidone, Martina De Santis, Gianluca Petris, Luis Juan Vicente Galietta, Daniele Arosio, Anna Cereseto
Cystic fibrosis (CF) is a life-shortening autosomal recessive disease caused by mutations in the CFTR gene, resulting in functional impairment of the encoded ion channel. F508del mutation, a trinucleotide deletion, is the most frequent cause of CF, affecting approximately 80% of persons with CF (pwCFs). Even though current pharmacological treatments alleviate the F508del-CF disease symptoms, there
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Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Maureen Buckley, Mariluz Araínga, Laura Maiorino, Ivan S. Pires, B.J. Kim, Katarzyna Kaczmarek Michaels, Jonathan Dye, Kashif Qureshi, Yiming J. Zhang, Howard Mak, Jon M. Steichen, William R. Schief, Francois Villinger, Darrell J. Irvine
mRNA delivered using lipid nanoparticles (LNPs) has become an important subunit vaccine modality, but mechanisms of action for mRNA vaccines remain incompletely understood. Here, we synthesized a metal chelator-lipid conjugate enabling positron emission tomography (PET) tracer labeling of LNP/mRNA vaccines for quantitative visualization of vaccine trafficking in live mice and non-human primates (NHPs)
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Effect of immunoadsorption on clinical presentation and immune alterations in COVID-19–induced and/or aggravated ME/CFS Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Moritz Anft, Lea Wiemers, Kamil S. Rosiewicz, Adrian Doevelaar, Sarah Skrzypczyk, Julia Kurek, Sviatlana Kaliszczyk, Maximilian Seidel, Ulrik Stervbo, Felix S. Seibert, Timm H. Westhoff, Nina Babel
Autoantibodies (AABs) are currently being investigated as causative or aggravating factors during post-COVID. In this study, we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection
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Efficient gene delivery admitted by small metabolites specifically targeting astrocytes in the mouse brain Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Haibin Zhou, Jiajing Dai, Dong Li, Luyao Wang, Meng Ye, Xiaoling Hu, Joseph LoTurco, Ji Hu, Wenzhi Sun
The development of efficient and targeted methods for delivering DNA in vivo has long been a major focus of research. In this study, we introduce a gene delivery approach admitted by small metabolites (gDAM) for the efficient and targeted delivery of naked DNA into astrocytes in the adult brains of mice. gDAM uses a straightforward combination of DNA and small metabolites, including glycine, L-proline
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Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe OTC deficiency Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Jenny Zhou, Shi Liang, Ling Yin, Andrea Frassetto, Anne-Renee Graham, Rebecca White, Maria Principe, Madelyn Severson, Tiffany Palmer, Shan Naidu, Eric Jacquinet, Mike Zimmer, Patrick F. Finn, Paolo G.V. Martini
Ornithine transcarbamylase deficiency (OTCD) is the most common urea-cycle disorder, characterized by hyperammonemia and accompanied by a high unmet patient need. mRNA therapies have been shown to be efficacious in hypomorphic Sparse-fur abnormal skin and hair (Spf-ash) mice, a model of late-onset disease. However, studying the efficacy of ornithine transcarbamylase (OTC) mRNA therapy in traditional
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Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Vicente Valenzuela, Daniela Becerra, José I. Astorga, Matías Fuentealba, Guillermo Diaz, Leslie Bargsted, Carlos Chacón, Alexis Martinez, Romina Gozalvo, Kasey Jackson, Vania Morales, Macarena Las Heras, Giovanni Tamburini, Leonard Petrucelli, S. Pablo Sardi, Lars Plate, Claudio Hetz
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The
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Scalable control of stem cell fate by riboswitch-regulated RNA viral vector without genomic integration Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Narae Kim, Yohei Yokobayashi
