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A BACH1 Inhibitor Ameliorates Myocardial Infarction and Limb Ischemia in Mice. Mol. Ther. (IF 12.0) Pub Date : 2025-07-16 Jiayi Lin,Xin Liu,Qinhan Li,Fei Ge,Jinghua Ma,Xianlong Ng,Qi Pan,Xiangxiang Wei,Qingjun Jiang,Jiayu Jin,Siyu Ma,Yunquan He,Yongbo Li,Nan Jiang,Yannan Hou,Yueyang Yu,Xiaoke Lin,Quanshan Jin,Chengguo Xu,Xinhong Wang,Xiuling Zhi,Qianqian Liang,Lindi Jiang,Elena Osto,Jieyu Guo,Xiu-Jie Wang,Dan Meng
The transcription factor BTB and CNC homology 1 (BACH1) is linked to coronary artery disease risk and impairs angiogenesis after ischemic injury. However, there is a scarcity of specific BACH1 inhibitors. This study identifies BI033 as a selective BACH1 inhibitor, confirming its binding to the 91st alanine in BACH1's N-terminal. BI033 shows lower toxicity in human umbilical vein endothelial cells (HUVECs)
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Nanobody-Engineered Bispecific IL-18 Mimetics Drive Antitumor Immunity by Engaging CD8+ T Cells and Evading IL-18BP in Preclinical Models. Mol. Ther. (IF 12.0) Pub Date : 2025-07-16 Yanyang Nan,Min Zhu,Qian Wang,Xiaoxue Du,Caili Xu,Yuping Huang,Yujie Liu,Shaoyuan Zhou,Yuluoyan Qiu,Xiao Chu,Dianwen Ju,Yakun Wan,Xuyao Zhang
Cytokines are promising in cancer immunotherapy, but their pleiotropic effects limit specificity and clinical utility. Through binding to IL-18Rα and IL-18Rβ, interleukin-18 (IL-18) stimulates innate lymphocytes and effector T cells for antitumor immunity. However, clinical trials of recombinant IL-18 have been hampered by IL-18 binding protein (IL-18BP), a secreted high-affinity decoy receptor. Here
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HSC Engraftment is Enhanced by Combining Mobilization with Anti-C-Kit and Anti-CD47 Based Conditioning in Hematopoietic Stem Cell Transplantation. Mol. Ther. (IF 12.0) Pub Date : 2025-07-16 Isabel Ojeda-Perez,Omaira Alberquilla-Fernandez,Aida García-Torralba,Mercedes Lopez-Santalla,Rebeca Sánchez-Domínguez,Jose-Carlos Segovia
A significant limitation of hematopoietic stem cell transplantation (HSCT) that reduces its application across more disease areas and more geographically diverse populations is the toxicity from chemotherapy-based conditioning. A potential solution is to replace chemotherapy with monoclonal antibodies, but the replacement must result in therapeutically relevant levels of engraftment. In some cases
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Efficient in vivo generation of CAR T cells using a retargeted 4th generation lentiviral vector. Mol. Ther. (IF 12.0) Pub Date : 2025-07-16 Tiziana Coradin,Amy L Keating,Alun R Barnard,Lynsey Whilding,Diana Pombal,Zara Hannoun,Jack Lewis,Gayathri Devarajan,Sharifah Iqball,Emma Burton,Sara Ferluga,Daniel M Jones,Ben M Alberts,Jordan Wright,Daniel C Farley,Deirdre M O'Connor,Ravi M Rao,Kyriacos A Mitrophanous,Yatish Lad,Rachael Nimmo
CAR T cell therapy has proven remarkably successful for the treatment of haematological malignancies. However, the bespoke manufacturing of autologous CAR T cells is complex and expensive. The development of methods for in vivo engineering of T cells will enable generation of CAR T cells directly within the patient, bypassing the need for ex vivo manufacturing thereby enabling greater access for patients
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Exendin-4 enhances insulin-positive phenotype of human pluripotent stem cell-derived β cells during transplantation. Mol. Ther. (IF 12.0) Pub Date : 2025-07-16 Kelly M Crumley,Elizabeth J Bealer,Anne C Lietzke,Scott A Soleimanpour,Lonnie D Shea
An emerging technique for the treatment of type 1 diabetes, which is characterized by hyperglycemia resulting from the loss of insulin-secreting β cells, involves transplantation of human pluripotent stem cell (hPSC)-derived β cells. This transplantation procedure can induce normoglycemia, yet the efficiency of cell survival and function post transplantation remain opportunities for improvement. Here
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AAV-microutrophin gene therapy confers long-term cardioprotection against pharmacologic and exercise-induced injury in dystrophin deficiency. Mol. Ther. (IF 12.0) Pub Date : 2025-07-16 Coral M Kasden,Maria P Corzo,Christopher D Greer,Tanvi Singh,Rufranshell Reyes,Alaine Castillo,Zoltan Arany,Benjamin W Kozyak,Hansell H Stedman
