journal
https://read.qxmd.com/read/38608701/retraction-notice-to-corrigendum-to-development-of-nonviral-vectors-targeting-the-brain-as-a-therapeutic-approach-for-parkinson-s-disease-and-other-brain-disorders
#1
Hayate Javed, Sindhu A Menon, Karima M Al-Mansoori, Abdelmojib Al-Wandi, Nour K Majbour, Mustafa T Ardah, Shiji Varghese, Nishant N Vaikath, M Emdadul Haque, Mimoun Azzouz, Omar Ma El-Agnaf
No abstract text is available yet for this article.
April 11, 2024: Molecular Therapy
https://read.qxmd.com/read/38608700/retraction-notice-to-development-of-nonviral-vectors-targeting-the-brain-as-a-therapeutic-approach-for-parkinson-s-disease-and-other-brain-disorders
#2
Hayate Javed, Sindhu A Menon, Karima M Al-Mansoori, Abdelmojib Al-Wandi, Nour K Majbour, Mustafa T Ardah, Shiji Varghese, Nishant N Vaikath, M Emdadul Haque, Mimoun Azzouz, Omar Ma El-Agnaf
No abstract text is available yet for this article.
April 11, 2024: Molecular Therapy
https://read.qxmd.com/read/38605519/mrna-lnp-vaccine-induced-cd8-t-cells-protect-mice-from-lethal-sars-cov-2-infection-in-the-absence-of-specific-antibodies
#3
JOURNAL ARTICLE
Brian Montoya, Carolina R Melo-Silva, Lingjuan Tang, Samita Kafle, Peter Lidskiy, Csaba Bajusz, Máté Vadovics, Hiromi Muramatsu, Edit Abraham, Zoltan Lipinszki, Debotri Chatterjee, Gabrielle Scher, Juliana Benitez, Molly M H Sung, Ying K Tam, Nicholas J Catanzaro, Alexandra Schäfer, Raul Andino, Ralph S Baric, David R Martinez, Norbert Pardi, Luis J Sigal
The role of CD8+ T-cells in SARS-CoV-2 pathogenesis or mRNA-LNP vaccine-induced protection from lethal COVID-19 is unclear. Using mouse-adapted SARS-CoV-2 virus (MA30) in C57BL/6 mice, we show that CD8+ T-cells are unnecessary for the intrinsic resistance of female or the susceptibility of male mice to lethal SARS-CoV-2 infection. Also, mice immunized with a di-proline prefusion-stabilized full-length SARS-CoV-2 Spike (S-2P) mRNA-LNP vaccine, which induces Spike-specific antibodies and CD8+ T-cells specific for the Spike-derived VNFNFNGL peptide, are protected from SARS-CoV-2 infection-induced lethality and weight loss, while mice vaccinated with mRNA-LNPs encoding only VNFNFNGL are protected from lethality but not weight loss...
April 10, 2024: Molecular Therapy
https://read.qxmd.com/read/38584391/engineering-allorejection-resistant-car-nkt-cells-from-hematopoietic-stem-cells-for-off-the-shelf-cancer-immunotherapy
#4
JOURNAL ARTICLE
Yan-Ruide Li, Yang Zhou, Jiaji Yu, Yichen Zhu, Derek Lee, Enbo Zhu, Zhe Li, Yu Jeong Kim, Kuangyi Zhou, Ying Fang, Zibai Lyu, Yuning Chen, Yanxin Tian, Jie Huang, Xinjian Cen, Tiffany Husman, Jae Min Cho, Tzung Hsiai, Jin J Zhou, Pin Wang, Benjamin R Puliafito, Sarah M Larson, Lili Yang
The clinical potential of current FDA-approved chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy is encumbered by its autologous nature, which presents notable challenges related to manufacturing complexities, heightened costs, and limitations in patient selection. Therefore, there is a growing demand for off-the-shelf universal cell therapies. In this study, we have generated universal CAR-engineered NKT (U CAR-NKT) cells by integrating iNKT TCR engineering and HLA gene editing on HSCs, along with an ex vivo, feeder-free HSC differentiation culture...
April 6, 2024: Molecular Therapy
https://read.qxmd.com/read/38582964/transient-tcr-based-t-cell-therapy-in-a-patient-with-advanced-treatment-resistant-msi-high-colorectal-cancer
#5
JOURNAL ARTICLE
Solrun Melkorka Maggadottir, Svein Dueland, Nadia Mensali, Hanne Hamre, Per Arne Andresen, Marit Renée Myhre, Hedvig V Juul, Iris Bigalke, Marianne Lundby, Turid Kirsti Hønnåshagen, Stein Sæbøe-Larssen, Dag Josefsen, Trond Hagtvedt, Sébastien Wälchli, Gunnar Kvalheim, Else Marit Inderberg
We previously demonstrated the anti-tumor effectiveness of transiently TCR redirected T cells recognizing a frameshift mutation in TGFβRII. We here describe a clinical protocol using mRNA TCR modified T cells to treat a patient with progressive, treatment-resistant metastatic MSI-H colorectal cancer. Following 12 escalating doses of autologous T cells electroporated with in vitro transcribed Radium-1 TCR mRNA we assessed T cell cytotoxicity, phenotype and cytokine production. Tumor markers and growth on CT scans were evaluated and immune cell tumor infiltrate at diagnosis assessed...
