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Effective knockdown-replace gene therapy in a novel mouse model of DNM1 developmental and epileptic encephalopathy Mol. Ther. (IF 12.1) Pub Date : 2024-08-10 Devin J. Jones, Divya Soundararajan, Noah K. Taylor, Osasumwen V. Aimiuwu, Pranav Mathkar, Amy Shore, Jia Jie Teoh, Wanqi Wang, Tristan T. Sands, Matthew C. Weston, Scott Q. Harper, Wayne N. Frankel
Effective gene therapy for gain-of-function or dominant-negative disease mutations may require eliminating expression of the mutant copy together with wild-type replacement. We evaluated such a knockdown-replace strategy in a mouse model of disease, a debilitating and intractable neurodevelopmental epilepsy. To challenge the approach robustly, we expressed a patient-based variant in GABAergic neurons—which
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T cell specific in vivo gene delivery with DART-AAVs targeted to CD8 Mol. Ther. (IF 12.1) Pub Date : 2024-08-08 M.B. Demircan, L.J. Zinser, A. Michels, M. Guaza-Lasheras, F. John, J.M. Gorol, S.A. Theuerkauf, D.M. Günther, D. Grimm, F.R. Greten, P. Chlanda, F.B. Thalheimer, C.J. Buchholz
One of the biggest challenges for gene therapy are vectors mediating highly selective gene transfer into a defined population of therapy-relevant cells. Here we present DARPin-targeted AAVs (DART-AAVs) displaying DARPins specific for human and murine CD8. Insertion of DARPins into the GH2/GH3 loop of the capsid protein 1 (VP1) of AAV2 and AAV6 resulted in high selectivity for CD8-positive T cells with
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Small-molecule-based targeted therapy in liver cancer Mol. Ther. (IF 12.1) Pub Date : 2024-08-08 Yue Ming, Yanqiu Gong, Xuewen Fu, Xinyu Ouyang, Yong Peng, Wenchen Pu
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve
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Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion Mol. Ther. (IF 12.1) Pub Date : 2024-08-05 Troy C. Lund, Paul J. Orchard, David R. Nascene, Carina J. King, Jennifer Braun, Stuti Thakkar, Willa Durose, Ilya Shestopalov, Himal Thakar, Ashish O. Gupta
A 9-year-old boy with adrenoleukodystrophy due to whole-gene deletion was diagnosed with active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hematopoietic cell transplant (HCT) with autologous CD34 cells transduced with an -expressing lentiviral vector (eli-cel [elivaldogene autotemcel]) as part of the ALD-104 clinical trial. Fifty
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Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency Mol. Ther. (IF 12.1) Pub Date : 2024-08-05 Jitka Rybova, Teresa Sundararajan, Ladislav Kuchar, Theresa A. Dlugi, Petr Ruzicka, William M. McKillop, Jeffrey A. Medin
Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment
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The ARDS microenvironment enhances MSC-induced repair via VEGF in experimental acute lung inflammation Mol. Ther. (IF 12.1) Pub Date : 2024-08-05 Courteney Tunstead, Evelina Volkova, Hazel Dunbar, Ian J. Hawthorne, Alison Bell, Louise Crowe, Joanne C. Masterson, Claudia C. Dos Santos, Bairbre McNicholas, John G. Laffey, Karen English
Clinical trials investigating the potential of mesenchymal stromal cells (MSCs) for the treatment of inflammatory diseases, such as acute respiratory distress syndrome (ARDS), have been disappointing, with less than 50% of patients responding to treatment. Licensed MSCs show enhanced therapeutic efficacy in response to cytokine-mediated activation signals. There are two distinct sub-phenotypes of ARDS:
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T cell-redirecting therapies in hematological malignancies: Current developments and novel strategies for improved targeting Mol. Ther. (IF 12.1) Pub Date : 2024-08-05 Georgina S.F. Anderson, Michael A. Chapman
T cell-redirecting therapies (TCRTs), such as chimeric antigen receptor (CAR) or T cell receptor (TCR) T cells and T cell engagers, have emerged as a highly effective treatment modality, particularly in the B and plasma cell-malignancy setting. However, many patients fail to achieve deep and durable responses; while the lack of truly unique tumor antigens, and concurrent on-target/off-tumor toxicities