Duchenne muscular dystrophy (DMD) is the most common childhood-onset muscle degenerative disease, caused by genetic deficiency of dystrophin, resulting in premature death due to cardiorespiratory failure. Gene therapy clinical trials employing adeno-associated virus (AAV) systemically delivering miniaturized dystrophin have provided mixed results with lingering concerns about safety, long-term efficacy
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Neo-antigen tumor vaccination depends on CD4-licensing conveyed by adeno-associated virus like particles. Mol. Ther. (IF 12.0) Pub Date : 2025-07-16 Lasse Neukirch,Silke Uhrig-Schmidt,Katharina von Werthern,Alexandra Tuch,Joscha A Kraske,Yanhong Lyu,Benedicte Lenoir,Stefan B Eichmüller,Marten Meyer,Inka Zörnig,Dirk Jäger,Patrick Schmidt
Personalized treatment has become a realistic option for tumor patients, accelerated by significantly reduced sequencing costs of tumor genomes and advances in vaccine formulations. The druggability of cancer neo-antigens caused by individual mutations is centered in this effort. We here use an AAV-based VLP platform to compose a neo-antigen specific protein vaccine that is effective in a murine prevention
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Disruption of the Nucleolin-CXCR4 Interaction by the DNA Aptamer HY-4 Halts Colorectal Cancer Metastasis. Mol. Ther. (IF 12.0) Pub Date : 2025-07-15 Yunyi Liu,Yatao Wu,Changyue Yuan,Bei Hu,Yuxi Xu,Hailong Ou,Juan Li,Dan Qi,Bi Shi,Yiliang Wu,Jason H Huang,Erxi Wu,Xiaoxiao Hu
Colorectal cancer, characterized by its aggressive metastatic behavior and often poor prognosis, urgently necessitates improved diagnostic and therapeutic strategies. This study introduces HY-4, an aptamer developed via a non-SELEX method, which shows exceptional specificity and affinity for nucleolin (NCL), a highly expressed oncogenic protein in various cancers. With remarkable biocompatibility,
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IGFBP7: A potential target for tubular lipogenesis in CKD Mol. Ther. (IF 12.0) Pub Date : 2025-07-09 Min Liu, Fan Yi
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Long-term effects of s-KL treatment in wild-type mice: Enhancing longevity, physical well-being, and neurological resilience Mol. Ther. (IF 12.0) Pub Date : 2025-07-05 Joan Roig-Soriano, Ángel Edo, Sergi Verdés, Carlos Martín-Alonso, Cristina Sánchez-de-Diego, Laura Rodriguez-Estevez, Antonio L. Serrano, Carmela R. Abraham, Assumpció Bosch, Francesc Ventura, Bryen A. Jordan, Pura Muñoz-Cánoves, Miguel Chillón
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Peeling back the layers of immunogenicity in CRISPR-Cas9-based genomic medicine Mol. Ther. (IF 12.0) Pub Date : 2025-07-01 Virpi Stigzelius, Anna Lina Cavallo, Rakesh Kantilal Chandode, Roberto Nitsch
The CRISPR-Cas9 system is rewriting the treatment of genetic diseases, offering unprecedented potential for detrimental and previously untreatable diseases. As this technology advances toward wider utilization in clinical applications, the immunogenicity of Cas9 nuclease has emerged as a potential challenge for in vivo therapies. Immune recognition of CRISPR-Cas9 components can trigger both innate
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Recovery of cone-mediated vision in Lebercilin-associated severe retinal ciliopathy (LCA5) after gene therapy: One-year results of a phase Ib/IIa trial Mol. Ther. (IF 12.0) Pub Date : 2025-07-01 Tomas S. Aleman, Katherine E. Uyhazi, Alejandro J. Roman, Mariejel L. Weber, Erin C. O’Neil, Malgorzata Swider, Alexander Sumaroka, Katherine H. Maguire, Elena M. Aleman, Arlene J. Santos, Rebecca J. Kim, Kelsey M. Parchinski, Andrew Billek, Makayla Fradin, William Chung, Paris Margaritis, Junwei Sun, Drew H. Scoles, Vivian Wu, Alexandra V. Garafalo, Ashwath Jayagopal, Ben Yerxa, Sarah Tuller, Albert
We assessed the preliminary safety of a recombinant adeno-associated virus serotype 8 vector carrying the native human LCA5 cDNA (OPGx-001) in LCA5-associated Leber congenital amaurosis (LCA5-LCA), a congenital blindness. The phase 1b/2a trial (NCT05616793) is a nonrandomized, single ascending, dose-escalation study. Three subjects with LCA5-LCA (ages 19, 26, and 34 years old) received uniocular subretinal