April 6, 2024: Molecular Therapy
https://read.qxmd.com/read/38582966/fast-accurate-ranking-of-engineered-proteins-by-target-binding-propensity-using-structure-modeling
#6
JOURNAL ARTICLE
Xiaozhe Ding, Xinhong Chen, Erin E Sullivan, Timothy F Shay, Viviana Gradinaru
Deep learning-based methods for protein structure prediction have achieved unprecedented accuracy. Yet, their utility in the engineering of protein-based binders remains constrained due to a gap between the ability to predict the structures of candidate proteins and the ability to assess which of those proteins are more probable to bind to a target. To bridge this gap, we introduce Automated Pairwise Peptide-Receptor AnalysIs for Screening Engineered proteins (APPRAISE), a method for predicting the target binding propensity of engineered proteins...
April 5, 2024: Molecular Therapy
https://read.qxmd.com/read/38582965/decoding-and-overcoming-t-cell-exhaustion-epigenetic-and-transcriptional-dynamics-in-car-t-cells-against-solid-tumors
#7
REVIEW
Taeyoung Ahn, Eun-Ah Bae, Hyungseok Seo
T cell exhaustion, which is observed in various chronic infections and malignancies, is characterized by elevated expression of multiple inhibitory receptors, impaired effector functions, decreased proliferation, and reduced cytokine production. Notably, while adoptive T cell therapies, such as chimeric antigen receptor (CAR)-T therapy, have shown promise in treating cancer and other diseases, the efficacy of these therapies is often compromised by T cell exhaustion. It is imperative, therefore, to understand the mechanisms underlying this exhaustion to promote advances in T cell-related therapies...
April 5, 2024: Molecular Therapy
https://read.qxmd.com/read/38582963/talen-mediated-intron-editing-of-hspcs-enables-transgene-expression-restricted-to-the-myeloid-lineage
#8
JOURNAL ARTICLE
Eduardo Seclen, Jessica C Jang, Aminah O Lawal, Sylvain Pulicani, Alex Boyne, Diane Tkach, Alexandre Juillerat, Philippe Duchateau, Julien Valton
Gene therapy in hematopoietic stem and progenitor cells (HSPCs) shows great potential for the treatment of inborn metabolic diseases. Typical HSPC gene therapy approaches rely on constitutive promoters to express a therapeutic transgene, which is associated with multiple disadvantages. Here, we propose a novel promoter-less intronic gene editing approach that triggers transgene expression only after cellular differentiation into the myeloid lineage. We integrated a splicing-competent eGFP cassette into the first intron of CD11b and observed expression of eGFP in the myeloid lineage but minimal to no expression in HSPCs or differentiated non-myeloid lineages...
April 5, 2024: Molecular Therapy
https://read.qxmd.com/read/38582962/a-p21-atd-mouse-model-for-monitoring-and-eliminating-senescent-cells-and-its-application-in-liver-regeneration-post-injury
#9
JOURNAL ARTICLE
Miaomiao Chen, Guoxiu Wu, Yanli Lu, Shiwen Sun, Zhao Yu, Xin Pan, Wenjian Chen, Hongyu Xu, Hua Qiu, Weizhi He, Xiuhua Li, Xicheng Wang, Yi Luo, Yuan Du, Jialing Wu, Ke Wei, Wencheng Zhang, Zhongmin Liu, Zhiying He
Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- [Akaluc - tdTomato - Diphtheria Toxin Receptor (DTR)] (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing and eliminating of p21-expressing senescent cells...
April 5, 2024: Molecular Therapy
https://read.qxmd.com/read/38582961/interaction-of-smac-diablo-with-a-survivin-birc5-derived-peptide-alters-essential-cancer-hallmarks-tumor-growth-inflammation-and-immunosuppression
#10
JOURNAL ARTICLE
M Santhanam, S Kumar Pandey, A Shteinfer-Kuzmine, A Paul, N Abusiam, R Zalk, V Shoshan-Barmatz
SMAC/Diablo is known as a pro-apoptotic mitochondrial protein released into the cytosol in response to apoptotic signals. We recently reported SMAC overexpression in cancers as essential for cell proliferation and tumor growth due to non-apoptotic functions including phospholipid synthesis regulation. These functions may be associated with its interactions with partner proteins. Using a peptide array with 768 peptides derived from 11 selected SMAC-interacting proteins, we identified SMAC-interacting sequences...
