Molecular Therapy最新文献_第4页

Virus-free CRISPR knockin of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells. 无病毒的CRISPR敲入嵌合抗原受体到KLRC1中，产生有效的gd2特异性自然杀伤细胞。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-14 DOI: 10.1016/j.ymthe.2025.01.024

Keerthana Shankar, Isabelle Zingler-Hoslet, Diana M Tabima, Seth Zima, Lei Shi, Kirstan Gimse, Matthew H Forsberg, Varun Katta, Sage Z Davis, Daniel Maldonado, Brittany E Russell, Muhammed Murtaza, Shengdar Q Tsai, Jose M Ayuso, Christian M Capitini, Krishanu Saha

{"title":"Virus-free CRISPR knockin of a chimeric antigen receptor into KLRC1 generates potent GD2-specific natural killer cells.","authors":"Keerthana Shankar, Isabelle Zingler-Hoslet, Diana M Tabima, Seth Zima, Lei Shi, Kirstan Gimse, Matthew H Forsberg, Varun Katta, Sage Z Davis, Daniel Maldonado, Brittany E Russell, Muhammed Murtaza, Shengdar Q Tsai, Jose M Ayuso, Christian M Capitini, Krishanu Saha","doi":"10.1016/j.ymthe.2025.01.024","DOIUrl":"10.1016/j.ymthe.2025.01.024","url":null,"abstract":"Natural killer (NK) cells are an appealing off-the-shelf, allogeneic cellular therapy due to their cytotoxic profile. However, their activity against solid tumors remains suboptimal in part due to the upregulation of NK-inhibitory ligands, such as HLA-E, within the tumor microenvironment. Here, we utilize CRISPR-Cas9 to disrupt the KLRC1 gene (encoding the HLA-E-binding NKG2A receptor) and perform non-viral insertion of a GD2-targeting chimeric antigen receptor (CAR) within NK cells isolated from human peripheral blood. Genome editing with CRISPR-Cas9 ribonucleoprotein complexes yields efficient genomic disruption of the KLRC1 gene with 98% knockout efficiency and specific knockin of the GD2 CAR transgene as high as 23%, with minimal off-target activity as shown by CHANGE-seq, in-out PCR, amplicon sequencing, and long-read whole-genome sequencing. KLRC1-GD2 CAR NK cells display high viability and proliferation, as well as precise cellular targeting and potency against GD2+ human tumor cells. Notably, KLRC1-GD2 CAR NK cells overcome HLA-E-based inhibition in vitro against HLA-E-expressing, GD2+ melanoma cells. Using a single-step, virus-free genome editing workflow, this study demonstrates the feasibility of precisely disrupting inhibitory signaling within NK cells via CRISPR-Cas9 while expressing a CAR to generate potent allogeneic cell therapies against HLA-E+ solid tumors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pancreatic cancer-derived extracellular vesicles remodel the tumor microenvironment and enhance chemoresistance by delivering KRAS^G12D protein to cancer-associated fibroblasts. 胰腺癌来源的细胞外囊泡通过向癌症相关成纤维细胞传递KRASG12D蛋白来重塑肿瘤微环境并增强化疗耐药。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-13 DOI: 10.1016/j.ymthe.2025.01.023

Xinyuan Liu, Jiaqi Yang, Sicong Huang, Yifan Hong, Yupeng Zhu, Jianing Wang, Yi Wang, Tingbo Liang, Xueli Bai

{"title":"Pancreatic cancer-derived extracellular vesicles remodel the tumor microenvironment and enhance chemoresistance by delivering KRASG12D protein to cancer-associated fibroblasts.","authors":"Xinyuan Liu, Jiaqi Yang, Sicong Huang, Yifan Hong, Yupeng Zhu, Jianing Wang, Yi Wang, Tingbo Liang, Xueli Bai","doi":"10.1016/j.ymthe.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.01.023","url":null,"abstract":"KRAS mutations are instrumental in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the efficacy of direct targeting of KRAS mutations to inhibit tumor development remains doubtful. It is therefore necessary to gain a deeper insight into the mechanism in which KRAS mutations influence the effectiveness of clinical treatments. In this study, KRASG12D protein was detected in cancer-associated fibroblasts (CAFs) from clinical samples of pancreatic ductal adenocarcinoma (PDAC). In vitro experiments demonstrated that KRASG12D protein in CAFs was not expressed from its own mutant gene but was derived from the ingestion of tumor cell-derived extracellular vesicles (EVs). The presence of KRASG12D protein in CAFs resulted in enhanced proliferation and migration. Furthermore, KRASG12D-containing CAFs were observed to promote tumor chemoresistance to gemcitabine treatment both in vitro and in vivo. Application of a KRAS mutation-specific inhibitor, MRTX1133, has been demonstrated to reverse chemoresistance in PDAC. Moreover, clinical data suggest that patients with KRAS mutations have poorer prognosis following adjuvant chemotherapy. These findings elucidate the mechanism by which oncogenic KRAS mutations promote cancer chemoresistance and remodel tumor environment in a non-autonomous manner, suggesting a novel strategy for targeting KRAS mutations to enhance chemosensitivity in PDAC.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A new era of Molecular Therapy: My vision for the future of the journal as the incoming Editor-in-Chief. 分子疗法的新时代：作为即将上任的主编，我对杂志未来的展望。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-12 DOI: 10.1016/j.ymthe.2024.12.056