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miR-375 protects against acetaminophen-induced acute liver failure by orchestrating pharmacogene expression Mol. Ther. (IF 12.0) Pub Date : 2025-06-30 Yi Wang, Jinghua Liu, Sha Zhu, Shiliang Hu, Xiupeng Chen, Elisabet Mandon, Ngoc Tam Tran, Songbo Zhang, Yangran Qi, Hong Ma, Ran He, Yu Cao, Qin Su, Thomas L. Gallagher, Zixiu Li, Chan Zhou, Phillip W.L. Tai, Guangping Gao, Jun Xie
Acetaminophen (APAP) overdose is a leading cause of acute liver failure (ALF), primarily through the excessive production of N-acetyl-p-benzoquinone imine (NAPQI). N-acetylcysteine (NAC) is the Food and Drug Administration-approved treatment for APAP overdose, but there is a growing interest in microRNAs as potential therapeutic agents. We delivered miR-375 ectopically via a liver-tropic adeno-associated
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Epigen-mediated mechanisms to alleviate glucose homeostasis disruptions in diet-induced obese and STZ-induced diabetic mice Mol. Ther. (IF 12.0) Pub Date : 2025-06-30 Ka-Ying Chan, Chu-Jun Deng, Dilun Chen, Tak-Ho Lo, Shiqi Jia, Pauline Po Yee Lui, Chi-Ming Wong
Epidermal growth factor receptor (EGFR) plays a crucial role in cellular processes such as development and tissue repair, with dysregulation linked to various diseases, including those affecting energy metabolism. Previous studies have reported that EGFR ligands enhance glucose homeostasis through various mechanisms across different tissues. However, epigen, the latest EGFR ligand, has not been thoroughly
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Circulating urobilinogen contributes to inflammation, intestinal permeability, and corticosteroid non-response in severe alcohol-associated hepatitis Mol. Ther. (IF 12.0) Pub Date : 2025-06-30 Manisha Yadav, Abhishak Gupta, Babu Mathew, Gaurav Tripathi, Nishu Dalal, Neha Sharma, Pushpa Yadav, Gaurav Yadav, Rita Singh, Vasundhra Bindal, Rimsha Saif, Sanju Yadav, Nupur Sharma, Sushmita Pandey, Sadam H. Bhat, Ravinder Singh, Jitender Kumar, Manish Kushwaha, Tahseen Khan, Narendra Kumar Sharma, Ashima Bhaskar, Ved Prakash Dwivedi, Anil Kumar, Niraj Kumar, Dinesh Mani Tripathi, Nirupama Trehanpati
Severe alcohol-associated hepatitis (SAH) is a life-threatening condition with high mortality rates and poor response to prednisolone therapy. Identifying reliable early predictors of therapy response and survival is critical. Plasma metabolomics was conducted on 70 SAH patients (50 responders and 20 non-responders) to identify biomarkers for non-response and early mortality. These findings were validated
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Galectin-4 potentiates CD8+ T cell immunity by enhancing MHC-I expression on dendritic cells: Therapeutic implications for cancer and viral infection Mol. Ther. (IF 12.0) Pub Date : 2025-06-30 In-Gu Lee, Jeonghyeon Lee, Hyeong-Rae Kim, Younghyun Lim, Hye-Won Yu, Tae-Hyung Kim, Bumsuk Hahm, Hyun Ah Kang, So-Hee Hong, Young-Jin Seo
Galectin-4 (Gal-4), a member of the β-galactoside-binding galectin family, plays a role in various physiological processes, including tumor progression and intestinal disorders. However, its contribution to adaptive immunity remains poorly understood. In this study, Gal-4 is identified as a critical factor for effective generation of CD8+ T cell responses against tumors and viral infections. Gal-4-deficient
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CD19xCD3 T cell engager blinatumomab effective in refractory generalized myasthenic syndromes Mol. Ther. (IF 12.0) Pub Date : 2025-06-28 Tobias Ruck, Niklas Huntemann, Menekse Öztürk, Stefanie Schreiber, Stefanie Lichtenberg, Lars Masanneck, Christopher Nelke, Hend Ben Moussa, Thomas Ulrych, Marc Seifert, Dimitrios Mougiakakos, Sascha Dietrich, Sven G. Meuth
In this case series, we report the first off-label use of the CD19xCD3 T cell engager blinatumomab in two patients with generalized myasthenia gravis (MG). Refractory MG remains a major therapeutic challenge, with patients experiencing severe disability and potentially life-threatening crises despite intensive immunotherapy. This study evaluates the clinical efficacy and safety of short-term blinatumomab
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Targeting NLRP3/caspase-1/GSDMD to treat inner ear injury from labyrinthine hemorrhage Mol. Ther. (IF 12.0) Pub Date : 2025-06-28 Qiong Wu, Mingwei Xu, Yuan Yao, Tianyu Gong, Qin Zhang, Yulian Jin, Jun Yang, Qing Zhang