Transgene expression in stem cells is a powerful means of regulating cellular properties and differentiation into various cell types. However, existing vectors for transgene expression in stem cells suffer from limitations such as the need for genomic integration, the transient nature of gene expression, and the inability to temporally regulate transgene expression, which hinder biomedical and clinical
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Focused ultrasound and microbubble-mediated delivery of CRISPR-Cas9 ribonucleoprotein to human induced pluripotent stem cells Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Kyle Hazel, Davindra Singh, Stephanie He, Zakary Guertin, Mathieu C. Husser, Brandon Helfield
CRISPR-Cas9 ribonucleoproteins (RNPs) have been heavily considered for gene therapy due to their high on-target efficiency, rapid activity, and lack of insertional mutagenesis relative to other CRISPR-Cas9 delivery formats. Genetic diseases such as hypertrophic cardiomyopathy currently lack effective treatment strategies and are prime targets for CRISPR-Cas9 gene editing technology. However, current
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The high efficacy of claudin18.2-targeted CAR-T cell therapy in advanced pancreatic cancer with an antibody-dependent safety strategy Mol. Ther. (IF 12.1) Pub Date : 2025-01-10 Guocheng Zhong, Xiaomin Zhang, Ruocong Zhao, Zheng Guo, Chenguang Wang, Chuan Yu, Dongzhe Liu, Ke Hu, Yujie Gao, Bochen Zhao, Xianhao Liu, Xuanren Shi, Lei Chen, Yisheng Li, Li Yu
Pancreatic cancer (PC) is one of the most lethal digestive system tumors. Claudin18.2 is highly expressed in PC tissue and could serve as a suitable target for CAR-T therapy. In the present study, we reported the utilization of tEGFR-expressing claudin18.2-targeted CAR-T cells to treat 3 patients with advanced PC. Intriguingly, all 3 patients achieved disease remission after CAR-T cell infusion, with
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Emerging combined CAR-NK cell therapies in cancer treatment: Finding a dancing partner Mol. Ther. (IF 12.1) Pub Date : 2025-01-03 Hamed Hosseinalizadeh, Li-Shu Wang, Hamed Mirzaei, Zohreh Amoozgar, Lei Tian, Jianhua Yu
In recent decades, immunotherapy with chimeric antigen receptors (CARs) has revolutionized cancer treatment and given hope where other cancer therapies have failed. CAR-natural killer (NK) cells are NK cells that have been engineered ex vivo with a CAR on the cell membrane with high specificity for specific target antigens of tumor cells. The impressive results of several studies suggest that CAR-NK
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ATGL regulates renal fibrosis by reprogramming lipid metabolism during the transition from AKI to CKD Mol. Ther. (IF 12.1) Pub Date : 2025-01-02 Xiaofan Li, Jianwen Chen, Jun Li, Yixuan Zhang, Jikai Xia, Hongjian Du, Chunjia Sheng, Mengjie Huang, Wanjun Shen, Guangyan Cai, Lingling Wu, Xueyuan Bai, Xiangmei Chen
Acute kidney injury (AKI) can progress to chronic kidney disease (CKD) and subsequently to renal fibrosis. Poor repair of renal tubular epithelial cells (TECs) after injury is the main cause of renal fibrosis. Studies have shown that restoring damaged fatty acid β-oxidation (FAO) can reduce renal fibrosis. Adipose triglyceride lipase (ATGL) is a key enzyme that regulates lipid hydrolysis. This study
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Hyperactive delta isoform of PI3 kinase enables long-distance regeneration of adult rat corticospinal tract Mol. Ther. (IF 12.1) Pub Date : 2025-01-01 Kristyna Karova, Zuzana Polcanova, Lydia Knight, Stepanka Suchankova, Bart Nieuwenhuis, Radovan Holota, Vit Herynek, Lucia Machova Urdzikova, Rostislav Turecek, Jessica C. Kwok, Joelle van den Herik, Joost Verhaagen, Richard Eva, James W. Fawcett, Pavla Jendelova
Neurons in the CNS lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonizes PI3K signaling by hydrolyzing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study