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The role of the mitochondrial protein VDAC1 in inflammatory bowel disease: a potential therapeutic target Mol. Ther. (IF 12.4) Pub Date : 2024-03-13 Ankit Verma, Srinivas Pittala, Belal Alhozeel, Anna Shteinfer-Kuzmine, Ehud Ohana, Rajeev Gupta, Jay H. Chung, Varda Shoshan-Barmatz
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In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice Mol. Ther. (IF 12.4) Pub Date : 2024-03-07 Desirée Böck, Ilma M. Revers, Anastasia S.J. Bomhof, Anne E.J. Hillen, Claire Boeijink, Lucas Kissling, Sabina Egli, Miguel A. Moreno-Mateos, Marjo S. van der Knaap, Niek P. van Til, Gerald Schwank
Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors
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The extracellular cyclophilin A-integrin β2 complex as a therapeutic target of viral pneumonia Mol. Ther. (IF 12.4) Pub Date : 2024-03-07 Xiaoyuan Bai, Wenxian Yang, Yuna Zhao, Tongtong Cao, Runshan Lin, Pengtao Jiao, Heqiao Li, Huizi Li, Jie Min, Xiaoxiao Jia, He Zhang, Wenhui Fan, Xiaojuan Jia, Yuhai Bi, Wenjun Liu, Lei Sun
The acute respiratory virus infection can induce uncontrolled inflammatory responses, such as cytokine storm and viral pneumonia, which are the major causes of death in clinical cases. Cyclophilin A (CypA) is mainly distributed in the cytoplasm of resting cells and released into the extracellular space in response to inflammatory stimuli. Extracellular CypA (eCypA) is upregulated and promotes inflammatory
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ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production Mol. Ther. (IF 12.4) Pub Date : 2024-03-07 Xichun Xia, Leqing Zhu, Miaomiao Xu, Zhiwei Lei, Hai Yu, Guangqiang Li, Xiao Wang, Hongling Jia, Zhinan Yin, Fang Huang, Yunfei Gao
Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation
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On- and off-target effects of paired CRISPR-Cas nickase in primary human cells Mol. Ther. (IF 12.4) Pub Date : 2024-03-07 Julia Klermund, Manuel Rhiel, Thomas Kocher, Kay Ole Chmielewski, Johannes Bischof, Geoffroy Andrieux, Melina el Gaz, Stefan Hainzl, Melanie Boerries, Tatjana I. Cornu, Ulrich Koller, Toni Cathomen
Undesired on- and off-target effects of CRISPR-Cas nucleases remain a challenge in genome editing. While the use of Cas9 nickases has been shown to minimize off-target mutagenesis, their use in therapeutic genome editing has been hampered by a lack of efficacy. To overcome this limitation, we and others have developed double-nickase-based strategies to generate staggered DNA double-strand breaks to
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Autologous gene therapy for hemoglobinopathies: From bench to patient’s bedside Mol. Ther. (IF 12.4) Pub Date : 2024-03-07 Franco Locatelli, Marina Cavazzana, Haydar Frangoul, Josu de la Fuente, Mattia Algeri, Roland Meisel
In recent years, a growing number of clinical trials have been initiated to evaluate gene therapy approaches for the treatment of patients with transfusion-dependent β-thalassemia and sickle cell disease (SCD). Therapeutic modalities being assessed in these trials utilize different molecular techniques, including lentiviral vectors to add functional copies of the gene encoding the hemoglobin β subunit
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Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke Mol. Ther. (IF 12.4) Pub Date : 2024-03-07 Jia Nong, Patrick M. Glassman, Vladimir V. Shuvaev, Sahily Reyes-Esteves, Helene C. Descamps, Raisa Y. Kiseleva, Tyler E. Papp, Mohamad-Gabriel Alameh, Ying K. Tam, Barbara L. Mui, Serena Omo-Lamai, Marco E. Zamora, Tea Shuvaeva, Evguenia Arguiri, Xijing Gong, Taylor V. Brysgel, Ai Wen Tan, Ashley G. Woolfork, Aalim Weljie, Christoph A. Thaiss, Jacob W. Myerson, Drew Weissman, Scott E. Kasner, Hamideh
Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase
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C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis Mol. Ther. (IF 12.4) Pub Date : 2024-03-06 Baokui Ye, Binfeng Chen, Chaohuan Guo, Ningjing Xiong, Yuefang Huang, Mengyuan Li, Yimei Lai, Jin Li, Mianjing Zhou, Shuang Wang, Shuyi Wang, Niansheng Yang, Hui Zhang
Podocytes are essential to maintaining the integrity of the glomerular filtration barrier, but they are frequently affected in lupus nephritis (LN). Here, we show that the significant upregulation of Drp1 phosphorylation in podocytes promotes mitochondrial fission, leading to mitochondrial dysfunction and podocyte injury in LN. Inhibition or knockdown of Drp1 promotes mitochondrial fusion and protects
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Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo Mol. Ther. (IF 12.4) Pub Date : 2024-03-06 Kari-Ann Takano, Anita A.L. Wong, Rebecca Brown, Kathy Situ, Bernadette Anne Chua, Angel Elma Abu, Truc T. Pham, Glania Carel Reyes, Sangeetha Ramachandran, Masakazu Kamata, Melody M.H. Li, Ting-Ting Wu, Dinesh S. Rao, Vaithilingaraja Arumugaswami, Kenneth Dorshkind, Steve Cole, Kouki Morizono
While studying transgene expression after systemic administration of lentiviral vectors, we found that splenic B cells are robustly transduced, regardless of the types of pseudotyped envelope proteins. However, the administration of two different pseudotypes resulted in transduction of two distinct B cell populations, suggesting that each pseudotype uses unique and specific receptors for its attachment
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Engineering small-molecule and protein drugs for targeting bone tumors Mol. Ther. (IF 12.4) Pub Date : 2024-03-06 Yixian Wang, Chenhang Wang, Meng Xia, Zeru Tian, Joseph Zhou, Julian Meyer Berger, Xiang Zhang, Han Xiao
Bone cancer is common and severe. Both primary (e.g., osteosarcoma, Ewing sarcoma) and secondary (e.g., metastatic) bone cancers lead to significant health problems and death. Currently, treatments such as chemotherapy, hormone therapy, and radiation therapy are used to treat bone cancer, but they often only shrink or slow tumor growth and do not eliminate cancer completely. The bone microenvironment
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Nr4a1 enhances Wnt4 transcription to promote mesenchymal stem cell osteogenesis and alleviates inflammation-inhibited bone regeneration Mol. Ther. (IF 12.4) Pub Date : 2024-03-01 Yangshuai Gao, Yuming Zou, Dimitri Sokolowskei, Xin Xing, Robert J. Tower, Zejia Lai, Jiawei Shi, Liheng Zhu, Quan Zheng, Aaron W. James, Jiajia Xu, Zhongmin Zhang
Intense inflammatory response impairs bone marrow mesenchymal stem cell (BMSC)-mediated bone regeneration, with transforming growth factor (TGF)-β1 being the most highly expressed cytokine. However, how to find effective and safe means to improve bone formation impaired by excessive TGF-β1 remains unclear. In this study, we found that the expression of orphan nuclear receptor Nr4a1, an endogenous repressor
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Gene therapy approaches for obesity-induced adipose neuropathy: Device-targeted AAV-mediated neurotrophic factor delivery to adipocytes in subcutaneous adipose Mol. Ther. (IF 12.4) Pub Date : 2024-03-01 Magdalena Blaszkiewicz, Tianyi Tao, Kofi Mensah-Arhin, Jake W. Willows, Rhiannon Bates, Wei Huang, Lei Cao, Rosemary L. Smith, Kristy L. Townsend
Maintaining functional adipose innervation is critical for metabolic health. We found that subcutaneous white adipose tissue (scWAT) undergoes peripheral neuropathy (PN) with obesity, diabetes, and aging (reduced small-fiber innervation and nerve/synaptic/growth-cone/vesicle markers, altered nerve activity). Unlike with nerve injuries, peripheral nerves do not regenerate with PN, and therefore new
