Molecular Therapy最新文献_第7页

Characterization of humoral and cellular immunity induced by mRNA vaccines expressing norovirus VP1 proteins in mice and nonhuman primates. 表达诺如病毒VP1蛋白的mRNA疫苗在小鼠和非人灵长类动物中诱导的体液和细胞免疫特性

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-12 DOI: 10.1016/j.ymthe.2025.09.023

Jiajie Wei,Karin Bystol,Leah Alabanza,Shuhui Lim,Jamie Greig,Pooja Gopal,Judith M Reyes Ballista,Jennifer D Galli,Christopher Warren,Andrew Swartz,Courtney David,Uijin Jeong,Estibaliz Gonzalez-Fernandez,Lizzy Aurora DeWitt,Gwenny Go,Athena Lago,Scott Radcliffe,Corey D May Fulton,Pamela Shen,Arthur Fridman,John Gaspar,Amanda Pirrone,Zhiyun Wen,Gregory O'Donnell,Lauren Austin,David McKenney,Paula Krosky,Yaping Liu,Andrew J Bett,Lan Zhang

{"title":"Characterization of humoral and cellular immunity induced by mRNA vaccines expressing norovirus VP1 proteins in mice and nonhuman primates.","authors":"Jiajie Wei,Karin Bystol,Leah Alabanza,Shuhui Lim,Jamie Greig,Pooja Gopal,Judith M Reyes Ballista,Jennifer D Galli,Christopher Warren,Andrew Swartz,Courtney David,Uijin Jeong,Estibaliz Gonzalez-Fernandez,Lizzy Aurora DeWitt,Gwenny Go,Athena Lago,Scott Radcliffe,Corey D May Fulton,Pamela Shen,Arthur Fridman,John Gaspar,Amanda Pirrone,Zhiyun Wen,Gregory O'Donnell,Lauren Austin,David McKenney,Paula Krosky,Yaping Liu,Andrew J Bett,Lan Zhang","doi":"10.1016/j.ymthe.2025.09.023","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.023","url":null,"abstract":"Noroviruses are a leading cause of acute gastroenteritis across all age groups, associated with ∼18% of diarrheal disease globally. Infections span a broad clinical spectrum, ranging from asymptomatic and self-limiting illnesses to hospitalizations and deaths. No preventative vaccines or targeted therapies are currently available. In this study, we designed vaccine candidates containing mRNAs encoding norovirus VP1 proteins of genotypes GI.1, GII.2, GII.3, GII.4, and GII.6, and evaluated their immunogenicity in mice and nonhuman primates (NHPs). In mice, all five mRNAs, dosed separately or together, elicited serum IgG antibodies that bound to norovirus virus-like particles (VLPs), serum antibodies that blocked the binding of VLPs to histo-blood group antigens (HBGA), and norovirus-specific T cell responses. In NHPs, a pentavalent vaccine candidate induced strong humoral and cellular immune responses against each genotype included in the vaccine. Furthermore, compared to VLPs, mRNAs induced similar levels of humoral and cellular responses and comparable levels of durability, as measured by serum antibody titers. Our results indicate that a multivalent mRNA vaccine candidate encoding norovirus VP1 proteins is immunogenic in preclinical models and is a promising candidate to be evaluated in clinical trials.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056681","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

High-Fidelity AaCas12bMax Enables the Development of an Engineered T Cell Therapy with Enhanced Safety and Functional Fitness. 高保真的AaCas12bMax使开发具有增强安全性和功能适应性的工程T细胞疗法成为可能。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-12 DOI: 10.1016/j.ymthe.2025.09.009

Jingwei Sun,Ke Liu,Yao Sheng,Hongwei Zhang,Jingman Wang,Yueqiang Wang,Rui Tian,Xi Zhu,Shin-Shay Tian,Pin Wang,Xiaoping Zhao,Yarong Liu