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TIPE2 gene transfer ameliorates aging-associated osteoarthritis in a progeria mouse model by reducing inflammation and cellular senescence Mol. Ther. (IF 12.1) Pub Date : 2024-08-05 Ping Guo, Xueqin Gao, Anna-Laura Nelson, Matthieu Huard, Aiping Lu, William Sealy Hambright, Johnny Huard
Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely
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Reprogramming tumor immune microenvironment by milbemycin oxime results in pancreatic tumor growth suppression and enhanced anti-PD-1 efficacy Mol. Ther. (IF 12.1) Pub Date : 2024-08-03 Shreyas Gaikwad, Sanjay K. Srivastava
Pancreatic ductal adenocarcinoma (PDAC) has a survival rate of 12%, and multiple clinical trials testing anti-PD-1 therapies against PDAC have failed, suggesting a need for a novel therapeutic strategy. In this study, we evaluated the potential of milbemycin oxime (MBO), an antiparasitic compound, as an immunomodulatory agent in PDAC. Our results show that MBO inhibited the growth of multiple PDAC
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A platform to deliver single and bi-specific Cas9/guide RNA to perturb genes in vitro and in vivo Mol. Ther. (IF 12.1) Pub Date : 2024-07-31 Yi-Jia Li, Sheng-Hsuan Chien, Rui Huang, Andreas Herrmann, Qianqian Zhao, Pei-Chuan Li, Chunyan Zhang, Antons Martincuks, Nicole Lugo Santiago, Katherine Zong, Piotr Swiderski, Ross A. Okimoto, Mihae Song, Lorna Rodriguez, Stephen J. Forman, Xiuli Wang, Hua Yu
Although CRISPR-Cas9 technology is poised to revolutionize the treatment of diseases with underlying genetic mutations, it faces some significant issues limiting clinical entry. They include low-efficiency systemic delivery and undesired off-target effects. Here, we demonstrate, by modifying Cas9 with phosphorothioate-DNA oligos (PSs), that one can efficiently deliver single and bi-specific CRISPR-Cas9/guide
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Dual neutralization of influenza virus hemagglutinin and neuraminidase by a bispecific antibody leads to improved antiviral activity Mol. Ther. (IF 12.1) Pub Date : 2024-07-31 Romila Moirangthem, Sapir Cordela, Dina Khateeb, Ben Shor, Ivan Kosik, Dina Schneidman-Duhovny, Michal Mandelboim, Friederike Jönsson, Jonathan W. Yewdell, Timothée Bruel, Yotam Bar-On
Targeting multiple viral proteins is pivotal for sustained suppression of highly mutable viruses. In recent years, broadly neutralizing antibodies that target the influenza virus hemagglutinin and neuraminidase glycoproteins have been developed, and antibody monotherapy has been tested in preclinical and clinical studies to treat or prevent influenza virus infection. However, the impact of dual neutralization
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Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease Mol. Ther. (IF 12.1) Pub Date : 2024-07-31 Varun Katta, Kiera O’Keefe, Yichao Li, Thiyagaraj Mayurathan, Cicera R. Lazzarotto, Rachael K. Wood, Rachel M. Levine, Alicia Powers, Kalin Mayberry, Garret Manquen, Yu Yao, Jingjing Zhang, Yoonjeong Jang, Nikitha Nimmagadda, Erin A. Dempsey, GaHyun Lee, Naoya Uchida, Yong Cheng, Frank Fazio, Tim Lockey, Mike Meagher, Akshay Sharma, John F. Tisdale, Sheng Zhou, Jonathan S. Yen, Mitchell J. Weiss, Shengdar
Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although
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Armored bicistronic CAR T cells with dominant-negative TGF-β receptor II to overcome resistance in glioblastoma Mol. Ther. (IF 12.1) Pub Date : 2024-07-31 Nannan Li, Jesse L. Rodriguez, Yibo Yin, Meghan T. Logun, Logan Zhang, Shengkun Yu, Kelly A. Hicks, Jiasi Vicky Zhang, Laura Zhang, Chuncheng Xie, Jiabin Wang, Tianyu Wang, Jiayi Xu, Joseph A. Fraietta, Zev A. Binder, Zhiguo Lin, Donald M. O’Rourke
Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells used to eliminate tumor cells. The human transforming
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Tumor-intrinsic CDC42BPB confers resistance to anti-PD-1 immune checkpoint blockade in breast cancer Mol. Ther. (IF 12.1) Pub Date : 2024-07-31 Ravindra Pramod Deshpande, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Eleanor C. Smith, John Hunting, Jimmy Ruiz, Wencheng Li, Kounosuke Watabe
Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor. We have used the CRISPR-Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor-intrinsic kinases conferring resistance to anti-PD-1 immune checkpoint blockade. We have identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immune
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In vivo genome editing for inherited retinal disease: Opportunities and challenges Mol. Ther. (IF 12.1) Pub Date : 2024-07-30 Rob W.J. Collin, Bart P. Leroy
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Mapping the cancer surface proteome in search of target antigens for immunotherapy Mol. Ther. (IF 12.1) Pub Date : 2024-07-27 Francesco Di Meo, Brandon Kale, John M. Koomen, Fabiana Perna
Immune-based therapeutic interventions recognizing proteins localized on the cell surface of cancer cells are emerging as a promising cancer treatment. Antibody-based therapies and engineered T cells are now approved by the Food and Drug Administration to treat some malignancies. These therapies utilize a few cell surface proteins highly expressed on cancer cells to release the negative regulation
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CITED4 gene therapy protects against maladaptive cardiac remodeling after ischemia/reperfusion injury in mice Mol. Ther. (IF 12.1) Pub Date : 2024-07-26 Carolin Lerchenmüller, Margaret H. Hastings, Charles P. Rabolli, Fynn Betge, Mani Roshan, Laura X. Liu, Xiaojun Liu, Chiara Heß, Jason D. Roh, Colin Platt, Vassilios Bezzerides, Martin Busch, Hugo A. Katus, Norbert Frey, Patrick Most, Anthony Rosenzweig
Cardiac signaling pathways functionally important in the heart’s response to exercise often protect the heart against pathological stress, potentially providing novel therapeutic targets. However, it is important to determine which of these pathways can be feasibly targeted . Transgenic overexpression of exercise-induced CITED4 has been shown to protect against adverse remodeling after ischemia/reperfusion
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CRISPR-mediated ablation of TP53 and EGFR mutations enhances gefitinib sensitivity and anti-tumor efficacy in lung cancer Mol. Ther. (IF 12.1) Pub Date : 2024-07-25 A-Rum Yoon, Soyeon Lee, Ju Hee Kim, Yejin Park, Taeyoung Koo, Chae-Ok Yun
Multiple pathogenic single-nucleotide polymorphisms (SNPs) have been identified as contributing factors in the aggravation of cancer prognosis and emergence of drug resistance in various cancers. Here, we targeted mutated and oncogenes harboring single-nucleotide missense mutations (T790M and R273H) that are associated with gefitinib resistance. Co-delivery of adenine base editor (ABE) and and SNP
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Specific targeting of cancer vaccines to antigen-presenting cells via an endogenous TLR2/6 ligand derived from cysteinyl-tRNA synthetase 1 Mol. Ther. (IF 12.1) Pub Date : 2024-07-25 Hyeong Yun Kim, Seongmin Cho, Sang Bum Kim, Ee Chan Song, Wonchul Jung, Yun Gyeong Shin, Ji Hun Suh, Jihye Choi, Ina Yoon, Uijoo Kim, Hamin Ban, Sunkyo Hwang, Jeongwon Mun, Joohee Park, Nayoung Kim, Youngjin Lee, Myung Hee Kim, Sunghoon Kim
Cancer vaccines have been developed as a promising way to boost cancer immunity. However, their clinical potency is often limited due to the imprecise delivery of tumor antigens. To overcome this problem, we conjugated an endogenous Toll-like receptor (TLR)2/6 ligand, UNE-C1, to human papilloma virus type 16 (HPV-16)-derived peptide antigen, E7, and found that the UNE-C1-conjugated cancer vaccine (UCV)
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A systematic review of immunosuppressive protocols used in AAV gene therapy for monogenic disorders Mol. Ther. (IF 12.1) Pub Date : 2024-07-22 Besarte Vrellaku, Ilda Sethw Hassan, Rebecca Howitt, Christopher P. Webster, Eli Harriss, Fraser McBlane, Corinne Betts, Jorge Schettini, Mattia Lion, John E. Mindur, Michael Duerr, Pamela J. Shaw, Janine Kirby, Mimoun Azzouz, Laurent Servais
