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Nebulization of a mRNA-encoded monoclonal antibody for passive immunization of foals against Rhodococcus equi. Mol. Ther. (IF 12.1) Pub Date : 2025-06-14 Rebecca M Legere,Jeannine A Ott,Cristina Poveda,Daryll Vanover,Karin E R Borba,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,Phillip J Santangelo,Jeroen Pollet,Noah D Cohen
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 12.1) 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
TAR 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, was generated
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Gene Therapy with covalently-closed-end AAV vector for Spinal Muscular Atrophy. Mol. Ther. (IF 12.1) 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 vector (cceAAV) is a new generation of self-complementary vector (scAAV) which does not utilize a mutant 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 many that lost their self-complementary configuration
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Precise Progerin Targeting Using RfxCas13d: A Therapeutic Avenue for Hutchinson-Gilford Progeria Syndrome. Mol. Ther. (IF 12.1) 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,Young-Ho Park,Sun-Uk 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 12.1) 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 a
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RNA-DNA hybrid binding domain broadens the editing window of base editors. Mol. Ther. (IF 12.1) 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 12.1) 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 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 lowering
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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 12.1) 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 (Y2R), 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 12.1) 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 12.1) 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 12.1) 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 12.1) 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 12.1) 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 12.1) 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 12.1) Pub Date : 2025-05-30 Ting Yin, Leitian 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
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Targeting CD117 on hematopoietic stem and progenitor cells impairs CAR T cell activity Mol. Ther. (IF 12.1) Pub Date : 2025-05-30 Rubina Thomas, Julie K. Ritchey, John F. DiPersio, Miriam Y. Kim
CD117 is a cell-surface receptor expressed on hematopoietic stem and progenitor cells and acute myeloid leukemia (AML), and thus CD117-targeting chimeric antigen receptor T cells (CART117) can function as both conditioning for hematopoietic stem cell transplantation and a therapy for AML. We developed human and mouse CART117s to evaluate the safety and feasibility of targeting CD117 in preclinical
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Dual blockade of TNFR2 and CD47 reshape tumor immune microenvironment and improve antitumor effects in colorectal cancer Mol. Ther. (IF 12.1) Pub Date : 2025-05-30 Xiaozhen Kang, Yuxin Li, Yifeng Han, Mengdi Wu, Peng Qian, Jie Dong, Jiwu Wei
Colorectal cancer (CRC) is a major cause of cancer deaths, with poor outcomes in advanced stages. CD47, overexpressed in CRC, helps tumors evade immune detection by blocking macrophage phagocytosis, while CD47 blockade has shown limited efficacy in CRC. Our study showed that dual blockade of CD47 and TNFR2 demonstrated synergistic antitumor effects in murine CRC models. Since TNFR2 was highly expressed