{"title":"High-Fidelity AaCas12bMax Enables the Development of an Engineered T Cell Therapy with Enhanced Safety and Functional Fitness.","authors":"Jingwei Sun,Ke Liu,Yao Sheng,Hongwei Zhang,Jingman Wang,Yueqiang Wang,Rui Tian,Xi Zhu,Shin-Shay Tian,Pin Wang,Xiaoping Zhao,Yarong Liu","doi":"10.1016/j.ymthe.2025.09.009","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.009","url":null,"abstract":"CRISPR-Cas systems have transformed genome editing, yet the commonly used Streptococcus pyogenes Cas9 (SpCas9) is limited by off-target effects and chromosomal instability. Here, we characterize AaCas12bMAX, an engineered Alicyclobacillus acidiphilus Cas12b variant, as a high-precision editing platform optimized for tumor infiltrating lymphocyte (TIL) therapy. Using an FDA-compliant safety assessment framework, we systemically compared AaCas12bMAX- and SpCas9-edited TIL products in terms of on-target efficiency, genome-wide off-target activity, and structural variants (SVs) formation. AaCas12bMAX achieved >80% on-target editing efficiency with undetectable off-target events and a 3.3-fold reduction in SVs relative to SpCas9. Mechanistic studies revealed different DNA repair kinetics in AaCas12bMAX-edited cells, reducing sustained DNA damage responses and chromosomal instability. Structural modeling suggested a more stable enzyme-sgRNA-DNA ternary complex, enabling stringent PAM specificity and minimal mismatch tolerance. Functionally, AaCas12bMAX-edited TILs exhibited superior therapeutic potential, including enhanced cellular fitness, a twofold increase in expansion capacity, and enrichment of stem-like tumor-reactive CD39-CD69-CD8+ subsets. Together, these results establish AaCas12bMAX as a robust, clinically translatable platform that improves the safety and functional limitations of SpCas9, enabling the development of next-generation T cell therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"87 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056676","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

The future of gene therapy: Safer vectors, sharper focus: High-profile failures demand deep root cause analysis - but the transformative potential of AAV remains within reach if the field is willing to learn and evolve. 基因治疗的未来：更安全的载体，更清晰的焦点：引人注目的失败需要深入的根本原因分析，但如果该领域愿意学习和发展，AAV的变革潜力仍然是可以实现的。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-12 DOI: 10.1016/j.ymthe.2025.08.029

Jeffrey S Chamberlain,Beverly L Davidson,Lindsey A George,Barry J Byrne,David Barrett

引用次数: 0

Elesclomol-Copper combination synergistically targets mitochondrial metabolism in cancer stem cells to overcome chemoresistance in pancreatic ductal adenocarcinoma. 依来克洛莫-铜联合靶向肿瘤干细胞的线粒体代谢，克服胰腺导管腺癌的化疗耐药。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-10 DOI: 10.1016/j.ymthe.2025.09.004

Qian Yu,Ke Jiang,Siyu Ma,Quan Zheng,Serena Tondi,Chiara Reina,Berina Šabanović,Chenlei Wen,Baiyong Shen,Alexandra Aicher,Haiyun Song,Yinxing Ma,Christopher Heeschen

{"title":"Elesclomol-Copper combination synergistically targets mitochondrial metabolism in cancer stem cells to overcome chemoresistance in pancreatic ductal adenocarcinoma.","authors":"Qian Yu,Ke Jiang,Siyu Ma,Quan Zheng,Serena Tondi,Chiara Reina,Berina Šabanović,Chenlei Wen,Baiyong Shen,Alexandra Aicher,Haiyun Song,Yinxing Ma,Christopher Heeschen","doi":"10.1016/j.ymthe.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.004","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis, partly due to cancer stem cells (CSCs) that drive progression and treatment resistance. We explored the therapeutic potential of inducing cuproptosis, a copper-dependent regulated cell death, in CSC-enriched PDAC models. Using human and murine PDAC models, we evaluated elesclomol, a copper transport enhancer. Elesclomol alone had minimal effects; combined with copper chloride (CuCl2), it significantly and irreversibly reduced CSC phenotypes without affecting non-transformed cells. Mechanistically, only the combination raised intracellular copper ions 2-4-fold, decreased iron-sulfur cluster proteins, and caused fatty acylated DLAT accumulation in mitochondria, triggering cuproptosis, particularly in CSCs. It also selectively inhibited copper-dependent antioxidant SOD1 in PDAC cells, impairing oxidative stress defense and sensitizing them to copper-induced death. To enhance clinical relevance, CuCl2 was replaced with hollow mesoporous copper sulfide nanoparticles releasing copper ions. Either combined with or loaded with elesclomol, these nanoparticles similarly increased copper levels and inhibited PDAC spheroid formation. In vivo, in aggressive immunocompetent murine PDAC models, this nanoparticle-based treatment significantly improved gemcitabine response. These findings identify nanoparticle-mediated cuproptosis induction, combined with standard chemotherapy, as an innovative CSC-targeting strategy to improve PDAC outcomes, offering new hope for PDAC patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"59 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032140","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