The emergence of adeno-associated virus (AAV)-based gene therapy has brought hope to patients with severe monogenic disorders. However, immune responses to AAV vectors and transgene products present challenges that require effective immunosuppressive strategies. This systematic review focuses on the immunosuppressive protocols used in 38 clinical trials and 35 real-world studies, considering a range
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Safety and efficacy studies of CRISPR-Cas9 treatment of sickle cell disease highlights disease-specific responses Mol. Ther. (IF 12.1) Pub Date : 2024-07-22 Giacomo Frati, Megane Brusson, Gilles Sartre, Bochra Mlayah, Tristan Felix, Anne Chalumeau, Panagiotis Antoniou, Giulia Hardouin, Jean-Paul Concordet, Oriana Romano, Giandomenico Turchiano, Annarita Miccio
Fetal hemoglobin (HbF) reactivation expression through CRISPR-Cas9 is a promising strategy for the treatment of sickle cell disease (SCD). Here, we describe a genome editing strategy leading to reactivation of HbF expression by targeting the binding sites (BSs) for the lymphoma-related factor (LRF) repressor in the γ-globin promoters. CRISPR-Cas9 treatment in healthy donor (HD) and patient-derived
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Molecular Therapy’s growing influence Mol. Ther. (IF 12.1) Pub Date : 2024-07-21 Roland W. Herzog, Rory Bricker-Anthony
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RNA therapeutics targeting PD-L1 is a promising immune-activation strategy against difficult-to-treat cancers Mol. Ther. (IF 12.1) Pub Date : 2024-07-21 Li Ding, Bin Deng, Gang Chen
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The first medical education program on gene and gene-modified cell therapies for Latin America Mol. Ther. (IF 12.1) Pub Date : 2024-07-20 Carlos Javier Alméciga-Díaz
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Can self-amplifying RNA vaccines and viruses exchange genetic material? Mol. Ther. (IF 12.1) Pub Date : 2024-07-20 Irafasha C. Casmil, Anna K. Blakney
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Harnessing extracellular vesicles for pancreatic fibrosis therapy Mol. Ther. (IF 12.1) Pub Date : 2024-07-20 Sylwia Bobis-Wozowicz, Pawel E. Ferdek
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Transforming care for spinal muscular atrophy: A critical look at treatment paradigms Mol. Ther. (IF 12.1) Pub Date : 2024-07-20 Aravindhan Veerapandiyan, Ruthwik Duvuru
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Extracellular vesicle surface display enhances the therapeutic efficacy and safety profile of cancer immunotherapy Mol. Ther. (IF 12.1) Pub Date : 2024-07-20 Migara Kavishka Jayasinghe, Yock Sin Lay, Dawn Xiao Tian Liu, Chang Yu Lee, Chang Gao, Brendon Zhijie Yeo, Faith Yuan Xin How, Rebecca Carissa Prajogo, Dong Van Hoang, Hong Anh Le, Thach Tuan Pham, Boya Peng, Cao Dai Phung, Daniel G. Tenen, Minh T.N. Le
Immunotherapy has emerged as a mainstay in cancer therapy, yet its efficacy is constrained by the risk of immune-related adverse events. In this study, we present a nanoparticle-based delivery system that enhances the therapeutic efficacy of immunomodulatory ligands while concurrently limiting systemic toxicity. We demonstrate that extracellular vesicles (EVs), lipid bilayer enclosed particles released
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Preclinical studies of gene replacement therapy for CDKL5 deficiency disorder Mol. Ther. (IF 12.1) Pub Date : 2024-07-20 Gregory Voronin, Jana Narasimhan, Jamila Gittens, Josephine Sheedy, Philip Lipari, Melinda Peters, Steven DeMarco, Liangxian Cao, Yakov Varganov, Min Jung Kim, Lisset Pear, Eman Fotouh, Supriya Sinha, Balmiki Ray, Michael C. Wu, Padmaja Yalamanchili, Christopher Southgate, Joseph Pick, Khalil Saadipour, Stephen Jung, Jeanee Lee, Anna Mollin, Ellen M. Welch, Zhijian Wu, Marla Weetall
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by a mutation in the X-linked gene. CDKL5 is a serine/threonine kinase that is critical for axon outgrowth and dendritic morphogenesis as well as synapse formation, maturation, and maintenance. This disorder is characterized by early-onset epilepsy, hypotonia, and failure to reach cognitive