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Essential role of CD56dimNKG2C+ NK cells trained by SARS-CoV-2 vaccines in protecting against COVID-19 Mol. Ther. (IF 12.1) Pub Date : 2025-05-30 Huiwen Zheng, Yanli Chen, Jing Li, Yifan Zhang, Heng Li, Xin Zhao, Zhanlong He, Yun Liao, Zihan Zhang, Haijing Shi, Fengmei Yang, Yunguang Hu, Yadong Li, Jiali Li, Yuping Zhao, Xinglong Zhang, Jingsi Yang, Qihan Li, Longding Liu
The adaptive immune protection elicited by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been proven to control the severity of novel coronavirus disease 2019 (COVID-19). However, the contributions of innate lymphoid cells formed from immunization are poorly defined in vaccine evaluation. Here, we highlight how the natural killer (NK) and macrophage (Mϕ) cells’ response
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The landscape of cell and gene therapy today Mol. Ther. (IF 12.1) Pub Date : 2025-05-29 David Barrett, Daniel Digaudio
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A novel CD3ε fusion receptor allows use of T cell engagers on TCR-less allogeneic CAR T cells to improve activity and prevent antigen escape Mol. Ther. (IF 12.1) Pub Date : 2025-05-28 Dan Lu, Hui-Yi Chu, Soo Park, Mark Landon, Masanao Tsuda, Earl Avramis, Carissa Dege, Thomas Dailey, Yijia Pan, Sandeep Kothapally Hanok, Matthew Denholtz, Ramzey Abujarour, Tom Lee, John Goulding, Martin Hosking, Jodie Goodridge, Eigen Peralta, Bahram Valamehr
Chimeric antigen receptor (CAR) T cell therapies have shown clinical success in treating hematologic malignancies. However, heterogeneous target antigen expression can impair the durability of response. Combining CAR and T cell engagers (TCEs) targeting additional tumor antigens can address tumor heterogeneity and antigen escape. In allogeneic settings, eliminating the T cell receptor (TCR) of the
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Airway-applied mRNA vaccine needs tailored sequence design and high standard purification that removes devastating dsRNA contaminant Mol. Ther. (IF 12.1) Pub Date : 2025-05-28 Jingjing Zhang, Chao Li, Yuheng Liu, Rui Liao, Dian He, Lifeng Xu, Tingting Chen, Qin Xiao, Mingxing Luo, Yang Chen, Yali Li, Huaxing Zhu, Joseph Rosenecker, Xiaoyan Ding, Shuchen Pei, Shan Guan
The development of mucosal mRNA vaccines is promising but extremely challenging. Major efforts have been focused on optimizing delivery systems, but it is still unknown whether the intrinsic quality of mRNA components significantly impacts the potency of airway-inoculated mRNA vaccines. Here, we systematically demonstrate that mucosal mRNA vaccine requires higher standards of purification and a tailor-designed
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Axonal transport of AAV vectors from the superior olivary complex yields high-efficiency cochlea transduction in adult rodents Mol. Ther. (IF 12.1) Pub Date : 2025-05-28 Jerusha Naidoo, Yin Ren, Matthew Rocco, Eric Bielefeld, Allison O’Brien, Hsuan-Chih Kuo, Nathan McFarland, Matthew Avenarius, Manpreet Takhar, Geneva Frank, Victor Van Laar, Krystof Bankiewicz
Significant breakthroughs have been made in translation of adeno-associated virus (AAV) vectors for hearing disorders targeting auditory hair cells (HCs). In addition to HCs, spiral ganglion neurons (SGNs) are also impacted in a large number of sensorineural hearing loss cases in adults. However when administered directly into the cochlea in rodents aged older than P1–P3, AAV-mediated SGN transduction
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Lung endothelial transduction in a patient that succumbed to acute respiratory distress syndrome following high-dose rAAV9 gene therapy Mol. Ther. (IF 12.1) Pub Date : 2025-05-28 Juliette Hordeaux, R. Jason Lamontagne, Sushobhana Bandyopadhyay, Peter Bell, James M. Wilson, Terence R. Flotte
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China’s first approved gene therapy for hemophilia B: A new era for global AAV-based treatments Mol. Ther. (IF 12.1) Pub Date : 2025-05-28 Hongying Wei, Weidong Xiao, Jing Dai