Sudden sensorineural hearing loss (SSNHL) is a prevalent condition in otolaryngology with poorly understood mechanisms. Inner ear labyrinthine hemorrhage (IELH) is a potentially significant cause. Our study focused on the NLR family pyrin domain containing 3 (NLRP3) inflammasome activation following IELH and the protective role of the NLRP3 inhibitor CY-09. In mice with IELH, significant increases
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3AIM-seq: Quality assessment of mRNA therapeutics using sequencing for 3′ poly(A) tails of in vitro-transcribed mRNA Mol. Ther. (IF 12.0) Pub Date : 2025-06-28 Jina Seo, Hyo-Jung Park, Ayoung Oh, Chang Beom Jeong, Sohee Kim, Sojeong Lee, Chuna Kim, Hyeshik Chang, Jae-Hwan Nam, Daechan Park
In vitro-transcribed (IVT) mRNA therapeutics are promising for preventing and treating diseases, including infectious diseases and cancer, by delivering nucleic acid sequences. Assessing the stability of mRNA sequences and poly(A) tail length is crucial to minimize adverse effects and ensure drug efficacy. However, accurately measuring long homopolymeric nucleotides remains technically challenging
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Complement activation in a phase Ib study of fordadistrogene movaparvovec for Duchenne muscular dystrophy Mol. Ther. (IF 12.0) Pub Date : 2025-06-28 Barry J. Byrne, Russell J. Butterfield, Perry B. Shieh, Edward C. Smith, Christoph Licht, Michael Binks, Sandra Casinghino, Marielle Delnomdedieu, Kodihalli C. Ravindra, Tara McDonnell, Kelly Ryan, Martin Schulz, Qi Shen, Heliang Shi, Madhu P. Sirivelu, Vishal S. Vaidya, Laurence Whiteley, Daniel I. Levy
Thrombotic microangiopathy (TMA) has been reported as an uncommon but severe adverse effect of recombinant adeno-associated virus (rAAV)-based gene therapy. Here, we describe in detail the occurrences of clinically evident TMA following infusion of the rAAV9-based therapy fordadistrogene movaparvovec (1 or 3 × 1014 vg/kg) in 22 participants with Duchenne muscular dystrophy (DMD). Three participants
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Cardiac safety of fordadistrogene movaparvovec gene therapy in Duchenne muscular dystrophy: Initial observations from a phase 1b trial Mol. Ther. (IF 12.0) Pub Date : 2025-06-28 Sarah P. Sherlock, Daniel I. Levy, Avery McIntosh, Perry B. Shieh, Edward C. Smith, Tara G. McDonnell, Kelly A. Ryan, Marielle Delnomdedieu, Michael Binks, Ashwin K. Lal, Russell J. Butterfield
Fordadistrogene movaparvovec (FM; PF-06939926) is a recombinant adeno-associated virus serotype-9 gene-replacement construct containing a mini-dystrophin transgene in development for Duchenne muscular dystrophy (DMD). We present findings of cardiac safety assessments in participants with DMD during a 1-year follow-up from an ongoing phase 1b multicenter, single-arm, open-label trial of low- and high-dose
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Targeting WNT5A noncanonical signaling attenuates renal fibrosis progression in acute kidney injury Mol. Ther. (IF 12.0) Pub Date : 2025-06-27 Sijie Gu, Haoran Feng, Xiaomei Li, Yang Dong, Yonglin Peng, Qiye Liu, Xuhao Zhang, Jiayin You, Jinwei Zhu, Xiaodong Zhao, Xizhi Guo, Niansong Wang, Ying Fan
Preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a considerable clinical challenge. In this study, we elucidate the role of WNT5A in accelerating the AKI-to-CKD transition and its underlying mechanisms. Renal biopsies from patients with AKI showed marked upregulation of WNT5A and its receptor, CD146, in proximal tubules, with higher expression in patients
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Epigenetic networks coordinate DNA methylation across the genome Mol. Ther. (IF 12.0) Pub Date : 2025-06-27 Wolfgang Wagner
The epigenetic landscape governs cell fate decisions during development, aging, and disease. Despite considerable progress in the understanding of DNA methylation (DNAm), the mechanisms that orchestrate its coordinated regulation across the genome remain largely elusive. Recent breakthroughs in sequencing technologies and epigenetic editing tools enable a more comprehensive exploration of these epigenetic