Nature-inspired IL-1 targeted therapy to treat chronic inflammatory diseases. 受自然启发的IL-1靶向治疗慢性炎症性疾病。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-10 DOI: 10.1016/j.ymthe.2025.09.008

Yeon-Suk Yang,Mi-Jeong Kim,Sachin Chaugule,Emma Mayer,Ngoc DeSouza,Hong Ma,Jun Xie,Ki-Young Lee,Shaoguang Li,Ellen Gravallese,Guangping Gao,Jae-Hyuck Shim

{"title":"Nature-inspired IL-1 targeted therapy to treat chronic inflammatory diseases.","authors":"Yeon-Suk Yang,Mi-Jeong Kim,Sachin Chaugule,Emma Mayer,Ngoc DeSouza,Hong Ma,Jun Xie,Ki-Young Lee,Shaoguang Li,Ellen Gravallese,Guangping Gao,Jae-Hyuck Shim","doi":"10.1016/j.ymthe.2025.09.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.008","url":null,"abstract":"The interleukin (IL)-1 pathway is a key mediator of inflammation and innate immune responses. Its dysregulation contributes to rheumatoid arthritis (RA) and autoinflammatory diseases (AIDs). In this study, we develop a recombinant adeno-associated virus (rAAV)-based gene therapy to deliver an inflammation-inducible, secreted human IL-1 receptor antagonist (sIL-1Ra) as a complementary approach to existing IL-1 blockers. rAAV-mediated expression of sIL-1Ra dampens IL-1 signaling and inflammatory arthritis in mice. As the expression of endogenous sIL-1Ra is tightly regulated by inflammation, we developed an rAAV vector that produces sIL-1Ra in response to pro-inflammatory cytokines and bone morphogenic proteins (BMPs) enriched in the inflamed joints of patients with RA. Remarkably, inflammation-inducible sIL-1Ra is more effective than constitutively expressed sIL-1Ra in ameliorating inflammatory arthritis in the mouse model of RA. These mice showed a significant reduction in circulating immune cells, expression of the genes associated with inflammatory responses, joint swelling, and bone destruction. Similar to patients with deficiency of IL-1Ra (DIRA), IL-1Ra-deficient mice spontaneously develop inflammatory arthritis and skeletal abnormalities, which are almost completely reversed by a single systemic administration of the sIL-1Ra-expressing rAAV vector. Collectively, our results highlight inflammation-inducible IL-1-targeted therapy using an rAAV vector as a long-lasting, pathophysiologic treatment for chronic inflammatory diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"116 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032057","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

TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1. xox诱导的lnc-SUMF2-8通过溶酶体依赖的TCF-1降解破坏CD8+ T细胞的抗肿瘤功能和抗pd -1应答。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-10 DOI: 10.1016/j.ymthe.2025.09.006

Pan Jiang,Dongming Chen,Jialin Chen,Junbin Wu,Yumin Zhong,Sijing Huang,Xiaoxin Mu,Xiaojie Lu,Xiaochen Wang

{"title":"TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1.","authors":"Pan Jiang,Dongming Chen,Jialin Chen,Junbin Wu,Yumin Zhong,Sijing Huang,Xiaoxin Mu,Xiaojie Lu,Xiaochen Wang","doi":"10.1016/j.ymthe.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.006","url":null,"abstract":"The reduction of TCF-1 during CD8+ T cell exhaustion leads to attenuated antitumor activity and diminished responsiveness to immune checkpoint inhibitors. However, how TCF-1 is downregulated remains unclear. Here, we showed that during CD8+ T cell exhaustion, lnc-SUMF2-8, induced by transcription factor TOX, can bind to cytosolic TCF-1, and direct it to the lysosome for degradation. The reduction of TCF-1 promotes Texprog differentiation into Texint/eff and further drives functional Tex cells into a fully dysfunctional Texterm state. We demonstrated that TCF-1 reduction during T cell exhaustion is initiated by lnc-SUMF2-8-dependent lysosomal degradation of TCF-1 protein, followed by transcriptional suppression of TCF7 mRNA. Deletion of lnc-SUMF2-8 blocks lysosomal TCF-1 degradation, which maintains stable TCF-1 levels in Tex cells, thereby expands the anti-PD-1-responsive Texprog cells, and enhances the persistence of functional CD8+ T cells. Our findings suggest targeting lnc-SUMF2-8 could enhance the anti-tumor CD8+ T-cells function and synergistically improve the efficacy of anti-PD-1 treatment and CAR-T cell therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"135 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032161","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