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Perspective: Advancing safe and effective DNA therapeutics using bioactive lipid nanoparticles Mol. Ther. (IF 12.1) Pub Date : 2025-05-28 Manthan N. Patel, Sachchidanand Tiwari, Jacob S. Brenner
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Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice Mol. Ther. (IF 12.1) Pub Date : 2025-05-28 Roy C. Levitt, Munal B. Kandel, Gerald Z. Zhuang, William F. Goins, Konstantinos D. Sarantopoulos, Joseph C. Glorioso
Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while
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Ablation of dysmorphic neurons is a safe and effective treatment for focal cortical dysplasia II Mol. Ther. (IF 12.1) Pub Date : 2025-05-27 Ying Xu, Jun Li, Zihao Wang, Rongrong Lu, Yingying Liu, Min Wang, Hao Li, Rui Zhao, Weijun Feng
Focal cortical dysplasia type II (FCDII) is a leading cause of refractory epilepsy in children, yet treatment options remain limited. The most frequent genetic cause of FCDII is mosaic and somatic variants in genes of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, leading to hyperactivation of mTOR signaling. The presence of dysmorphic
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Intraperitoneal infusion of NKG2D CAR-NK cells induces endogenous CD8+ T cell activation in patients with advanced colorectal cancer Mol. Ther. (IF 12.1) Pub Date : 2025-05-27 Bin Li, Xudong Zhu, Jingyu Ge, Hangyu Zhang, Yang Gao, Xuanwen Bao, Xiaomeng Dai, Zhicheng Du, Xiaoxuan Tu, Zhou Tong, Qihan Fu, Dongxue Hu, Weihong Tian, Yi Zheng, Lulu Liu, Peng Zhao, Weijia Fang, Shu Wang, Dongrui Wang
Peritoneal metastasis (PM) is a prevalent mode of metastasis in colorectal cancer (CRC) with rapid disease progression and limited treatment options. Locoregional infusion of immune cells have been explored in different types of solid tumors, but the feasibility and safety of locoregional chimeric antigen receptor-natural killer (CAR-NK) cells in treating CRC-PM is still unknown. We report the results
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Reprogramming the neuroblastoma tumor immune microenvironment to enhance GPC2 CAR T cells Mol. Ther. (IF 12.1) Pub Date : 2025-05-27 Anna Maria Giudice, Sydney L. Roth, Stephanie Matlaga, Evan Cresswell-Clay, Pamela Mishra, Patrick M. Schürch, Kwame Attah M. Boateng-Antwi, Minu Samanta, Guillem Pascual-Pasto, Vincent Zecchino, Timothy T. Spear, Brendan McIntyre, Neil Chada, Tingting Wang, Lingling Liu, Ruoning Wang, John T. Wilson, Adam J. Wolpaw, Kristopher R. Bosse
Poor tumor trafficking and the immunosuppressive tumor microenvironment (TME) limit chimeric antigen receptor (CAR) T cell efficacy in solid tumors, such as neuroblastoma. We previously optimized GPC2 CARs in human neuroblastoma xenografts leading to clinical translation; however, there have not been preclinical studies using immunocompetent models. Thus, here we generated murine GPC2 CAR T cells using
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Disease-modifying, multidimensional efficacy of putaminal CaV1.3-shRNA gene therapy in aged parkinsonism male and female macaques Mol. Ther. (IF 12.1) Pub Date : 2025-05-27 Kathy Steece-Collier, Margaret E. Caulfield, Molly J. Vander Werp, Scott J. Muller, Jennifer A. Stancati, Yaping Chu, Ivette M. Sandoval, Timothy J. Collier, Jeffrey H. Kordower, Fredric P. Manfredsson
There remain several unmet clinical needs in Parkinson’s disease (PD) including waning and incomplete efficacy of symptomatic therapies, development of medication side effects (i.e., levodopa-induced dyskinesias [LID]) and unfettered disease progression. CaV1.3 calcium channels are therapeutic targets of intense interest in PD. We developed an RNA interference (RNAi)-based vector approach utilizing