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Synergic activity of FGFR2 and MEK inhibitors in the treatment of FGFR2-amplified cancers of unknown primary Mol. Ther. (IF 12.1) Pub Date : 2024-07-20 Andrea Cavazzoni, Irene Salamon, Claudia Fumarola, Giulia Gallerani, Noemi Laprovitera, Francesco Gelsomino, Mattia Riefolo, Karim Rihawi, Elisa Porcellini, Tania Rossi, Martina Mazzeschi, Maria Naddeo, Salvatore Serravalle, Elisabetta Broseghini, Federico Agostinis, Olivier Deas, Roberta Roncarati, Giorgio Durante, Ilaria Pace, Mattia Lauriola, Ingrid Garajova, George A. Calin, Massimiliano Bonafè
Patients with cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies. Experimental models are pivotal for CUP biology investigation and drug testing. We derived two CUP cell lines (CUP#55 and #96) and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines and PDXs underwent histological, immune-phenotypical
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Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine Mol. Ther. (IF 12.1) Pub Date : 2024-07-19 Saru Basnet, Mirte Van der Heijden, Dafne C.A. Quixabeira, Elise Jirovec, Susanna A.M. Grönberg-Vähä-Koskela, James H.A. Clubb, Anna Kanerva, Santeri Pakola, Lyna Haybout, Victor Arias, Otto Hemminki, Tatiana Kudling, Sadia Zafar, Victor Cervera-Carrascon, Joao M. Santos, Akseli Hemminki
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The tricky second album: Licensure of an mRNA vaccine for respiratory syncytial virus Mol. Ther. (IF 12.1) Pub Date : 2024-07-03 John S. Tregoning
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lnc-Rps4l-encoded peptide RPS4XL regulates RPS6 phosphorylation and inhibits the proliferation of PASMCs caused by hypoxia Mol. Ther. (IF 12.1) Pub Date : 2024-07-02 Yiying Li, Junting Zhang, Hanliang Sun, Yujie Chen, Wendi Li, Xiufeng Yu, Xijuan Zhao, Lixin Zhang, Jianfeng Yang, Wei Xin, Yuan Jiang, Guilin Wang, Wenbin Shi, Daling Zhu
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Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing Mol. Ther. (IF 12.1) Pub Date : 2024-07-02 Tyler F. Hill, Parnal Narvekar, Gregory D. Asher, Jasmine N. Edelstein, Nathan D. Camp, Annaiz Grimm, Kerri R. Thomas, Michael D. Leiken, Katherine M. Molloy, Peter J. Cook, Sean P. Arlauckas, Richard A. Morgan, Sarah K. Tasian, David J. Rawlings, Richard G. James
Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3
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Discovery of a novel inhibitor of macropinocytosis with antiviral activity Mol. Ther. (IF 12.1) Pub Date : 2024-07-02 Bartlomiej Porebski, Wanda Christ, Alba Corman, Martin Haraldsson, Myriam Barz, Louise Lidemalm, Maria Häggblad, Juliana Ilmain, Shane C. Wright, Matilde Murga, Jan Schlegel, Malin Jarvius, Maris Lapins, Erdinc Sezgin, Gira Bhabha, Volker M. Lauschke, Jordi Carreras-Puigvert, Miguel Lafarga, Jonas Klingström, Daniela Hühn, Oscar Fernandez-Capetillo
Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using high-throughput microscopy, where we identified chemical entities capable of preventing infection with a pseudotype
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Optimized rAAV8 targeting acinar KLF4 ameliorates fibrosis in chronic pancreatitis via exosomes-enriched let-7s suppressing pancreatic stellate cells activation Mol. Ther. (IF 12.1) Pub Date : 2024-07-02 Yating Zhao, Yongpu Feng, Fengyuan Sun, Lei Li, Jiayu Chen, Yingxiao Song, Wenbo Zhu, Xiulin Hu, Zhaoshen Li, Fanyang Kong, Yiqi Du, Xiangyu Kong
Chronic pancreatitis (CP) is marked by progressive fibrosis and the activation of pancreatic stellate cells (PSCs), accompanied by the destruction of pancreatic parenchyma, leading to the loss of acinar cells (ACs). Few research studies have explored the mechanism by which damaged ACs (DACs) contribute to PSCs activation and pancreatic fibrosis. Currently, there are no effective drugs for curing CP
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Novel OX40 and 4-1BB derived spacers enhance CD30 CAR activity and safety in CD30 positive lymphoma models Mol. Ther. (IF 12.1) Pub Date : 2024-06-29 Lindsay Kua, Chee Hoe Ng, Jin Wei Tan, Hwee Ching Tan, Cheah Chen Seh, Fiona Wong, Richard Ong, Cliona M. Rooney, Joel Tan, Qingfeng Chen, Ivan D. Horak, Kar Wai Tan, Lionel Low