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ASOs are an effective treatment for disease-associated oligodendrocyte signatures in premanifest and symptomatic SCA3 mice Mol. Ther. (IF 12.4) Pub Date : 2024-02-29 Kristen H. Schuster, Annie J. Zalon, Danielle M. DiFranco, Alexandra F. Putka, Nicholas R. Stec, Sabrina I. Jarrah, Arsal Naeem, Zaid Haque, Hanrui Zhang, Yuanfang Guan, Hayley S. McLoughlin
Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventive or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, , producing an enlarged polyglutamine tract in
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Lentiviral expression of wild-type LAMA3A restores cell adhesion in airway basal cells from children with epidermolysis bullosa Mol. Ther. (IF 12.4) Pub Date : 2024-02-29 Chun Hang Lau, Maral J. Rouhani, Elizabeth F. Maughan, Jessica C. Orr, Krishna K. Kolluri, David R. Pearce, Elizabeth K. Haughey, Liam Sutton, Sam Flatau, Pablo Lopez Balboa, Maria Laura Bageta, Christopher O’Callaghan, Claire M. Smith, Sam M. Janes, Richard Hewitt, Gabriela Petrof, Anna E. Martinez, John A. McGrath, Colin R. Butler, Robert E. Hynds
The hallmark of epidermolysis bullosa (EB) is fragile attachment of epithelia due to genetic variants in cell adhesion genes. We describe 16 EB patients treated in the ear, nose, and throat department of a tertiary pediatric hospital linked to the United Kingdom’s national EB unit between 1992 and 2023. Patients suffered a high degree of morbidity and mortality from laryngotracheal stenosis. Variants
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Activation of the YAP/KLF5 transcriptional cascade in renal tubular cells aggravates kidney injury Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 Yang Liu, Yu Wang, Chunhua Xu, Yu Zhang, Yang Wang, Jinzhong Qin, Hui-Yao Lan, Li Wang, Yu Huang, Kingston Kinglun Mak, Zhihua Zheng, Yin Xia
The Hippo/YAP pathway plays a critical role in tissue homeostasis. Our previous work demonstrated that renal tubular YAP activation induced by double knockout (dKO) of the upstream Hippo kinases Mst1 and Mst2 promotes tubular injury and renal inflammation under basal conditions. However, the importance of tubular YAP activation remains to be established in injured kidneys in which many other injurious
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CD20 CAR T cells safely and reversibly ablate B cell follicles in a non-human primate model of HIV persistence Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 John K. Bui, Carly E. Starke, Nikhita H. Poole, Blake J. Rust, Keith R. Jerome, Hans-Peter Kiem, Christopher W. Peterson
Chimeric antigen receptor (CAR) T cell therapies have demonstrated immense clinical success for B cell and plasma cell malignancies. We tested their impact on the viral reservoir in a macaque model of HIV persistence, comparing the functions of CD20 CAR T cells between animals infected with simian/human immunodeficiency virus (SHIV) and uninfected controls. We focused on the potential of this approach
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Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 Ziyi Liu, Hanbing Zhang, Guodong Hong, Xiuli Bi, Jun Hu, Tiancheng Zhang, Yachun An, Na Guo, Fengyue Dong, Yu Xiao, Wen Li, Xiaoxu Zhao, Bo Chu, Siwei Guo, Xiaohan Zhang, Renjie Chai, Xiaolong Fu
Cisplatin-induced hearing loss is a common side effect of cancer chemotherapy in clinics; however, the mechanism of cisplatin-induced ototoxicity is still not completely clarified. Cisplatin-induced ototoxicity is mainly associated with the production of reactive oxygen species, activation of apoptosis, and accumulation of intracellular lipid peroxidation, which also is involved in ferroptosis induction
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SMART-lipid nanoparticles enabled mRNA vaccine elicits cross-reactive humoral responses against the omicron sub-variants Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 Gokulnath Mahalingam, Hari Krishnareddy Rachamalla, Porkizhi Arjunan, Karthik V. Karuppusamy, Yogapriya Periyasami, Aruna Mohan, Kanimozhi Subramaniyam, Salma M, Vigneshwar Rajendran, Mahesh Moorthy, George M. Varghese, Kumarasamypet M. Mohankumar, Saravanabhavan Thangavel, Alok Srivastava, Srujan Marepally