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Therapeutic applications of interface-mimicking peptides for targeting the SARS-CoV-2 NSP12-NSP8 RdRp complex Mol. Ther. (IF 12.1) Pub Date : 2025-05-27 Mark Anthony B. Casel, Jae-Woo Ahn, Hyunjoon Kim, Isaac Choi, Seung-Gyu Jang, Rare Rollon, Ho-Young Ji, Mina Yu, Seong Cheol Min, Min-Suk Song, Young Ki Choi
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication depends on the NSP12-NSP8-NSP7 complex, which plays a critical role in enhancing RNA-dependent RNA polymerase (RdRp) activity. NSP8 is particularly essential, stabilizing the RdRp complex and supporting viral replication across diverse variants. To disrupt this crucial interaction, we designed four NSP8-derived peptides—N8-Pepα
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Allogeneic CAR T cells: A new player in the field and the peculiar opportunities of the hospital exemption path Mol. Ther. (IF 12.1) Pub Date : 2025-05-24 Francesca Del Bufalo, Concetta Quintarelli, Franco Locatelli
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Novel photoreceptor-specific promoters for gene therapy in mid- to late-stage retinal degeneration Mol. Ther. (IF 12.1) Pub Date : 2025-05-21 Raghavi Sudharsan, Leonardo Murgiano, Aditi Ahuja, Yu Sato, Jennifer Kwok, Natalia Dolgova, Svetlana Savina, Morgan Sedorovitz, Valerie L. Dufour, Gustavo D. Aguirre, Leah C. Byrne, William A. Beltran
Inherited retinal degenerations (IRDs) cause progressive photoreceptor loss, leading to vision impairment. Gene therapy using adeno-associated viral (AAV) vectors holds immense promise for treating these conditions. However, achieving optimal gene expression at mid to late stages of retinal degeneration remains challenging due to scarcity of efficient photoreceptor-specific promoters expressed at these
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Clinical advances in gene, cell, and RNA therapies Mol. Ther. (IF 12.1) Pub Date : 2025-05-20 Michael C. Milone, Jorge Mansilla-Soto, Norbert Pardi, Lindsey A. George, Barry J. Byrne, Roland W. Herzog
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GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice Mol. Ther. (IF 12.1) Pub Date : 2025-05-19 Wen Mei, Guangda Xiang, Yixiang Li, Huan Li, Lingwei Xiang, Junyan Lu, Lin Xiang, Jing Dong, Min Liu
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Patient-centered long-term follow-up for gene therapies aligns with ethics and science Mol. Ther. (IF 12.1) Pub Date : 2025-05-15 Carolyn Riley Chapman, Timothy P. Cripe, Alison S. Bateman-House
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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 : 2025-05-14 Haibin Zhou, Jiajing Dai, Dong Li, Luyao Wang, Meng Ye, Xiaoling Hu, Joseph LoTurco, Ji Hu, Wenzhi Sun
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RNAi-mediated silencing of SOD1 profoundly extends survival and functional outcomes in ALS mice Mol. Ther. (IF 12.1) Pub Date : 2025-05-09 Alexandra Weiss, James W. Gilbert, Iris Valeria Rivera Flores, Jillian Belgrad, Chantal Ferguson, Elif O. Dogan, Nicholas Wightman, Kit Mocarski, Dimas Echeverria, Ashley L. Harkins, Ashley Summers, Brianna Bramato, Nicholas McHugh, Raymond Furgal, Nozomi Yamada, David Cooper, Kathryn Monopoli, Bruno M.D.C. Godinho, Matthew R. Hassler, Ken Yamada, Paul Greer, Nils Henninger, Robert H. Brown Jr., Anastasia
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition, with 20% of familial and 2%–3% of sporadic cases linked to mutations in the cytosolic superoxide dismutase (SOD1) gene. Mutant SOD1 protein is toxic to motor neurons, making SOD1 gene suppression a promising approach, supported by preclinical data and the 2023 Federal Drug Administration (FDA) approval of the GapmeR ASO targeting
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Restoring AIBP expression in the retina provides neuroprotection in glaucoma Mol. Ther. (IF 12.1) Pub Date : 2025-05-09 Won-Kyu Ju, Keun-Young Kim, Tonking Bastola, Ziyao Shen, Seunghwan Choi, Guy A. Perkins, Sinwoo Hwang, Jungsu Kim, Jin-Woo Kwon, Muna Poudel, Sébastien Phan, Fan Xia, Shuizhen Shi, Hyunkyung Cho, Hua Liu, Wenbo Zhang, Robert N. Weinreb, Mark H. Ellisman, Yury I. Miller, Soo-Ho Choi