April 5, 2024: Molecular Therapy
https://read.qxmd.com/read/38582960/identification-of-memory-mechanism-in-tissue-resident-stem-cells-via-angptl4-beyond-immune-cells-upon-viral-antigen-exposure
#11
JOURNAL ARTICLE
Eun-Kyung Min, Soo-Rim Kim, Choon-Mi Lee, Kun-Hee Na, Chan Hum Park, Byung-Chul Oh, YunJae Jung, In-Sun Hong
Although memory functions of immune cells characterized by increased resistance to subsequent infections after initial pathogen exposure are well-established, it remains unclear whether non-immune cells, especially tissue-resident stem cells, exhibit similar memory mechanisms. The present study revealed that detrimental effects of initial viral antigen exposure (human papillomavirus, HPV) on diverse stem cell functions were significantly exacerbated upon subsequent secondary exposure both in vitro and in vivo...
April 5, 2024: Molecular Therapy
https://read.qxmd.com/read/38579728/hit-and-run-epigenome-editing-durably-lowers-cholesterol-in-mice
#12
JOURNAL ARTICLE
Renzhi Han
No abstract text is available yet for this article.
April 4, 2024: Molecular Therapy
https://read.qxmd.com/read/38574737/advances-and-transgressions-of-nuclear-transport-checkpoint-inhibitors
#13
LETTER
Jacek Hawiger
No abstract text is available yet for this article.
April 3, 2024: Molecular Therapy
https://read.qxmd.com/read/38566414/an-innate-immune-response-to-the-adeno-associated-virus-aav-genome-decreases-cortical-dendritic-complexity-and-disrupts-synaptic-transmission
#14
JOURNAL ARTICLE
Christos M Suriano, Neerav Kumar, Jessica L Verpeut, Jie Ma, Caroline Jung, Connor E Dunn, Brigett V Carvajal, Ai Vy Nguyen, Lisa M Boulanger
Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, and are the basis of FDA-approved neuron-targeting gene therapies. Here we find that an innate immune response to the AAV genome reduces dendritic length and complexity and disrupts synaptic transmission in mouse somatosensory cortex. Dendritic loss is apparent three weeks after injection of experimentally relevant viral titers, is not restricted to a particular capsid serotype, transgene, promoter, or production facility, and cannot be explained by responses to surgery or transgene expression...
April 1, 2024: Molecular Therapy
https://read.qxmd.com/read/38556794/transplantation-of-dorsal-root-ganglia-overexpressing-the-nachbac-sodium-channel-improves-locomotion-after-complete-sci
#15
JOURNAL ARTICLE
Sonia Hingorani, Guillem Paniagua Soriano, Carlos Sánchez Huertas, Eva María Villalba Riquelme, Eric López Mocholi, Beatriz Martínez Rojas, Ana Alastrué Agudo, Sebastián Dupraz, Antonio Vicente Ferrer Montiel, Victoria Moreno Manzano
Spinal cord injury (SCI) is a debilitating condition currently lacking treatment. Severe SCI causes the loss of most supraspinal inputs and neuronal activity caudal to the injury, which, coupled with the limited endogenous capacity for spontaneous regeneration, can lead to complete functional loss even in anatomically incomplete lesions. We hypothesized that transplantation of mature dorsal root ganglia (DRG), genetically modified to express the NaChBac sodium channel, could serve as a therapeutic option for functionally complete SCI...
March 30, 2024: Molecular Therapy
https://read.qxmd.com/read/38556793/crispr-cas9n-mediated-elane-promoter-editing-for-gene-therapy-of-severe-congenital-neutropenia
#16
JOURNAL ARTICLE
Masoud Nasri, Malte Ritter, Perihan Mir, Benjamin Dannenmann, Masako M Kaufmann, Patricia Arreba-Tutusaus, Yun Xu, Natalia Borbaran-Bravo, Maksim Klimiankou, Claudia Lengerke, Cornelia Zeidler, Toni Cathomen, Karl Welte, Julia Skokowa
Severe congenital neutropenia (CN) is an inherited pre-leukemia bone marrow failure syndrome commonly caused by autosomal-dominant ELANE mutations (ELANE-CN). ELANE-CN patients are treated with daily injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, some patients do not respond to rhG-CSF, and approximately 15% of ELANE-CN patients develop myelodysplasia or acute myeloid leukemia. Here, we report the development of a curative therapy for ELANE-CN through inhibition of ELANE mRNA expression by introducing two single-strand DNA breaks at the opposing DNA strands of the ELANE promoter TATA-box using CRISPR/Cas9D10A nickases - termed MILESTONE...