The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has necessitated the development of broad cross-reactive vaccines. Recent findings suggest that enhanced antigen presentation could lead to cross-reactive humoral responses against the emerging variants. Toward enhancing the antigen presentation to dendritic cells (DCs), we developed a novel shikimoylated
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Hnrnpk protects against osteoarthritis through targeting WWC1 mRNA and inhibiting Hippo signaling pathway Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 Shun Zhang, Baolin Zhang, Zhiheng Liao, Yuyu Chen, Weimin Guo, Jinna Wu, Hengyu Liu, Ricong Weng, Deying Su, Gengjia Chen, Zhenzhen Zhang, Chuan Li, Jiahui Long, Ya Xiao, Yuan Ma, Taifeng Zhou, Caixia Xu, Peiqiang Su
Osteoarthritis (OA) is an age-related or post-traumatic degenerative whole joint disease characterized by the rupture of articular cartilage homeostasis, the regulatory mechanisms of which remain elusive. This study identifies the essential role of heterogeneous nuclear ribonucleoprotein K (hnRNPK) in maintaining articular cartilage homeostasis. Hnrnpk expression is markedly downregulated in human
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Stem cell-derived CAR T cells show greater persistence, trafficking, and viral control compared to ex vivo transduced CAR T cells Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 Mayra A. Carrillo, Anjie Zhen, Wenli Mu, Valerie Rezek, Heather Martin, Christopher W. Peterson, Hans-Peter Kiem, Scott G. Kitchen
Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells
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Osr1-mediated mesothelial transition of liver mesenchymal cells exacerbates fibrotic liver damage Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 Xinxin Nian, Pengyan Lin, Yunfei Bai, Donglin Yu, Xinyan Yang, Bin Zhou, Jie Gao, Yang Zhao
In chronic liver diseases, hepatic stellate cells (HSCs) are induced to form the myofibroblasts responsible for scar formation, leading to liver fibrosis and cirrhosis. Here, single-cell RNA sequencing with lineage tracing in nonalcoholic steatohepatitis (NASH) model mice reveals a subpopulation of HSCs transitioning back to a state resembling their developmental precursors, mesothelial cells (MCs)
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Therapeutic potential of RNA-enriched extracellular vesicles: The next generation in RNA delivery via biogenic nanoparticles Mol. Ther. (IF 12.4) Pub Date : 2024-02-27 Muskan Muskan, Pevindu Abeysinghe, Riccardo Cecchin, Heather Branscome, Kevin V. Morris, Fatah Kashanchi
Exosomes are extracellular vesicles (EVs) (∼50–150 nm) that have emerged as promising vehicles for therapeutic applications and drug delivery. These membrane-bound particles, released by all actively dividing cells, have the ability to transfer effector molecules, including proteins, RNA, and even DNA, from donor cells to recipient cells, thereby modulating cellular responses. RNA-based therapeutics
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Analysis of pre-treatment tumors reveals gatekeepers of response to CAR T cells Mol. Ther. (IF 12.4) Pub Date : 2024-02-22 Nathan Singh
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Inhibitory CARs fail to protect from immediate T cell cytotoxicity Mol. Ther. (IF 12.4) Pub Date : 2024-02-22 Maximilian A. Funk, Gerwin Heller, Petra Waidhofer-Söllner, Judith Leitner, Peter Steinberger
Chimeric antigen receptors (CARs) equipped with an inhibitory signaling domain (iCARs) have been proposed as strategy to increase on-tumor specificity of CAR-T cell therapies. iCARs inhibit T cell activation upon antigen recognition and thereby program a Boolean NOT gate within the CAR-T cell. If cancer cells do not express the iCAR target antigen while it is highly expressed on healthy tissue, CAR/iCAR