Glaucoma is a neurodegenerative disease manifested by retinal ganglion cell (RGC) death and irreversible blindness. We have identified apolipoprotein A-I binding protein (AIBP) that controls excessive cholesterol accumulation and neuroinflammation in the retina by upregulating the cholesterol transporter ABCA1 and reducing TLR4 signaling and mitochondrial dysfunction. Here, we demonstrated that AIBP
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Neuron-targeted gene therapy rescues multiple phenotypes of STXBP1-related disorders in mice and is well tolerated in nonhuman primates Mol. Ther. (IF 12.1) Pub Date : 2025-05-09 Rangoli Aeran, Annie Tanenhaus, Sheila M.S. Sears, Nathan J. Moerke, Adam Miller, Camille Artur, Yosr Bouhlal, Peter F. Bove, Alexander J. Diaz de Arce, Saki Shimizu, Jason Le, Keith Place, Dixon Hoffelt, Tselmeg Amarlkhagva, Jennifer Su, Ming Chen, Brooke A. Babineau, John McLaughlin, Myat Soe, Warren Macdonald, I. Winnie Lin, Dhruv Bole, Kristen M. Valentine, Elizabeth Hallam, Puja Dhanota, Serena
De novo heterozygous variants in the neuronal STXBP1 gene cause severe, early-onset developmental and epileptic encephalopathy. Adeno-associated virus (AAV)-based gene replacement therapy offers the potential for a one-time, disease-modifying approach for STXBP1-related disorders. However, off-target overexpression in the liver and in the dorsal root ganglion (DRG) are known potential toxicities of
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CD38hi macrophages promote fibrotic transition following acute kidney injury by modulating NAD+ metabolism Mol. Ther. (IF 12.1) Pub Date : 2025-05-09 Weijian Yao, Menghan Liu, Zehua Li, Lei Qu, Shuang Sui, Chengang Xiang, Lei Jiang, Suxia Wang, Gang Liu, Ying Chen, Li Yang
Acute kidney injury (AKI) encompasses a spectrum of conditions, varying from mild and self-limiting to severe cases that can lead to chronic kidney disease (CKD). Macrophages are crucial in the progression from AKI to CKD, yet the diversity of macrophage subsets complicates the identification of key functional types. We established a detailed single-cell atlas of mononuclear macrophages from the onset
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Highly conserved brain vascular receptor ALPL mediates transport of engineered AAV vectors across the blood-brain barrier Mol. Ther. (IF 12.1) Pub Date : 2025-05-08 Tyler C. Moyer, Brett A. Hoffman, Weitong Chen, Ishan Shah, Xiao-Qin Ren, Tatiana Knox, Jiachen Liu, Wei Wang, Jiangyu Li, Hamza Khalid, Anupriya S. Kulkarni, Munachiso Egbuchulam, Joseph Clement, Alexis Bloedel, Matthew Child, Rupinderjit Kaur, Emily Rouse, Kristin Graham, Damien Maura, Zachary Thorpe, Ambreen Sayed-Zahid, Charlotte Hiu-Yan Chung, Alexander Kutchin, Amy Johnson, Johnny Yao, Jeffrey
Delivery of systemically administered therapeutics to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB). Bioengineered adeno-associated virus (AAV) capsids have been shown to penetrate the BBB with great efficacy in mouse and non-human primate models, but their translational potential is often limited by species selectivity and undefined mechanisms of action. Here, we
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Renal tubular epithelial IGFBP7 interacts with PKM2 to drive renal lipid accumulation and fibrosis Mol. Ther. (IF 12.1) Pub Date : 2025-05-08 Ju-tao Yu, Shuai-shuai Xie, Xiao-yu Shen, Zeng Li, Xiao-wei Hu, Yao Zhang, Ze-hui Dong, Jia-nan Wang, Xiang-yu Li, Yu-hang Dong, Chao Li, Ming-lu Ji, Xiao-guo Suo, Chen Yang, Juan Jin, Wei Wang, Jia-gen Wen, Ming-ming Liu, Li Li, Qin Yang, Xiao-ming Meng