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Targeted in vivo delivery of genetic medicines utilizing an engineered lentiviral vector platform results in CAR T and NK cell generation Mol. Ther. (IF 12.0) Pub Date : 2025-06-27 James I. Andorko, Ronnie M. Russell, Bruce C. Schnepp, Daniel Grubaugh, Karla F. Mullen, Aoi Wakabayashi, Léolène J. Carrington, Thomas O’Malley, Leticia Kuri-Cervantes, Timothy D. Culp, Philip R. Johnson
The development of chimeric antigen receptor (CAR) T cell therapies has greatly impacted the treatment of B cell malignancies; however, manufacturing these patient-specific, autologous cell therapies is complex, costly, and requires preconditioning chemotherapy prior to infusion, limiting patient access. Here we describe the development of a lentiviral platform based on a novel, detargeted viral fusogen
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RNA interference targeting lipoprotein(a): A “big hit” against “little a”? Mol. Ther. (IF 12.0) Pub Date : 2025-06-26 Duncan J. Stewart, Katey J. Rayner
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In utero genetic therapy: Treatment of early onset neurological disorders before they start Mol. Ther. (IF 12.0) Pub Date : 2025-06-26 Beltran Borges, Stephen M. Brown, Tippi C. MacKenzie, Charlotte J. Sumner
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Ad-justing macrophages for cancer immunotherapy Mol. Ther. (IF 12.0) Pub Date : 2025-06-25 Giovanna Giacca, Mario Leonardo Squadrito
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Memory matters: T cell phenotype shapes CAR T cell fate Mol. Ther. (IF 12.0) Pub Date : 2025-06-25 Francesco Di Meo
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Improved SARS-CoV-2 vaccine based on intranasally administered replicon RNA Mol. Ther. (IF 12.0) Pub Date : 2025-06-24 Kenneth Lundstrom
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Harnessing engineered NK cells for refractory CD30+ lymphoma Mol. Ther. (IF 12.0) Pub Date : 2025-06-24 Yago Nieto, Katayoun Rezvani
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Extrachromosomal DNA maintenance and DNA damage response: A bidirectional axis in cancer progression and therapy Mol. Ther. (IF 12.0) Pub Date : 2025-06-24 Yang Meng, Zijun Feng, Junhong Han
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Double trouble: Non-relapse mortality with bispecific antibodies in lymphoma and myeloma Mol. Ther. (IF 12.0) Pub Date : 2025-06-24 Rahul Banerjee, Samuel Yamshon
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TNFAIP8L2 as a dual regulator of mTORC1 signaling: Implications for therapy in presbycusis Mol. Ther. (IF 12.0) Pub Date : 2025-06-24 Yanfei Wang, Xinmiao Fan, Liheng Li, Qing Yin Zheng
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Bispecific receptor decoys: A new player to a crowded field Mol. Ther. (IF 12.0) Pub Date : 2025-06-21 Glenn Yiu
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Harnessing B19-directed CAR T cells for AAV vector administration in seropositive patients: The importance of the niche Mol. Ther. (IF 12.0) Pub Date : 2025-06-21 Hanadi Saliba, David Alexandre Gross, Giuseppe Ronzitti
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Novel AAV-based GJB2 gene therapy restores hearing function Mol. Ther. (IF 12.0) Pub Date : 2025-06-21 Lukas D. Landegger
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Targeting EBV gp42 for nasopharyngeal carcinoma prevention Mol. Ther. (IF 12.0) Pub Date : 2025-06-21 Cong Sun, Le-Le Zhang, Mu-Sheng Zeng
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Beyond the bench: Revitalizing ataluren development for rare genetic disorders Mol. Ther. (IF 12.0) Pub Date : 2025-06-21 Valentino Bezzerri, Marco Cipolli
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Retraction Notice to: LncRNA ODRUL Contributes to Osteosarcoma Progression through the miR-3182/MMP2 Axis Mol. Ther. (IF 12.0) Pub Date : 2025-06-19 Kun-Peng Zhu, Xiao-Long Ma, Chun-Lin Zhang
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Effective use of BCMA-targeting bispecific T cell-engaging antibody in treatment-refractory LRP4+ myasthenia gravis Mol. Ther. (IF 12.0) Pub Date : 2025-06-17 Stefanie Schreiber, Marwa Al-Dubai, Stefan Vielhaber, Lora Lefterova, Sascha Dietrich, Tobias Ruck, Sven Meuth, Denise Walther, Dimitrios Mougiakakos