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Trial offers hope to children with hypoplastic left heart syndrome Mol. Ther. (IF 12.4) Pub Date : 2024-02-20 Joshua T. Maxwell, Graça Almeida-Porada, Christopher D. Porada
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TCR-like antibody and GITR signaling lead to effective CAR-T against solid tumor Mol. Ther. (IF 12.4) Pub Date : 2024-02-20 Nicholas R.J. Gascoigne
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C3d-Targeted factor H inhibits tissue complement in disease models and reduces glomerular injury without affecting circulating complement Mol. Ther. (IF 12.4) Pub Date : 2024-02-20 Fei Liu, Sarah T. Ryan, Kelly C. Fahnoe, Jennifer G. Morgan, Anne E. Cheung, Michael J. Storek, Alejandro Best, Hui A. Chen, Monica Locatelli, Shuyun Xu, Enno Schmidt, Leon F. Schmidt-Jiménez, Katja Bieber, Joel M. Henderson, Christine G. Lian, Admar Verschoor, Ralf J. Ludwig, Ariela Benigni, Giuseppe Remuzzi, David J. Salant, Susan L. Kalled, Joshua M. Thurman, V. Michael Holers, Shelia M. Violette
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Defining the activity of pro-reparative extracellular vesicles in wound healing based on miRNA payloads and cell type-specific lineage mapping Mol. Ther. (IF 12.4) Pub Date : 2024-02-19 Dong Jun Park, Wooil Choi, Sakeef Sayeed, Robert A. Dorschner, Joseph Rainaldi, Kayla Ho, Jenny Kezios, John P. Nolan, Prashant Mali, Todd Costantini, Brian P. Eliceiri
Small extracellular vesicles (EVs) are released by cells and deliver biologically active payloads to coordinate the response of multiple cell types in cutaneous wound healing. Here we used a cutaneous injury model as a donor of pro-reparative EVs to treat recipient diabetic obese mice, a model of impaired wound healing. We established a functional screen for microRNAs (miRNAs) that increased the pro-reparative
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Mono-amino acid linkers enable small molecule-drug conjugates highly potent by conditional release Mol. Ther. (IF 12.4) Pub Date : 2024-02-17 Yan Zheng, Ruolin Xu, Hong Cheng, Wanyi Tai
The endosome cleavable linkers have been widely employed by antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs) to control the accurate release of payloads. An effective linker should provide stability in systemic circulation but efficient payload release at its targeted tumor sites. This conflicting requirement always leads to the way of linker design with increasing structural
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IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism Mol. Ther. (IF 12.4) Pub Date : 2024-02-14 Grazia Locafaro, Grazia Andolfi, Fabio Russo, Luca Cesana, Antonello Spinelli, Barbara Camisa, Fabio Ciceri, Angelo Lombardo, Attilio Bondanza, Maria Grazia Roncarolo, Silvia Gregori
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Robust miniature Cas-based transcriptional modulation by engineering Un1Cas12f1 and tethering Sso7d Mol. Ther. (IF 12.4) Pub Date : 2024-02-12 Xiangnan Wang, Lingyun Li, Li Guo, Ying Feng, Zengming Du, Wei Jiang, Xia Wu, Jing Zheng, Xiao Xiao, Hui Zheng, Yadong Sun, Hanhui Ma
The miniature V-F CRISPR-Cas12f system has been repurposed for gene editing and transcription modulation. The small size of Cas12f satisfies the packaging capacity of adeno-associated virus (AAV) for gene therapy. However, the efficiency of Cas12f-mediated transcriptional activation varies among different target sites. Here, we developed a robust miniature Cas-based transcriptional activation or silencing
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A potential bivalent mRNA vaccine candidate protects against both RSV and SARS-CoV-2 infections Mol. Ther. (IF 12.4) Pub Date : 2024-02-09 Namei Wu, Jiachen Zhang, Yanqiong Shen, Xinghai Zhang, Jinge Zhou, Yan Wu, Entao Li, Xiaoming Meng, Xia Chuai, Sandra Chiu, Yucai Wang