Complement C4b as a Key Mediator of Synaptic Loss and Cognitive Decline in Brain Aging. 补体C4b是脑衰老中突触丧失和认知能力下降的关键介质。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-09 DOI: 10.1016/j.ymthe.2025.09.005

Yi Zheng,Ting Liu,Lunan Luo,Feiyang Li,Cheng Tang,Changling Xu,Cheng Chen,Lu Yang,Ying Xiao,Ziyan Wang,Qing Yuan,Min Zheng,Hao Li,Jing Yang

{"title":"Complement C4b as a Key Mediator of Synaptic Loss and Cognitive Decline in Brain Aging.","authors":"Yi Zheng,Ting Liu,Lunan Luo,Feiyang Li,Cheng Tang,Changling Xu,Cheng Chen,Lu Yang,Ying Xiao,Ziyan Wang,Qing Yuan,Min Zheng,Hao Li,Jing Yang","doi":"10.1016/j.ymthe.2025.09.005","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.005","url":null,"abstract":"Brain aging is a major risk factor for cognitive decline and neurodegenerative diseases, driven by synaptic loss, reduced synaptic function, and inflammation. However, the molecular mechanisms underlying these dysfunctions remain unclear. Here, we conducted comparative transcriptomic analyses of brain regions (cortex and hippocampus) and kidney tissues, a peripheral organ with documented age-related dysfunction. Our study uncovered common and tissue-specific aging molecular signatures, highlighting the complexity of aging-related gene expression dynamics. Notably, we identified complement component C4b as a key mediator linking inflammation to synaptic degeneration. Experimental modulation of C4b expression in aged neurons restored synaptic integrity and neuronal activity in vitro, while in vivo CRISPR-Cas13d-mediated suppression enhanced synaptic density and improved cognitive performance in aged mice. These findings establish C4b as a critical driver of age-associated cognitive decline and a promising therapeutic target for mitigating neurodegenerative changes.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"33 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032056","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

AAV-mediated delivery of a broadly neutralizing anti-flavivirus antibody protects against dengue and Zika viruses in a mouse model. 在小鼠模型中，aav介导的广泛中和性抗黄病毒抗体的递送可预防登革热和寨卡病毒。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-09 DOI: 10.1016/j.ymthe.2025.09.007

Hui-Ying Ko,Ya-Yuan Li,Yogy Simanjuntak,Han-Peng Yu,Ming-Tsai Chiang,Che-Yu Lee,Jian-Jong Liang,Yi-Ling Lee,Cheng-Pu Sun,Po-Sheng Wang,Pei-Yun Shu,Tsai-Ying Yen,Mi-Hua Tao,Yi-Ling Lin

{"title":"AAV-mediated delivery of a broadly neutralizing anti-flavivirus antibody protects against dengue and Zika viruses in a mouse model.","authors":"Hui-Ying Ko,Ya-Yuan Li,Yogy Simanjuntak,Han-Peng Yu,Ming-Tsai Chiang,Che-Yu Lee,Jian-Jong Liang,Yi-Ling Lee,Cheng-Pu Sun,Po-Sheng Wang,Pei-Yun Shu,Tsai-Ying Yen,Mi-Hua Tao,Yi-Ling Lin","doi":"10.1016/j.ymthe.2025.09.007","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.007","url":null,"abstract":"Flaviviruses contain many important human pathogens such as dengue virus (DENV) and Zika virus (ZIKV), for which effective and safe vaccines are still lacking, mainly because pre-existing cross-reactive non-neutralizing antibodies may exacerbate subsequent infections with related flaviviruses. To overcome this challenge, we explore Vectored ImmunoProphylaxis (VIP), which involves the passive transfer of protective antibody genes via viral vectors for in vivo expression. We utilized a recombinant adeno-associated virus (rAAV) to express a broad anti-flavivirus neutralizing human monoclonal antibody, bnAb 752-2C8, and tested its protection against four serotypes of DENV and ZIKV. The bnAb 752-2C8 antibody gene was cloned into an AAV plasmid and the recombinant AAV (rAAV) was successfully generated to express bnAb 752-2C8. After a single dose of rAAV administration into AGB6 mice, the human antibody concentrations increased to ∼1000 μg/mL and remained elevated for at least 48 weeks. VIP-treated mice were completely protected from a lethal challenge of DENVs and ZIKV, while control mice without bnAb 752-2C8 all succumbed to infection. Our results demonstrate the effectiveness of rAAV in delivering bnAb 752-2C8 for long-term protection against multiple flaviviruses, providing a potential strategy to control flavivirus infections and possibly other viral diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"49 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032058","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