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease affecting the neuromuscular junction. Refractory MG, particularly in cases associated with rare anti-low-density lipoprotein receptor-related protein 4 (LRP4) antibodies, presents significant treatment challenges. Teclistamab, a bispecific antibody targeting B cell maturation antigen (BCMA) and CD3, redirects T cells against plasma cells
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CRISPR for cystic fibrosis: Advances and insights from a systematic review Mol. Ther. (IF 12.0) Pub Date : 2025-06-17 Lucia Nicosia, Patrick T. Harrison
Cystic fibrosis (CF) is a severe genetic disorder caused by loss-of-function mutations in the CFTR gene. Gene-editing approaches have the potential to correct such mutations. This systematic review outlines the mechanisms of the main CRISPR-based technologies, and, through cross-study comparisons, analyzes 27 research articles that applied them to target CF-causing variants. We report and discuss the
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mRNA-LNP vaccines against hepatitis B virus induce protective immune responses in preventive and chronic mouse challenge models Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 María José Limeres, Rocio Gambaro, Malin Svensson, Silvia Fraude-El Ghazi, Leah Pretsch, Daniel Frank, German A. Islan, Ignacio Rivero Berti, Matthias Bros, Ying K. Tam, Hiromi Muramatsu, Norbert Pardi, Stephan Gehring, Maximiliano L. Cacicedo
Over 300 million people worldwide suffer from chronic hepatitis B virus (HBV) infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic
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Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 David D. Fuller, Sabhya Rana, Prajwal P. Thakre, Ethan S. Benevides, Megan K. Pope, Adrian G. Todd, Victoria N. Jensen, Lauren Vaught, Denise A. Cloutier, Roberto A. Ribas, Reece C. Larson, Matthew S. Gentry, Ramon C. Sun, Vijay Chandran, Manuela Corti, Darin J. Falk, Barry J. Byrne
Absence of functional acid-α-glucosidase (GAA) leads to early onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model (Gaa−/−) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline)
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Nebulization of an mRNA-encoded monoclonal antibody for passive immunization of foals against Rhodococcus equi Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Rebecca M. Legere, Jeannine A. Ott, Cristina Poveda, Daryll Vanover, Karin E.R. Borba, Jae Yeon Joo, Cameron L. Martin, Bibiana P. da Silveira, Jocelyne M. Bray, Kerstin Landrock, Gus A. Wright, J. Chistensen Blazier, Andrew E. Hillhouse, Ashley L. Benham-Duret, Brandon Mistretta, Rafaela L. Klein, Sarah M. Thompson, Amelia R. Woolums, Michael F. Criscitiello, Luc R. Berghman, Angela I. Bordin, Philip
Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against
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A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Greg del Val, Florence Gauye, Mickaël Audrain, Sébastien Menant, Monisha Ratnam, Elodie Chevalier, Romain Ollier, Daisy Bhatia, Tamara Seredenina, Tariq Afroz, Andrea Pfeifer, Marie Kosco-Vilbois, Damien Nevoltris
Transactive response DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891
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Gene therapy with covalently closed-end AAV vector for spinal muscular atrophy Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Haolin Duan, Ciliu Zhang, Zhongliang Zhang, Xiaole Wang, Junping Zhang, Lifen Yang, Fang He, Leilei Mao, Li Yang, Zou Pan, Renzhi Han, Weiming Wang, Dao Pan, Fei Yin, Weidong Xiao, Jing Peng
Covalently closed-end adeno-associated virus (cceAAV) vector is a new generation of self-complementary adeno-associated virus (scAAV) vector that does not utilize a mutant inverted terminal repeat (ITR) for vector production. Importantly, packaged genomes of these cceAAV vectors are markedly more intact than traditional scAAVs, which typically contain a large fraction of incomplete genomes, including
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Precise progerin targeting using RfxCas13d: A therapeutic avenue for Hutchinson-Gilford progeria syndrome Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Unbin Chae, Hae-Jun Yang, Hanseop Kim, Seung Hwan Lee, Dong Gil Lee, Jeong Young Koo, Seung-Min Ha, Seo-Jong Bak, Mina Joo, Hyun Hee Nam, Kyung-Seob Lim, Philyong Kang, Hee-Chang Son, You Jeong An, Young-Hyun Kim, In-Sung Song, Sang-Hee Lee, Hae Rim Kim, Sang-Mi Cho, Eun-Kyoung Kim, Ki-Hoan Nam, Kyung-Sook Chung, Jae-Yoon Kim, Seon-Yeop Kim, Seon-Kyu Kim, Seon-Young Kim, Dong-Seok Lee, Jin-Man Kim