As the world continues to confront severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV) is also causing severe respiratory illness in millions of infants, elderly individuals, and immunocompromised people globally. Exacerbating the situation is the fact that co-infection with multiple viruses is occurring, something which has greatly increased the clinical
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Retraction Notice to: Exosome-Mediated miR-155 Transfer from Smooth Muscle Cells to Endothelial Cells Induces Endothelial Injury and Promotes Atherosclerosis Mol. Ther. (IF 12.4) Pub Date : 2024-02-09 Bin Zheng, Wei-na Yin, Toru Suzuki, Xin-hua Zhang, Yu Zhang, Li-li Song, Li-shuang Jin, Hong Zhan, Hong Zhang, Jin-shui Li, Jin-kun Wen
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Alternative immune effector cells picking up speed Mol. Ther. (IF 12.4) Pub Date : 2024-02-09 Evan Weber, Marie Bleakley, James C. Cronk, Nirali N. Shah, Fabiana Perna
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miRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence Mol. Ther. (IF 12.4) Pub Date : 2024-02-09 Dong-Ping Chen, Jun-Cheng Wang, Zheng-Yu Liu, Pei-Lin Li, Ka-Wo Chan, Xiang-Ning Wu, Wu-De-Xin Yao, Tingting Yao, Dong-Ming Kuang, Yuan Wei
Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remains elusive. Here, we showed, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8% ± 2.6%/27.9% ± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma
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Ultrasound-mediated gene delivery specifically targets liver sinusoidal endothelial cells for sustained FVIII expression in hemophilia A mice Mol. Ther. (IF 12.4) Pub Date : 2024-02-09 Savannah M. Lawton, Megan A. Manson, Meng-Ni Fan, Ting-Yen Chao, Chun-Yu Chen, Peter Kim, Carley Campbell, Xiaohe Cai, Amber Vander Kooi, Carol H. Miao
The ability to target the native production site of factor VIII (FVIII)—liver sinusoidal endothelial cells (LSECs)—can improve the outcome of hemophilia A (HA) gene therapy. By testing a matrix of ultrasound-mediated gene delivery (UMGD) parameters for delivering a GFP plasmid into the livers of HA mice, we were able to define specific conditions for targeted gene delivery to different cell types in
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Hitchhiking of Cas9 with nucleus-localized proteins impairs its controllability and leads to efficient genome editing of NLS-free Cas9 Mol. Ther. (IF 12.4) Pub Date : 2024-02-09 Wenfeng Zhang, Haozheng Wang, Zhongtao Luo, Yingzhen Jian, Chenyu Gong, Hui Wang, Xinjian Lin, Meilin Liu, Yangmin Wang, Hongwei Shao
CRISPR-Cas9 is the most commonly used genome-editing tool in eukaryotic cells. To modulate Cas9 entry into the nucleus to enable control of genome editing, we constructed a light-controlled CRISPR-Cas9 system to control exposure of the Cas9 protein nuclear localization signal (NLS). Although blue-light irradiation was found to effectively control the entry of Cas9 protein into the nucleus with confocal
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M2 macrophages secrete glutamate-containing extracellular vesicles to alleviate osteoporosis by reshaping osteoclast precursor fate Mol. Ther. (IF 12.4) Pub Date : 2024-02-07 Xiaoyuan Huang, Yanhua Lan, Jiahui Shen, Xiaomin Zhao, Yanyan Zhou, Wenzhi Wu, Jiajie Mao, Yuzhu Wu, Zhijian Xie, Zhuo Chen
Osteoclast precursors (OCPs) are thought to commit to osteoclast differentiation, which is accelerated by aging-related chronic inflammation, thereby leading to osteoporosis. However, whether the fate of OCPs can be reshaped to transition into other cell lineages is unknown. Here, we showed that M2 macrophage-derived extracellular vesicles (M2-EVs) could reprogram OCPs to downregulate osteoclast-specific
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High-dose systemic adeno-associated virus vector administration causes liver and sinusoidal endothelial cell injury Mol. Ther. (IF 12.4) Pub Date : 2024-02-06 Juliette Hordeaux, R. Jason Lamontagne, Chunjuan Song, George Buchlis, Cecilia Dyer, Elizabeth L. Buza, Ali Ramezani, Erik Wielechowski, Jenny A. Greig, Jessica A. Chichester, Peter Bell, James M. Wilson