Renal fibrosis serves as a critical pathological mechanism driving the progression of chronic kidney disease (CKD). However, the pathogenesis and therapeutic targets involved in this process remain unclear. Interestingly, we currently found that IGFBP7 is highly expressed in tubular epithelial cells (TECs) from the fibrotic kidneys of human patients and animal models. However, their functional roles
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Concept CARs are picking up speed Mol. Ther. (IF 12.1) Pub Date : 2025-05-08 Jorge Mansilla-Soto, Michael C. Milone
The field of adoptive T cell immunotherapy has been dominated by a chimeric antigen receptor (CAR) design that combines antigen recognition through antibody-derived domains and signaling into a single polypeptide. This conventional design redirects the immense cytotoxic potential of T cells toward tumors, and it is the core of several commercially marketed CAR-T cell products. Recent research in the
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Intrinsic/proximal cell surface marker logic-gated extracellular targeted protein degradation in specific cell population Mol. Ther. (IF 12.1) Pub Date : 2025-05-07 Yafeng Wang, Guiquan Zhang, Ping Rong, Panpan Guo, Shisheng Huang, Yang Hang, Pei Wang, Lin Tang, Xiaojing Li, Xiaojun Tang, Shuai Ding, Xingxu Huang, Jianghuai Liu, Lingyun Sun
Molecular tether-mediated extracellular targeted protein degradation (eTPD) presents an innovative technology and underlies a promising drug modality. However, to precisely implement eTPD within specific cell compartments remains a significant challenge. As eTPD depends on the degrader molecule expression and activity, we first seek to expand the panel of potential eTPD degraders. To this end, more
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Spatial multi-omics reveals the potential involvement of SPP1+ fibroblasts in determining metabolic heterogeneity and promoting metastatic growth of colorectal cancer liver metastasis Mol. Ther. (IF 12.1) Pub Date : 2025-05-07 Yuzhen Gao, Xiuping Zhang, Shenglong Xia, Qing Chen, Qingchao Tong, Shaobo Yu, Rui An, Cheng Cheng, Wenbo Zou, Leilei Liang, Xinyou Xie, Zhangfa Song, Rong Liu, Jun Zhang
This study investigates key microscopic regions involved in colorectal cancer liver metastasis (CRLM), focusing on the crucial role of cancer-associated fibroblasts (CAFs) in promoting tumor progression and providing molecular- and metabolism-level insights for its diagnosis and treatment using multi-omics. We followed 12 fresh surgical samples from 2 untreated CRLM patients. Among these, 4 samples
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FLT201, a novel liver-directed AAV gene therapy candidate for Gaucher disease type 1 Mol. Ther. (IF 12.1) Pub Date : 2025-05-07 Fabrizio Comper, Carlos J. Miranda, Benjamin Liou, Tihomir Dodev, Jey M. Jeyakumar, Miriam Canavese, Clement Cocita, Khashayar Khoshrou, Gustavo Tiscornia, Elisa Chisari, Emmaline Stotter, Erald Shehu, Sudharsan Sridharan, I-Mei Yu, Jalpa Pandya, Jaminder Khinder, Natalie Northcott, Petya Kalcheva, Samantha Correia, Ying Sun, Allison P. Dane, Rose Sheridan, Amit C. Nathwani, Romuald Corbau
Gaucher disease type 1 (GD1) is caused by mutations in the GBA1 gene, which result in deficient enzyme β-glucocerebrosidase (GCase) activity and production with the harmful accumulation of the lipid substrate glucocerebroside. Replacement of GCase is current standard of care for GD1; however, GCase has a relatively short active half-life at both physiological and lysosomal pH and biweekly intravenous
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Template-assisted sequence knockin rescues skeletal and cardiac muscle function in a deletion model of Duchenne muscular dystrophy Mol. Ther. (IF 12.1) Pub Date : 2025-05-07 Sina Fatehi, Matthew J. Rok, Ryan M. Marks, Emily Huynh, Natalie Kozman, Hong Anh Truong, Lijun Chi, Bei Yan, Enzhe Khazeeva, Paul Delgado-Olguin, Evgueni A. Ivakine, Ronald D. Cohn