Hutchinson-Gilford progeria syndrome (HGPS), an extremely rare progressive genetic disorder, is caused by a point mutation in LMNA that induces progerin production, which disrupts cellular function and triggers premature aging and mortality. Despite extensive efforts, HPGS remains incurable. We successfully implemented a strategy using RfxCas13d to selectively target progerin mRNA at specific junction
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AAV9-mediated gene supplementation therapy prevents and rescues arrhythmogenic cardiomyopathy in Pnpla2-mutated mice Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Xiulin Zhang, Congrui Wang, Yuan Chang, Hao Jia, Yue Zhang, Yifan Wang, Weiteng Wang, Han Han, Yuhong Hu, Xijia Shao, Shuang Wen, Siyu Tan, Ningning Zhang, Xiumeng Hua, Hao Cui, Xiao Chen, Jiangping Song
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder involving ventricular arrhythmias, cardiac dysfunction, and fibrofatty myocardial replacement. Current treatments are largely palliative, with heart transplantation as the only definitive option for advanced ACM. Here, we show that, building upon our previous identification of a patient with a PNPLA2c.G245A/c.G245A mutation, we developed
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RNA-DNA hybrid binding domain broadens the editing window of base editors Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Yue Yang, Zihao Fu, Shengcheng Deng, Guanglan Wu, Chuanle Wang, Xiao Luo, Rui Kang, Yuxi Chen, Chengxiang Peng, Pengfei Zhang, Kaixin Cui, Fen Wan, Junhua Wang, Qin Zhou, Wei Chen, Yuanyan Xiong, Wenbin Ma, Zhou Songyang, Puping Liang
Adenine base editors (ABEs) and cytosine base editors (CBEs) are prominent tools for precise genome editing but are hindered by limited editing activity at positions proximal to the protospacer adjacent motif (PAM). This study investigates the potential of enhancing base editors editing activity by fusing them with RNA-DNA hybrid binding domains (RHBDs). Specifically, fusing ABE8e with the RHBD of
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Blood phenylalanine lowering partially reverses white matter changes in a mouse model of phenylketonuria Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Rachna Manek, Weixiao Huang, Yinyin Huang, Lilu Guo, Cathleen S. Cornell, Mohammed Salman Shazeeb, Alexander Verbitsky, Robert Jackson, Jennifer Johnson, Patricia Berthelette, Dan Yu, Edith L. Pfister, Dinesh Bangari, Xiaoyou Ying, Dinesh Kumar, Christian Mueller, Sirkka Kyostio-Moore
Phenylketonuria (PKU) is a genetic defect caused by lack of the liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood phenylalanine (Phe) levels and neurotoxicity, which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe
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AAV-mediated gene therapy for focal epilepsy by expressing neuropeptide Y and Y2 receptor in rodent and non-human primate hippocampus Mol. Ther. (IF 12.0) Pub Date : 2025-06-14 Barbara Terzic, Esbjörn Melin, Pernilla Fagergren, David Dobry, Stefano Cattaneo, Iris Giupponi, Barbara Bettegazzi, Michele Simonato, Karin Agerman, Merab Kokaia, Lawrence Moon, Elizabeth Ramsburg
Epilepsy affects approximately 50 million people worldwide, and over 30% of patients are considered treatment resistant to currently available anti-seizure drugs. Neuropeptide Y (NPY) has been shown to inhibit excitatory synaptic transmission in hippocampal slices from human epilepsy patients via Y2 receptors (Y2Rs), and overexpression of NPY and/or Y2R in the hippocampus reduces seizures in rodent
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Therapeutic effect of galactosyltransferase- and sialyltransferase-encoding mRNA in rheumatoid arthritis Mol. Ther. (IF 12.0) Pub Date : 2025-06-13 Xinyi Peng, Yingyu Li, Xiu Sun, Guoru Ren, Haojun Li, Xiaocheng Wang, Peng George Wang, Qingwen Wang, Yang Ji
Glycoengineering of IgG, particularly Fc glycosylation, holds significant promise for treating autoimmune diseases by modulating antibody effector functions. However, methods that precisely control IgG glycosylation profiles in vivo are still lacking. In this study, by delivering mRNAs encoding the glycosyltransferases B4GALT1 and ST6GAL1 intravenously, we successfully expressed functional enzymes