We analyzed retrospective data from toxicology studies involving administration of high doses of adeno-associated virus expressing different therapeutic transgenes to 21 cynomolgus and 15 rhesus macaques. We also conducted prospective studies to investigate acute toxicity following high-dose systemic administration of enhanced green fluorescent protein-expressing adeno-associated virus to 10 rhesus
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Metabolic reprogramming directed by super-enhancers in tumors: An emerging landscape Mol. Ther. (IF 12.4) Pub Date : 2024-02-06 Zongjiang Zhou, Jinghe Li, Diabate Ousmane, Li Peng, Xiaoqing Yuan, Junpu Wang
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Prenatal delivery of a therapeutic antisense oligonucleotide achieves broad biodistribution in the brain and ameliorates Angelman syndrome phenotype in mice Mol. Ther. (IF 12.4) Pub Date : 2024-02-06 Maria T. Clarke, Laura Remesal, Lea Lentz, Danielle J. Tan, David Young, Slesha Thapa, Shalini R. Namuduri, Beltran Borges, Georgia Kirn, Jasmine Valencia, Manuel E. Lopez, Jan H. Lui, Lawrence R. Shiow, Scott Dindot, Saul Villeda, Stephan J. Sanders, Tippi C. MacKenzie
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Mechanical force determines chimeric antigen receptor microclustering and signaling Mol. Ther. (IF 12.4) Pub Date : 2024-02-06 Yue Qiu, Qingyue Xiao, Yucai Wang, Yichen Cao, Jing Wang, Zhengpeng Wan, Xiangjun Chen, Wanli Liu, Li Ma, Chenguang Xu
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Targeting RORγ inhibits the growth and metastasis of hepatocellular carcinoma Mol. Ther. (IF 12.4) Pub Date : 2024-02-03 Qianqian Liu, Junhua Wang, Huizi Sun, Zhenhua Zhang, Hong Wang, Shuai Ma, Chenxi Zhang, Qianqian Wang, Guodi Cai, Jianwei Zheng, Yichu Nie, Peiqing Liu, Junjian Wang
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SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation Mol. Ther. (IF 12.4) Pub Date : 2024-02-03 Yanan Li, Tingting Wang, Xiaolei Li, Wen Li, Yan Lei, Qianwen Shang, Zhiyuan Zheng, Jiankai Fang, Lijuan Cao, Daojiang Yu, Zhenzhen Meng, Shengchao Zhang, Rui Liu, Chunxiao Liu, Chenchang Xu, Yayun Ding, Yongjing Chen, Eleonora Candi, Gerry Melino, Ying Wang, Yufang Shi, Changshun Shao
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DLK1/DIO3 locus upregulation by a β-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis Mol. Ther. (IF 12.4) Pub Date : 2024-02-03 Julie Sanceau, Lucie Poupel, Camille Joubel, Isabelle Lagoutte, Stefano Caruso, Sandra Pinto, Christèle Desbois-Mouthon, Cécile Godard, Akila Hamimi, Enzo Montmory, Cécile Dulary, Sophie Chantalat, Amélie Roehrig, Kevin Muret, Benjamin Saint-Pierre, Jean-François Deleuze, Sophie Mouillet-Richard, Thierry Forné, Christophe F. Grosset, Jessica Zucman-Rossi, Sabine Colnot, Angélique Gougelet
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An empowered, clinically viable hematopoietic stem cell gene therapy for the treatment of multisystemic mucopolysaccharidosis type II Mol. Ther. (IF 12.4) Pub Date : 2024-02-03 Sabyasachi Das, Fatlum Rruga, Annita Montepeloso, Agnese Dimartino, Silvia Spadini, Guillaume Corre, Janki Patel, Eleonora Cavalca, Francesca Ferro, Alessandra Gatti, Rita Milazzo, Anne Galy, Letterio S. Politi, Gian Paolo Rizzardi, Giuliana Vallanti, Valentina Poletti, Alessandra Biffi
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Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice Mol. Ther. (IF 12.4) Pub Date : 2024-02-03 Dong Ho Shin, Hong Jiang, Andrew G. Gillard, Debora Kim, Xuejun Fan, Sanjay K. Singh, Teresa T. Nguyen, Sagar S. Sohoni, Andres R. Lopez-Rivas, Akhila Parthasarathy, Chibawanye I. Ene, Joy Gumin, Frederick F. Lang, Marta M. Alonso, Candelaria Gomez-Manzano, Juan Fueyo