Joseph C Glorioso

引用次数: 0

Depletion of alloreactive B cells by drug-resistant chimeric alloantigen receptor T cells to prevent transplant rejection. 用耐药嵌合同种异体抗原受体T细胞消耗同种异体反应性B细胞以防止移植排斥反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-11 DOI: 10.1016/j.ymthe.2025.01.009

Anna Christina Dragon, Agnes Bonifacius, Stefan Lienenklaus, Murielle Verboom, Jan-Phillipp Gerhards, Fabio Ius, Christian Hinze, Michael Hudecek, Constanca Figueiredo, Rainer Blasczyk, Britta Eiz-Vesper

{"title":"Depletion of alloreactive B cells by drug-resistant chimeric alloantigen receptor T cells to prevent transplant rejection.","authors":"Anna Christina Dragon, Agnes Bonifacius, Stefan Lienenklaus, Murielle Verboom, Jan-Phillipp Gerhards, Fabio Ius, Christian Hinze, Michael Hudecek, Constanca Figueiredo, Rainer Blasczyk, Britta Eiz-Vesper","doi":"10.1016/j.ymthe.2025.01.009","DOIUrl":"10.1016/j.ymthe.2025.01.009","url":null,"abstract":"Antibody-mediated rejection (AMR) remains a major complication after solid organ transplantation (SOT). Current treatment options are inefficient and result in drastic impairment of the general immunity. To selectively eliminate responsible alloreactive B cells characterized by anti-donor-HLA B cell receptors (BCRs), we generated T cells overcoming rejection by antibodies (CORA-Ts) engineered with a novel chimeric receptor comprising a truncated donor-HLA molecule as antigen recognition domain. As proof-of-concept, CORA receptors based on HLA-A∗02 were developed. In co-cultures with anti-HLA-A∗02 B cell lines, CORA-Ts were specifically activated, released pro-inflammatory mediators, and exhibited strong cytotoxicity resulting in an effective reduction of anti-HLA-A∗02 antibody release. Significant reduction of growth of an anti-HLA-A∗02 B cell line could be confirmed using an in vivo mouse model. Modification of the CORA receptor effectively abrogated T cell binding, thereby avoiding T cell sensitization. Additionally, using CRISPR-Cas9-mediated knockout of the FKBP12 gene, CORA-Ts were able to resist immunosuppressive treatment with tacrolimus, thereby allowing high efficiency in transplant patients. Our results demonstrate that CORA-Ts are able to specifically eliminate alloreactive, anti-HLA B cells, thus selectively preventing anti-HLA antibody release even under immunosuppressive conditions. This suggests CORA-Ts as potent approach to combat AMR and improve long-term graft survival in SOT patients while preserving their overall B cell immunity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Efficient gene delivery admitted by small metabolites specifically targeting astrocytes in the mouse brain. 小代谢物特异性靶向小鼠大脑星形胶质细胞的高效基因传递。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.006

Haibin Zhou, Jiajing Dai, Dong Li, Luyao Wang, Meng Ye, Xiaoling Hu, Joseph LoTurco, Ji Hu, Wenzhi Sun

{"title":"Efficient gene delivery admitted by small metabolites specifically targeting astrocytes in the mouse brain.","authors":"Haibin Zhou, Jiajing Dai, Dong Li, Luyao Wang, Meng Ye, Xiaoling Hu, Joseph LoTurco, Ji Hu, Wenzhi Sun","doi":"10.1016/j.ymthe.2025.01.006","DOIUrl":"10.1016/j.ymthe.2025.01.006","url":null,"abstract":"The development of efficient and targeted methods for delivering DNA in vivo has long been a major focus of research. In this study, we introduce a gene delivery approach admitted by small metabolites (gDAM) for the efficient and targeted delivery of naked DNA into astrocytes in the adult brains of mice. gDAM uses a straightforward combination of DNA and small metabolites, including glycine, L-proline, L-serine, L-histidine, D-alanine, Gly-Gly, and Gly-Gly-Gly, to achieve astrocyte-specific delivery of naked DNA, resulting in transient and robust gene expression in these cells. Using gDAM, we successfully co-deliver the PiggyBac transposon and the CRISPR-Cas9 system to induce long-term overexpression of the oncogene EGFRvIII and knockout of tumor suppressor genes Nf1, Pten, and Trp53 in astrocytes, leading to the development of astrocyte-derived gliomas in immunocompetent mice. Furthermore, gDAM facilitates the delivery of naked DNA to peripheral glioma astrocytes. The overexpression of interferon-β and granulocyte-macrophage colony-stimulating factor in these peripheral glioma astrocytes significantly prolongs the overall survival of mice bearing 73C glioma cells. This approach offers a new perspective on developing gene delivery systems that specifically target astrocytes to meet the varied needs of both research and gene therapy. The innovative strategy behind gDAM is expected to provide fresh inspiration in the quest for DNA delivery to other tissues, such as skeletal muscle and skin.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS. 免疫吸附对covid -19诱导和/或加重ME/CFS临床表现和免疫改变的影响