Restoring Chloride Efflux in Cystic Fibrosis with TMEM16a Antisense Oligonucleotides. 利用TMEM16a反义寡核苷酸恢复囊性纤维化中的氯化物外排。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-08 DOI: 10.1016/j.ymthe.2025.08.045

Christie Mitri,Nathalie Rousselet,Pauline Bardin,Madara Dias Wickramanayaka,Tobias Foussignière,Gabrielle Dupuis,Marion Leblanc,Victoire Gournet,Florence Sonneville,Harriet Corvol,Olivier Tabary

{"title":"Restoring Chloride Efflux in Cystic Fibrosis with TMEM16a Antisense Oligonucleotides.","authors":"Christie Mitri,Nathalie Rousselet,Pauline Bardin,Madara Dias Wickramanayaka,Tobias Foussignière,Gabrielle Dupuis,Marion Leblanc,Victoire Gournet,Florence Sonneville,Harriet Corvol,Olivier Tabary","doi":"10.1016/j.ymthe.2025.08.045","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.08.045","url":null,"abstract":"Patients with cystic fibrosis (CF) who are non-responsive to treatments due to specific mutations need alternative CFTR-independent therapies. This study aims to assess the impact of TMEM16a expression by a specific oligonucleotide (TMEM16a ASO) on dysregulated parameters in CF, which will help prepare for preclinical studies. In this study, we analyzed the effects of TMEM16a oligonucleotide within a CF context by evaluating the impact, optimal administration route, toxicity, and specificity in primary cells and various mouse models. The oligonucleotide enhances TMEM16a activity, increases Cl--efflux, and improves mucociliary clearance in cells from all individuals tested with CF. TMEM16a antisense oligonucleotide (ASO) effect is detectable in mice 30 days after subcutaneous injection, enhances TMEM16a mRNA expression, and significantly extends the lifespan of CF mice. Acute administration of 50 times the effective dose showed no toxicity. Importantly, TMEM16a ASO is highly specific, not inducing inflammation or altering intracellular calcium mobilization and cell proliferation, instilling confidence in its potential effectiveness. Our study demonstrates that TMEM16a ASO can compensate for CFTR deficiency in CF models. Additionally, it's important to note that this strategy could apply to all CF patients, regardless of their CFTR mutation, thereby broadening the scope of treatment options for CF.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"87 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025424","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

Immunology of RNA-based vaccines: the critical interplay between inflammation and expression. rna疫苗的免疫学：炎症和表达之间的关键相互作用。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-08 DOI: 10.1016/j.ymthe.2025.09.011

John S Tregoning,Ziyin Wang,Saranya Sridhar,Robin J Shattock,Frank DeRosa

{"title":"Immunology of RNA-based vaccines: the critical interplay between inflammation and expression.","authors":"John S Tregoning,Ziyin Wang,Saranya Sridhar,Robin J Shattock,Frank DeRosa","doi":"10.1016/j.ymthe.2025.09.011","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.011","url":null,"abstract":"Since its use during the COVID-19 pandemic, mRNA has emerged as a leading candidate vaccine platform for pandemic infections. A critical difference between RNA-encoded antigen and protein vaccines is that RNA-based vaccines require the antigen to be translated in the body, adding an important variable. Much of the research focus in the field has been on ways to increase expression, but inflammation plays a critical role. The vaccine delivered is a combination of the RNA and the formulation, so both elements need to be considered. Formulated RNA can act as a form of adjuvant but can also activate cellular pathways that inhibit expression. Expression and inflammation are interlinked, but independent - a deeper understanding of the quality and quantity of immune induction will help to develop more efficient RNA vaccines. Here we discuss factors that shape responses to RNA-based vaccines. These include the composition of the vaccine (the use of modified RNA bases, whether self-replicating or traditional mRNA, and critically, the formulation) and the type of cells which take up and translate the RNA. We then consider challenges presented by current generation RNA vaccines including clinical impact and how improved immunological understanding can inform the development of improved RNA vaccine platforms.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"138 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145025423","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