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Tau reduction with artificial microRNAs modulates neuronal physiology and improves tauopathy phenotypes in mice. Mol. Ther. (IF 12.4) Pub Date : 2024-02-03 Carolina Lucía Facal, Iván Fernández Bessone, Javier Andrés Muñiz, A. Ezequiel Pereyra, Olivia Pedroncini, Indiana Páez-Paz, Ramiro Clerici-Delville, Cayetana Arnaiz, Leandro Urrutia, Germán Falasco, Carla Verónica Argañaraz, Trinidad Saez, Antonia Marin-Burgin, Mariano Soiza-Reilly, Tomás Falzone, María Elena Avale
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m6A epitranscriptomic and epigenetic crosstalk in cardiac fibrosis Mol. Ther. (IF 12.4) Pub Date : 2024-02-03 Zhi-Yan Liu, Li-Chan Lin, Zhen-Yu Liu, Jing-Jing Yang, Hui Tao
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Development of CNS tropic AAV1-like variants with reduced liver-targeting following systemic administration in mice Mol. Ther. (IF 12.4) Pub Date : 2024-02-01 Matthieu Drouyer, Jessica Merjane, Deborah Nazareth, Maddison Knight, Suzanne Scott, Sophia H.Y. Liao, Samantha L. Ginn, Erhua Zhu, Ian E. Alexander, Leszek Lisowski
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Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats. Mol. Ther. (IF 12.4) Pub Date : 2024-01-29 Marjorie Kerzonkuf, Jérémy Verneuil, Cécile Brocard, Nejada Dingu, Virginie Trouplin, Jose Jorge Ramirez Franco, Marc Bartoli, Frédéric Brocard, Hélène Bras
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Current RNA strategies in treating cardiovascular diseases Mol. Ther. (IF 12.4) Pub Date : 2024-01-29 Shirley Pei Shan Chia, Jeremy Kah Sheng Pang, Boon-Seng Soh
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Inhibition of adenylyl cyclase 8 prevents the upregulation of Orai1 channel, which improves cardiac function after myocardial infarction Mol. Ther. (IF 12.4) Pub Date : 2024-01-29 Débora Falcón, Eva M. Calderón-Sánchez, Isabel Mayoral-González, Marta Martín-Bórnez, Alejandro Dominguez-Rodriguez, Encarnación Gutiérrez-Carretero, Antonio Ordóñez-Fernández, Juan Antonio Rosado, Tarik Smani
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Reprogramming natural killer cells for cancer therapy Mol. Ther. (IF 12.4) Pub Date : 2024-01-24 Kexin Wang, Linqin Wang, Yiyun Wang, Lu Xiao, Jieping Wei, Yongxian Hu, Dongrui Wang, He Huang
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Advanced gene-editing strategy for epidermolysis bullosa simplex Mol. Ther. (IF 12.4) Pub Date : 2024-01-23 Adam Sheriff, Joanna Jacków-Malinowska
Abstract not available
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Tetrahedral DNA loaded siCCR2 restrains M1 macrophage polarization to ameliorate pulmonary fibrosis in chemoradiation-induced murine model Mol. Ther. (IF 12.4) Pub Date : 2024-01-24 Chen Li, Xiaorong Feng, Songhang Li, Xing He, Zeli Luo, Xia Cheng, Jie Yao, Jie Xiao, Xiaofei Wang, Dingke Wen, Duanya Liu, Yanfei Li, Hong Zhou, Lu Ma, Tongyu Lin, Xiaoxiao Cai, Yunfeng Lin, Lu Guo, Mu Yang
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Recombinant neutralizing secretory IgA antibodies for preventing mucosal acquisition and transmission of SARS-CoV-2 Mol. Ther. (IF 12.4) Pub Date : 2024-01-24 Kathrin Göritzer, Elisabetta Groppelli, Clemens Grünwald-Gruber, Rudolf Figl, Fengfeng Ni, Huimin Hu, Yuncheng Li, Yalan Liu, Qinxue Hu, Rama Devudu Puligedda, Jae-Wan Jung, Richard Strasser, Scott Dessain, Julian K.-C. Ma
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Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression Mol. Ther. (IF 12.4) Pub Date : 2024-01-24 Vignesh Rajendiran, Nivedhitha Devaraju, Mahdi Haddad, Nithin Sam Ravi, Lokesh Panigrahi, Joshua Paul, Chandrasekar Gopalakrishnan, Stacia Wyman, Keerthiga Ariudainambi, Gokulnath Mahalingam, Yogapriya Periyasami, Kirti Prasad, Anila George, Dhiyaneshwaran Sukumaran, Sandhiya Gopinathan, Aswin Anand Pai, Yukio Nakamura, Poonkuzhali Balasubramanian, Rajasekaran Ramalingam, Saravanabhavan Thangavel,