The chimeric antigen receptor (CAR) derived from the CD30 specific murine antibody, HRS-3, has produced promising clinical efficacy with a favorable safety profile in the treatment of relapsed or refractory CD30-positive lymphomas. However, persistence of the autologous CAR-T cells was brief, and many patients relapsed a year after treatment. The lack of persistence may be attributed to the use of
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NKG2A genetic deletion promotes human primary NK cell anti-tumor responses better than an anti-NKG2A monoclonal antibody Mol. Ther. (IF 12.1) Pub Date : 2024-06-27 Ying Gong, Wilfred T.V. Germeraad, Xulin Zhang, Nisha Wu, Bo Li, Lynn Janssen, Zongzhong He, Marion J.J. Gijbels, Bodeng Wu, Birgit L.M.G. Gijsbers, Timo I. Olieslagers, Gerard M.J. Bos, Lei Zheng, Roel G.J. Klein Wolterink
Natural killer (NK) cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E to evade NK cell surveillance. Given the successes of immune checkpoint blockade in cancer therapy, NKG2A is an interesting novel target. However, anti-NKG2A antibodies have shown limited clinical response. In the
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An aptamer-mediated base editing platform for simultaneous knockin and multiple gene knockout for allogeneic CAR-T cells generation Mol. Ther. (IF 12.1) Pub Date : 2024-06-26 Immacolata Porreca, Robert Blassberg, Jennifer Harbottle, Bronwyn Joubert, Olga Mielczarek, Jesse Stombaugh, Kevin Hemphill, Jonathan Sumner, Deividas Pazeraitis, Julia Liz Touza, Margherita Francescatto, Mike Firth, Tommaso Selmi, Juan Carlos Collantes, Zaklina Strezoska, Benjamin Taylor, Shengkan Jin, Ceri M. Wiggins, Anja van Brabant Smith, John J. Lambourne
Gene editing technologies hold promise for enabling the next generation of adoptive cellular therapies. In conventional gene editing platforms that rely on nuclease activity, such as clustered regularly interspaced short palindromic repeats CRISPR-associated protein 9 (CRISPR-Cas9), allow efficient introduction of genetic modifications; however, these modifications occur via the generation of DNA double-strand
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Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss Mol. Ther. (IF 12.1) Pub Date : 2024-06-26 Chujiao Lin, Yeon-Suk Yang, Hong Ma, Zhihao Chen, Dong Chen, Aijaz Ahmad John, Jun Xie, Guangping Gao, Jae-Hyuck Shim
Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic
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Deficiency of galactosyl-ceramidase in adult oligodendrocytes worsens disease severity during chronic experimental allergic encephalomyelitis Mol. Ther. (IF 12.1) Pub Date : 2024-06-26 Natalia Saldivia, Gregory Heller, Diego Zelada, Jason Whitehair, Nikhil Venkat, Ashna Konjeti, Reina Savitzky, Shayla Samano, Daniel Simchuk, Richard van Breemen, Maria I. Givogri, Ernesto R. Bongarzone
Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development. However, the physiological consequence of GALC deficiency in the adult brain remains unknown. In this study, we found that mice with conditional ablation of GALC activity in post-myelinating oligodendrocytes were lethally sensitized when
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A “one size fits all” gene therapy for neurological disorders with mitochondrial dysfunction Mol. Ther. (IF 12.1) Pub Date : 2024-06-26 Qinglan Ling
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Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine Mol. Ther. (IF 12.1) Pub Date : 2024-06-22 Saru Basnet, Mirte Van der Heijden, Dafne C.A. Quixabeira, Elise Jirovec, Susanna A.M. Grönberg-Vähä-Koskela, James H.A. Clubb, Anna Kanerva, Santeri Pakola, Lyna Haybout, Victor Arias, Otto Hemminki, Tatiana Kudling, Sadia Zafar, Victor Cervera-Carrascon, Joao M. Santos, Akseli Hemminki
T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2. TILT-322
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Dual FKRP/FST gene therapy normalizes ambulation, increases strength, decreases pathology, and amplifies gene expression in LGMDR9 mice Mol. Ther. (IF 12.1) Pub Date : 2024-06-22 Patricia Lam, Deborah A. Zygmunt, Anna Ashbrook, Macey Bennett, Tatyana A. Vetter, Paul T. Martin
Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. To reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease
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LRG1 loss effectively restrains glomerular TGF-β signaling to attenuate diabetic kidney disease Mol. Ther. (IF 12.1) Pub Date : 2024-06-22 Xuan Wang, Zeguo Sun, Jia Fu, Zhengying Fang, Weijia Zhang, John C. He, Kyung Lee
Transforming growth factor (TGF)-β signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-β signaling regulators can substantially influence TGF-β′s effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly
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Preclinical evidence in the assembly of mammalian SWI/SNF complexes: Epigenetic insights and clinical perspectives in human lung disease therapy Mol. Ther. (IF 12.1) Pub Date : 2024-06-22 Octavio A. Trejo-Villegas, Irene H. Heijink, Federico Ávila-Moreno
The SWI/SNF complex, also known as the BRG1/BRM-associated factor (BAF) complex, represents a critical regulator of chromatin remodeling mechanisms in mammals. It is alternatively referred to as mSWI/SNF and has been suggested to be imbalanced in human disease compared with human health. Three types of BAF assemblies associated with it have been described, including (1) canonical BAF (cBAF), (2) polybromo-associated
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Prospects and challenges of tissue-derived extracellular vesicles Mol. Ther. (IF 12.1) Pub Date : 2024-06-22 Justin C. Lee, Roslyn M. Ray, Tristan A. Scott
Extracellular vesicles (EVs) are considered a vital component of cell-to-cell communication and represent a new frontier in diagnostics and a means to identify pathways for therapeutic intervention. Recently, studies have revealed the importance of tissue-derived EVs (Ti-EVs), which are EVs present in the interstitial spaces between cells, as they better represent the underlying physiology of complex
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A promising advance in blocking HTLV-1 transmission: Addressing a global public health problem Mol. Ther. (IF 12.1) Pub Date : 2024-06-21 Antonio Carlos Rosário Vallinoto
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AAV vectors for long-term gene therapy of hemophilia B: Are we there yet? Mol. Ther. (IF 12.1) Pub Date : 2024-06-21 Arun Srivastava
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Valproic Acid Confers Functional Pluripotency to Human Amniotic Fluid Stem Cells in a Transgene-free Approach Mol. Ther. (IF 12.1) Pub Date : 2024-06-20 Dafni Moschidou, Sayandip Mukherjee, Michael P. Blundell, Katharina Drews, Gemma N. Jones, Hassan Abdulrazzak, Beata Nowakowska, Anju Phoolchund, Kenneth Lay, T Selvee Ramasamy, Mara Cananzi, Daniel Nettersheim, Mark Sullivan, Jennifer Frost, Gudrun Moore, Joris R. Vermeesch, Nicholas M. Fisk, Adrian J. Thrasher, Anthony Atala, James Adjaye, Hubert Schorle, Paolo De Coppi, Pascale V. Guillot
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Dual-aptamer-engineered M1 macrophage with enhanced specific targeting and checkpoint blocking for solid-tumor immunotherapy Mol. Ther. (IF 12.1) Pub Date : 2024-06-20 Husun Qian, Yixin Fu, Minkang Guo, Yu Chen, Dian Zhang, Yu Wei, Fangfang Jin, Qian Zeng, Yange Wang, Chengsen Chai, Shijia Ding, Wei Cheng, Tingmei Chen
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Carbon monoxide licensing of MSCs enhances their efficacy through autophagy-mediated miRNA mechanisms Mol. Ther. (IF 12.1) Pub Date : 2024-06-20 Hazel Dunbar, Ian J. Hawthorne, Karen English
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Chopping down antibodies for a good cause Mol. Ther. (IF 12.1) Pub Date : 2024-06-18 Moanaro Biswas, Roland W. Herzog
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Clinical perspectives: Treating spinal muscular atrophy Mol. Ther. (IF 12.1) Pub Date : 2024-06-18 Molly A. McPheron, Marcia V. Felker
Spinal muscular atrophy is a rare and progressive neuromuscular disease that, without treatment, leads to progressive weakness and often death. A plethora of studies have led to the approval of three high-cost and effective treatments since 2016. These treatments, nusinersen, onasemnogene abeparvovec, and risdiplam, have not been directly compared and have varying challenges in administration. In this