Duchenne muscular dystrophy (DMD) poses challenges in therapy design due to dystrophin’s complex role in maintaining muscle function since the restoration of truncated protein products has failed to completely address the disease’s pathophysiology in clinical trials. As ∼70% of patients harbor deletions, strategies enabling targeted DNA insertion to restore full-length dystrophin protein are essential
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Therapeutic mRNA vaccine applications in oncology Mol. Ther. (IF 12.1) Pub Date : 2025-05-06 Leighton Elliott, Timothy Foster, Paul Castillo, Hector Mendez-Gomez, Elias J. Sayour
The emergence of mRNA vaccines for infectious diseases has heralded development for a slew of other indications, including cancer. Lipid particle delivery vehicles can protect RNA from degradation and promote delivery to intended targets in vivo. In this mini-review, we discuss mRNA vaccine mechanisms and capacity for enhancement followed by progress to date in the clinical development of mRNA cancer
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Understanding the role of NOTCH2 mutation in centronuclear myopathy Mol. Ther. (IF 12.1) Pub Date : 2025-05-06 Youxi Lin, Hang Zhou, Wenjun Hu, Bo Gao, Tongzhou Liang, Jincheng Qiu, Pengfei Li, Yichen Que, Chipiu Wong, Xianjian Qiu, Zhihuai Deng, Huihong Shi, Song Liu, Jianan Chen, Nianchun Liao, Qihui Chen, Xiaojuan Li, Anjing Liang, Wenjie Gao, Dongsheng Huang
NOTCH2 is a widely expressed protein that plays a crucial role in the normal development and function of various tissues, including skeletal muscle. This study focused on a pedigree with centronuclear myopathy, primarily characterized by muscle weakness and centralized nuclei, and identified the autosomal recessive NOTCH2p.I1689F mutation through whole-exome sequencing. Using a homologous mutant mouse
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SARS-CoV-2 N protein induces hypokalemia in acute kidney injury mice via ENaC-dependent mechanism Mol. Ther. (IF 12.1) Pub Date : 2025-05-06 Dan-Dan Zhang, Yang Liu, Wenbiao Wang, Wenjing Wu, Junzhe Chen, Lin Wan, Liumei Wu, Xiao-Ru Huang, Hui-Yao Lan, Xueqing Yu
Hypokalemia is a prevalent complication of COVID-19 patients with acute kidney injury (AKI); however, mechanisms have yet to be fully understood. By single-nucleus RNA sequencing, we found that COVID-19 patients with AKI were associated with a marked upregulation of the epithelial sodium channel (ENaC) in the renal tubular epithelial cells (TECs). By using a mouse model of AKI induced by kidney-specific
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Current clinical applications of AAV-mediated gene therapy Mol. Ther. (IF 12.1) Pub Date : 2025-05-05 Barry J. Byrne, Kevin M. Flanigan, Susan E. Matesanz, Richard S. Finkel, Megan A. Waldrop, Eleonora S. D'Ambrosio, Nicholas E. Johnson, Barbara K. Smith, Carsten Bönnemann, Sean Carrig, Joseph W. Rossano, Barry Greenberg, Laura Lalaguna, Enrique Lara-Pezzi, Sub Subramony, Manuela Corti, Claudia Mercado-Rodriguez, Carmen Leon-Astudillo, Rebecca Ahrens-Nicklas, Diana Bharucha-Goebel, Guangping Gao, Dominic
Currently, there are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population. Even among the 5% of patients with genetic disease that have treatment options, these therapeutics rarely address the underlying cause of disease but rather focus on managing or modifying symptoms and typically require recurrent, lifelong therapy. A therapeutic approach to genetic
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Locking CBL TKBD in its native conformation presents a novel therapeutic opportunity in mutant CBL-dependent leukemia Mol. Ther. (IF 12.1) Pub Date : 2025-05-05 Syed Feroj Ahmed, Jayanthi Anand, Wei Zhang, Lori Buetow, Loveena Rishi, Louise Mitchell, Jonathan Bohlen, Sergio Lilla, Gary J. Sibbet, Colin Nixon, Amrita Patel, Karolina A. Majorek, Sara Zanivan, Jacinta C. Bustamante, Sachdev S. Sidhu, Karen Blyth, Danny T. Huang
Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase critical for negatively regulating receptor protein tyrosine kinases (RTKs). Deleterious CBL mutants lose E3 activity, but act as adaptors that gain function to cause myeloproliferative neoplasms. Currently, there is no targeted treatment available for patients with CBL mutant-dependent disorders. By combining phage-display technology and structure-based
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High-dimensional temporal mapping of CAR T cells reveals phenotypic and functional remodeling during manufacturing Mol. Ther. (IF 12.1) Pub Date : 2025-05-01 Amaia Cadinanos-Garai, Christian L. Flugel, Anson Cheung, Enzi Jiang, Alix Vaissié, Mohamed Abou-el-Enein
Despite the notable success of chimeric antigen receptor (CAR) T cell therapies in hematological malignancies, clinical outcomes remain variable, making it critical to understand how manufacturing influences product composition and function. We developed a 36-marker spectral flow cytometry panel enabling integrated profiling of phenotypic, metabolic, and functional attributes across CAR T cell production
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Clinical applications of exon-skipping antisense oligonucleotides in neuromuscular diseases Mol. Ther. (IF 12.1) Pub Date : 2025-04-30 Laia Torres-Masjoan, Sara Aguti, Haiyan Zhou, Francesco Muntoni
Four exon-skipping antisense oligonucleotides (ASOs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD), including eteplirsen, golodirsen, viltolarsen, and casimersen. Current data from long-term real-world usage of these ASOs suggests a broad safety profile and a delay in muscle deterioration. Nevertheless, the exon-skipping efficacy
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Engineering TME-gated inducible CAR-T cell therapy for solid tumors Mol. Ther. (IF 12.1) Pub Date : 2025-04-30 Huong T.X. Nguyen, Byung-Gyu Kim, Jay T. Myers, Hao Yan, Satendra Kumar, Saada Eid, Wei Wang, Alex Y. Huang, Fu-Sen Liang
Autonomous “living drug” chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer medicine. However, concerns about on-target off-tumor T cell activation and resulting toxicities require advanced precise regulatory control systems for CAR-T. Here, we present a novel strategy using a genetic “AND” gate that integrates chemically induced proximity (CIP) and tumor-activated prodrug approaches
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BIN1 gene replacement reverses BIN1-related centronuclear myopathy Mol. Ther. (IF 12.1) Pub Date : 2025-04-29 Jacqueline Ji, Quentin Giraud, Nadège Diedhiou, Eva Lipkow, Coralie Spiegelhalter, Jocelyn Laporte
Centronuclear myopathies (CNMs) are severe genetic disorders characterized by generalized muscle weakness associated with organelle mispositioning in myofibers. Most CNM cases are caused by mutations in proteins involved in membrane remodeling, including amphiphysin 2 (BIN1). There is no treatment, and the pathological mechanisms are not understood. Here, we aimed to cure the Bin1-CNM mouse model (Bin1mck−/−)
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Truncated complement factor H Y402 gene therapy rescues C3 glomerulonephritis Mol. Ther. (IF 12.1) Pub Date : 2025-04-24 Lindsey A. Chew, Daniel Grigsby, C. Garren Hester, Joshua Amason, W. Kyle McPherson, Edward J. Flynn III, Meike Visel, Christopher R. Starr, John G. Flannery, Tylor R. Lewis, Catherine Bowes Rickman
There are no effective therapies for patients with dry age-related macular degeneration (AMD) or C3 glomerulonephritis (C3G). Unfortunately, past efforts to treat C3G using exogenous human complement factor H (CFH) found limited success due to immune rejection of a foreign protein response. AMD research has also faced myriad challenges, including the absence of an ideal therapeutic target and difficulties