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.007

Moritz Anft, Lea Wiemers, Kamil S Rosiewicz, Adrian Doevelaar, Sarah Skrzypczyk, Julia Kurek, Sviatlana Kaliszczyk, Maximilian Seidel, Ulrik Stervbo, Felix S Seibert, Timm H Westhoff, Nina Babel

{"title":"Effect of immunoadsorption on clinical presentation and immune alterations in COVID-19-induced and/or aggravated ME/CFS.","authors":"Moritz Anft, Lea Wiemers, Kamil S Rosiewicz, Adrian Doevelaar, Sarah Skrzypczyk, Julia Kurek, Sviatlana Kaliszczyk, Maximilian Seidel, Ulrik Stervbo, Felix S Seibert, Timm H Westhoff, Nina Babel","doi":"10.1016/j.ymthe.2025.01.007","DOIUrl":"10.1016/j.ymthe.2025.01.007","url":null,"abstract":"Autoantibodies (AABs) are currently being investigated as causative or aggravating factors during post-COVID. In this study, we analyze the effect of immunoadsorption therapy on symptom improvement and the relationship with immunological parameters in post-COVID patients exhibiting symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) induced or aggravated by an SARS-CoV-2 infection. This observational study includes 12 post-COVID patients exhibiting a predominance of ME/CFS symptoms alongside increased concentrations of autonomic nervous system receptor (ANSR) autoantibodies and neurological impairments. We found that following immunoadsorption therapy, the ANSR AABs were nearly eliminated from the patients' blood. The removal of immunoglobulin G antibodies was accompanied by a decrease of pro-inflammatory cytokines including interleukin (IL)-4, IL-2, IL-1β, tumor necrosis factor, and IL-17A serum levels, and a significant reduction of soluble spike protein. Notably, a strong positive correlation between pro-inflammatory cytokines and ASNR-AABs β1, β2, M3, and M4 was observed in spike protein-positive patients, whereas no such correlation was evident in spike protein-negative patients. Thirty days post-immunoadsorption therapy, patients exhibited notable improvement in neuropsychological function and a modest but statistically significant amelioration of hand grip strength was observed. However, neither self-reported symptoms nor scores on ME/CFS questionnaires showed a significant improvement and a rebound of the removed proteins occurring within a month.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142965993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates. 非人类灵长类动物mRNA疫苗递送的脂质纳米颗粒运输可视化

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.008

Maureen Buckley, Mariluz Araínga, Laura Maiorino, Ivan S Pires, B J Kim, Katarzyna Kaczmarek Michaels, Jonathan Dye, Kashif Qureshi, Yiming J Zhang, Howard Mak, Jon M Steichen, William R Schief, Francois Villinger, Darrell J Irvine

{"title":"Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates.","authors":"Maureen Buckley, Mariluz Araínga, Laura Maiorino, Ivan S Pires, B J Kim, Katarzyna Kaczmarek Michaels, Jonathan Dye, Kashif Qureshi, Yiming J Zhang, Howard Mak, Jon M Steichen, William R Schief, Francois Villinger, Darrell J Irvine","doi":"10.1016/j.ymthe.2025.01.008","DOIUrl":"10.1016/j.ymthe.2025.01.008","url":null,"abstract":"mRNA delivered using lipid nanoparticles (LNPs) has become an important subunit vaccine modality, but mechanisms of action for mRNA vaccines remain incompletely understood. Here, we synthesized a metal chelator-lipid conjugate enabling positron emission tomography (PET) tracer labeling of LNP/mRNA vaccines for quantitative visualization of vaccine trafficking in live mice and non-human primates (NHPs). Following intramuscular injection, we observed LNPs distributing through injected muscle tissue, simultaneous with rapid trafficking to draining lymph nodes (dLNs). Deltoid injection of LNPs mimicking human vaccine administration led to stochastic LNP delivery to three different sets of dLNs. LNP uptake in dLNs was confirmed by histology, and cellular analysis of tissues via flow cytometry identified antigen-presenting cells as the primary immune cell type responsible for early LNP uptake and mRNA translation. These results provide insights into the biodistribution of mRNA vaccines administered at clinically relevant doses, injection volumes, and injection sites in an important large animal model for vaccine development.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Scalable control of stem cell fate by riboswitch-regulated RNA viral vector without genomic integration. 无基因组整合的核糖体开关调节RNA病毒载体对干细胞命运的可扩展控制。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.005