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Safety concern of recombination between self-amplifying mRNA vaccines and viruses is mitigated in vivo Mol. Ther. (IF 12.1) Pub Date : 2024-06-17 Tessy A.H. Hick, Corinne Geertsema, Wilson Nguyen, Cameron R. Bishop, Linda van Oosten, Sandra R. Abbo, Troy Dumenil, Frank J.M. van Kuppeveld, Martijn A. Langereis, Daniel J. Rawle, Bing Tang, Kexin Yan, Monique M. van Oers, Andreas Suhrbier, Gorben P. Pijlman
Self-amplifying mRNA (SAM) vaccines can be rapidly deployed in the event of disease outbreaks. A legitimate safety concern is the potential for recombination between alphavirus-based SAM vaccines and circulating viruses. This theoretical risk needs to be assessed in the regulatory process for SAM vaccine approval. Herein, we undertake extensive and assessments to explore recombination between SAM vaccine
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Preclinical efficacy of a HER2 synNotch/CEA-CAR combinatorial immunotherapy against colorectal cancer with HER2 amplification Mol. Ther. (IF 12.1) Pub Date : 2024-06-17 Marco Cortese, Erica Torchiaro, Alice D’Andrea, Consalvo Petti, Federica Invrea, Letizia Franco, Chiara Donini, Valeria Leuci, Simonetta Maria Leto, Valentina Vurchio, Francesca Cottino, Claudio Isella, Sabrina Arena, Elisa Vigna, Andrea Bertotti, Livio Trusolino, Dario Sangiolo, Enzo Medico
HER2 amplification occurs in approximately 5% of colorectal cancer (CRC) cases and is associated only partially with clinical response to combined human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR)-targeted treatment. An alternative approach based on adoptive cell therapy using T cells engineered with anti-HER2 chimeric antigen receptor (CAR) proved to be toxic
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ASGCT 2024: Navigating the sea of gene and cell therapies Mol. Ther. (IF 12.1) Pub Date : 2024-06-15 Roland W. Herzog, Rory Bricker-Anthony
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Dedifferentiation-like reprogramming of degenerative nucleus pulposus cells into notochordal-like cells by defined factors Mol. Ther. (IF 12.1) Pub Date : 2024-06-15 Yuang Zhang, Chengzhen Liang, Haibin Xu, Yi Li, Kaishun Xia, Liyin Wang, Xianpeng Huang, Jiangjie Chen, Jiawei Shu, Feng Cheng, Kesi Shi, Jingkai Wang, Yiqing Tao, Shaoke Wang, Yongxiang Zhang, Hao Li, Shoumin Feng, Fangcai Li, Xiaopeng Zhou, Qixin Chen
The extensive degeneration of functional somatic cells and the depletion of endogenous stem/progenitor populations present significant challenges to tissue regeneration in degenerative diseases. Currently, a cellular reprogramming approach enabling directly generating corresponding progenitor populations from degenerative somatic cells remains elusive. The present study focused on intervertebral disc
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Building a novel TRUCK by harnessing the endogenous IFN-gamma promoter for cytokine expression Mol. Ther. (IF 12.1) Pub Date : 2024-06-15 Liya Ma, Kaiwen Zhang, Jian Xu, Jian Wang, Ting Jiang, Xiaolong Du, Jiaxin Zhang, Jing Huang, Fengyi Ren, Dong Liu, Weiwei Xue, Dongxu Kan, Mengjiao Yao, Yutian Liang, Hongxing Jason-Sun
Despite the remarkable success of chimeric antigen receptor (CAR) T therapy in hematological malignancies, its efficacy in solid tumors remains limited. Cytokine-engineered CAR T cells offer a promising avenue, yet their clinical translation is hindered by the risks associated with constitutive cytokine expression. In this proof-of-concept study, we leverage the endogenous interferon (IFN)-γ promoter
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CRISPR-mediated Sox9 activation and RelA inhibition enhance cell therapy for osteoarthritis Mol. Ther. (IF 12.1) Pub Date : 2024-06-14 Lan Zhao, Yumei Lai, Hongli Jiao, Jun Li, Ke Lu, Jian Huang
Osteoarthritis (OA) is a painful and debilitating disease affecting over 500 million people worldwide. Intraarticular injection of mesenchymal stromal cells (MSCs) shows promise for the clinical treatment of OA, but the lack of consistency in MSC preparation and application makes it difficult to further optimize MSC therapy and to properly evaluate the clinical outcomes. In this study, we used Sox9