March 30, 2024: Molecular Therapy
https://read.qxmd.com/read/38553852/targeting-the-nuclear-long-noncoding-transcript-lsp1p5-abrogates-extracellular-matrix-component-deposition-by-trans-upregulating-cebpa-in-keloids
#17
JOURNAL ARTICLE
Shuchen Gu, Xin Huang, Shenying Luo, Yunhan Liu, Yimin Khoong, Hsin Liang, Liying Tu, Ruoqing Xu, En Yang, Yixuan Zhao, Min Yao, Tao Zan
Keloids are characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix (ECM) and are a major global healthcare burden among cutaneous diseases. However, the function of long noncoding RNA (lncRNA)-mediated ECM remodeling during the pathogenesis of keloids is still unclear. Herein, we identified a long noncoding transcript, namely, lymphocyte-specific protein 1 pseudogene 5 (LSP1P5), that modulates ECM component deposition in keloids. First, high-throughput transcriptome analysis showed that LSP1P5 was selectively upregulated in keloids and correlated with more severe disease in a clinical keloid cohort...
March 28, 2024: Molecular Therapy
https://read.qxmd.com/read/38549378/gsnor-overexpression-enhances-car-t-stemness-and-anti-tumor-function-by-enforcing-mitochondrial-fitness
#18
JOURNAL ARTICLE
Qing Niu, Haixiao Zhang, Fang Wang, Xing Xu, Yuechen Luo, Baolin He, Mingxia Shi, Erlie Jiang, Xiaoming Feng
Chimeric antigen receptor T cell (CAR-T) has been developed as a promising agent for patients with refractory or relapsed lymphoma and leukemia, but not all the recipients could achieve a long-lasting remission. The limited capacity of in vivo expansion and memory differentiation post activation is one of the major reasons for suboptimal CAR-T therapeutic efficiency. Nitric oxide (NO) plays multifaceted roles in mitochondrial dynamics and T-cell activation, but its function on CAR-T cell persistence and anti-tumor efficacy remains unknown...
March 27, 2024: Molecular Therapy
https://read.qxmd.com/read/38549377/anti-cd45-pbd-based-antibody-drug-conjugates-are-effective-targeted-conditioning-agents-for-gene-therapy-and-stem-cell-transplant
#19
JOURNAL ARTICLE
Jenny Yeung, Aiyin Liao, Matthew Shaw, Soraia Silva, Winston Vetharoy, Diego Leon Rico, Ian Kirby, Francesca Zammarchi, Karin Havenith, Lolke de Haan, Patrick H van Berkel, Neil Sebire, Olumide K Ogunbiyi, Claire Booth, H Bobby Gaspar, Adrian J Thrasher, Kerry A Chester, Persis J Amrolia
Stem cell gene therapy and hematopoietic stem cell transplantation (SCT) and stem cell gene therapy require conditioning to ablate the recipient's hematopoietic stem cells (HSC) and create a niche for gene-corrected/donor HSCs. Conventional conditioning agents are non-specific, leading to off-target toxicities, resulting in significant morbidity and mortality. We developed tissue-specific anti-human CD45 antibody-drug conjugates (ADCs), using rat IgG2b anti-human CD45 antibody clones YTH24.5 and YTH54.12, conjugated to cytotoxic pyrrolobenzodiazepine (PBD) dimer payloads with cleavable (SG3249) or non-cleavable (SG3376) linkers...
March 27, 2024: Molecular Therapy
https://read.qxmd.com/read/38549376/rnai-mediated-silencing-of-stat3-pd-l1-in-tumor-associated-immune-cells-induces-robust-anti-tumor-effects-in-immunotherapy-resistant-tumors
#20
JOURNAL ARTICLE
Shanthi Ganesh, Min Ju Kim, Jenny Lee, Xudong Feng, Krisjanis Ule, Amy Mahan, Harini Sivagurunatha Krishnan, Zhe Wang, Maryam Yahyaee Anzahaee, Garima Singhal, Ilia Korboukh, Jennifer A Lockridge, Laura Sanftner, Rene Rijnbrand, Marc Abrams, Bob D Brown
Malignant tumors are often associated with an immunosuppressive tumor microenvironment (TME), rendering most of them resistant to standard-of-care immune checkpoint inhibitors (CPIs). Signal transducer and activator of transcription 3 (STAT3), a ubiquitously expressed transcription factor, has well-defined immunosuppressive functions in several leukocyte populations within the TME. Since the STAT3 protein has been challenging to target using conventional pharmaceutical modalities, we investigated the feasibility of applying systemically delivered RNA interference (RNAi) agents to silence its mRNA directly in tumor-associated immune cells...
March 27, 2024: Molecular Therapy
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