Narae Kim, Yohei Yokobayashi

引用次数: 0

Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe OTC deficiency. 表征一种新的条件敲除小鼠模型，以评估mRNA治疗在严重鸟氨酸转甲氨基酰基酶缺乏症中的疗效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.010

Jenny Zhou, Shi Liang, Ling Yin, Andrea Frassetto, Anne-Renee Graham, Rebecca White, Maria Principe, Madelyn Severson, Tiffany Palmer, Shan Naidu, Eric Jacquinet, Mike Zimmer, Patrick F Finn, Paolo G V Martini

{"title":"Characterization of a novel conditional knockout mouse model to assess efficacy of mRNA therapy in the context of severe OTC deficiency.","authors":"Jenny Zhou, Shi Liang, Ling Yin, Andrea Frassetto, Anne-Renee Graham, Rebecca White, Maria Principe, Madelyn Severson, Tiffany Palmer, Shan Naidu, Eric Jacquinet, Mike Zimmer, Patrick F Finn, Paolo G V Martini","doi":"10.1016/j.ymthe.2025.01.010","DOIUrl":"10.1016/j.ymthe.2025.01.010","url":null,"abstract":"Ornithine transcarbamylase deficiency (OTCD) is the most common urea-cycle disorder, characterized by hyperammonemia and accompanied by a high unmet patient need. mRNA therapies have been shown to be efficacious in hypomorphic Sparse-fur abnormal skin and hair (Spf-ash) mice, a model of late-onset disease. However, studying the efficacy of ornithine transcarbamylase (OTC) mRNA therapy in traditional knockout mice, a model for severe early-onset OTCD, is hampered by the rapid lethality of the model and poor lipid nanoparticle (LNP) uptake into neonatal mouse liver. We developed a novel tamoxifen-inducible mouse to study the effect of mRNA therapy in the context of complete or near-complete OTC loss in adult animals. Characterization of the model showed that it is highly reproducible, 100% penetrant, and phenocopies hallmarks of human disease, with animals exhibiting decreased body weight, hyperammonemia, and brain edema. Delivery of OTC mRNA increased survival, maintained body weight, delayed the onset of hyperammonemia, and reduced brain edema. Therefore, this model provides a platform to study LNP-mediated mRNA therapies for the treatment of late-onset OTCD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD. 在多种ALS/FTD临床前模型中，人工增强未折叠蛋白反应（UPR）可减少疾病特征。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-01-10 DOI: 10.1016/j.ymthe.2025.01.004

Vicente Valenzuela, Daniela Becerra, José I Astorga, Matías Fuentealba, Guillermo Diaz, Leslie Bargsted, Carlos Chacón, Alexis Martinez, Romina Gozalvo, Kasey Jackson, Vania Morales, Macarena Las Heras, Giovanni Tamburini, Leonard Petrucelli, S Pablo Sardi, Lars Plate, Claudio Hetz

{"title":"Artificial enforcement of the unfolded protein response reduces disease features in multiple preclinical models of ALS/FTD.","authors":"Vicente Valenzuela, Daniela Becerra, José I Astorga, Matías Fuentealba, Guillermo Diaz, Leslie Bargsted, Carlos Chacón, Alexis Martinez, Romina Gozalvo, Kasey Jackson, Vania Morales, Macarena Las Heras, Giovanni Tamburini, Leonard Petrucelli, S Pablo Sardi, Lars Plate, Claudio Hetz","doi":"10.1016/j.ymthe.2025.01.004","DOIUrl":"10.1016/j.ymthe.2025.01.004","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress. Here, we provide evidence of suboptimal activation of the UPR in ALS/FTD models under experimental ER stress. To artificially engage the UPR, we intracerebroventricularly administrated adeno-associated viruses (AAVs) to express the active form of XBP1 (XBP1s) in the nervous system of ALS/FTD models. XBP1s expression improved motor performance and extended lifespan of mutant SOD1 mice, associated with reduced protein aggregation. AAV-XBP1s administration also attenuated disease progression in models of TDP-43 and C9orf72 pathogenesis. Proteomic profiling of spinal cord tissue revealed that XBP1s overexpression improved proteostasis and modulated the expression of a cluster of synaptic and cell morphology proteins. Our results suggest that strategies to improve ER proteostasis may serve as a pan-therapeutic strategy to treat ALS/FTD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0