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Targeting RNA adenosine editing and modification enzymes for RNA therapeutics Mol. Ther. (IF 12.0) Pub Date : 2025-06-09 Nikolaos I. Vlachogiannis, Maria Polycarpou-Schwarz, Aikaterini-Paraskevi Avdi, Simon Tual-Chalot, Konstantinos Stellos
Adenosine-to-inosine (A-to-I) RNA editing, and N6 methyladenosine (m6A) are among the most abundant modifications in eukaryotic messenger RNA, affecting various aspects of RNA metabolism and cellular function, including proliferation, differentiation, responses to stressors, and cell death. Recent preclinical evidence suggests that both modifications play a significant role in multiple disorders, including
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Cancer-derived extracellular vesicles in natural killer cell immune evasion: Molecular mechanisms and therapeutic insights Mol. Ther. (IF 12.0) Pub Date : 2025-05-31 Elaina Coleborn, Raluca Ghebosu, Joy Wolfram, Fernando Souza-Fonseca-Guimaraes
Natural killer cells are innate lymphocytes equipped with the ability to rapidly identify and eliminate cancer cells. However, cancer cells release nanosized extracellular vesicles that can induce an immunosuppressive tumor microenvironment, subsequently hindering natural killer cell immunosurveillance. Studies have reported that extracellular vesicles derived from different cancers, such as acute
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Inhibition of NAD-GPx4 axis and MEK triggers ferroptosis to suppress pancreatic ductal adenocarcinoma Mol. Ther. (IF 12.0) Pub Date : 2025-05-30 Hui Jiang, Yusuke Satoh, Ryodai Yamamura, Takako Ooshio, Yang Luo, Han Hai, Takuya Otsuka, Soichiro Hata, Reo Sato, Taiga Hirata, Tsuyoshi Osawa, Keisuke Goda, Masahiro Sonoshita
Pancreatic ductal adenocarcinoma (PDAC) ranks among the most lethal malignancies, highlighting the critical need for innovative therapeutic strategies. In this study, we examined the roles of nicotinamide adenine dinucleotide (NAD) synthesis pathway in PDAC. Targeting the NAD synthesis pathway significantly mitigated lethality in a Drosophila model that recapitulated the PDAC genotype. Within this
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Quantifying the mutational landscape of retroviral and lentiviral vectors in gene therapy patients Mol. Ther. (IF 12.0) Pub Date : 2025-05-30 Kevyn L. Hart, Ralph Valentine Crisostomo, Annika Mittelhauser, Lingyu Zhan, Nika Kononov, Kathryn Bradford, Donald B. Kohn
Adenosine deaminase severe combined immunodeficiency (ADA-SCID) is a monogenic disorder caused by mutations in the ADA gene. Gene therapy using γ-retroviral and lentiviral vector gene addition approaches have shown curative results. We sequenced the ADA transgene in transduced CD3+ T cells, and in peripheral blood cells from patients treated with autologous CD34+ cells transduced with either a γ-retroviral
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Multi-engineered T cell vaccine boosting TCR-T cell therapy enhances anti-tumor function and eradicates heterogeneous solid tumors Mol. Ther. (IF 12.0) Pub Date : 2025-05-30 Xuan Che, Shen Zheng, Yuan Sun, Xiya Wang, Pengchong Zhang, Jixiang Cao, Yun Bai
T cell receptor (TCR)-engineered T cell therapy holds great promise for treating solid tumors, but the overall clinical efficacy remains limited. The vital challenge lies in the loss of TCR-targeted antigens and poor T cell persistence. Here, we demonstrate a novel approach to enhance TCR-T cell therapy and reject antigen-heterogeneous tumors through a multi-engineered T cell vaccine (Multi-Tvac).
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Podocyte FFAR4 deficiency aggravated glomerular diseases and aging Mol. Ther. (IF 12.0) Pub Date : 2025-05-30 Ting Yin, Letian Yang, Lei Tang, Jian Li, Dekai Liu, Fan Guo, Yingsong Mu, Qimei Wu, Yuying Feng, Zhouke Tan, Ping Fu, Xiaoniao Chen, Liang Ma
Podocyte injury contributes to the progression of glomerular disease and aging; however, causative molecular/physiological pathways are poorly defined, and there are few therapies to improve kidney outcomes. We previously reported that free fatty acid receptor 4 (FFAR4) agonist TUG891 improved podocyte injury to alleviate renal inflammation and fibrosis in diabetic nephropathy. However, the role of