{"title":"Gene Therapy with covalently-closed-end AAV vector for Spinal Muscular Atrophy.","authors":"Haolin Duan,Ciliu Zhang,Zhongliang Zhang,Xiaole Wang,Junping Zhang,Lifen Yang,Fang He,Leilei Mao,Li Yang,Zou Pan,Renzhi Han,Weiming Wang,Dao Pan,Fei Yin,Weidong Xiao,Jing Peng","doi":"10.1016/j.ymthe.2025.06.028","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.028","url":null,"abstract":"Covalently closed-end adeno-associated virus vector (cceAAV) is a new generation of self-complementary vector (scAAV) which does not utilize a mutant ITR for vector production. Importantly, packaged genomes of these cceAAV vectors are markedly more intact than traditional scAAVs, which typically contain a large fraction of incomplete genomes, including many that lost their self-complementary configuration. Here, we report first-in-human experience with a cceAAV vector. High quality clinical grade cceAAV vector based on AAV9 produced in 200 liters of suspension 293 cells with a total yield of 4.3 × 1016 vector genomes (vg). Clinical trial in two spinal muscular atrophy (SMA) patients via intravenous injection at 12-24 months of age revealed no treatment-associated severe adverse events with a dose ranging from 6 × 1013 vg/kg to 1.2 × 1014 vg/kg. Both patients showed rapid improvements in motor capabilities after gene therapy, as evidenced by substantial gains in motor function and electrophysiological parameters and capacity for independent mobility. Our strategy enabled us to perform gene therapy in older SMA patients who had received initial treatment with RNA-splicing modifying drug during infancy. These early data provide preliminary evidence for clinical use of cceAAV vectors, though further validation in larger cohorts is warranted.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"12 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295808","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}
{"title":"Blood Phenylalanine lowering partially reverses white matter changes in a mouse model of Phenylketonuria.","authors":"Rachna Manek,Weixiao Huang,Yinyin Huang,Lilu Guo,Cathleen S Cornell,Mohammed Salman Shazeeb,Alexander Verbitsky,Robert Jackson,Jennifer Johnson,Patricia Berthelette,Dan Yu,Edith L Pfister,Dinesh Bangari,Xiaoyou Ying,Dinesh Kumar,Christian Mueller,Sirkka Kyostio-Moore","doi":"10.1016/j.ymthe.2025.06.020","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.020","url":null,"abstract":"Phenylketonuria (PKU) is a genetic defect caused by lack of liver enzyme phenylalanine hydroxylase (PAH). This deficiency results in elevated blood Phenylalanine (Phe) levels and neurotoxicity which is manifested by reduced brain size, lower neurotransmitter levels, and reduced myelination. The goal of this study was to investigate brain myelination defects and their reversibility upon blood Phe lowering by analyzing the corpus callosum (CC) of adult Pahenu2 (PAH-deficient) mice. MRI and immunostaining demonstrated a significant reduction in CC volume in Pahenu2 mice. Treatment with an adeno-associated vector (AAV) encoding mouse PAH for 3.5 months improved but did not completely normalize CC volume. Total cholesterol, a major component of myelin, was unchanged in the CC of Pahenu2 mouse while some sterol intermediates were significantly reduced by treatment. Single nuclei transcriptomics showed upregulation of oxidative stress-related pathways, and increased expression of transthyretin, ApoE, Cst3, and Cd81 in CC in Pahenu2 mice. Normalization of blood Phe restored gene expression to levels comparable to heterozygous mice and was associated with generation of differentiated myelin-producing oligodendrocyte subtypes and neuroprotective astrocytes. In summary, Pahenu2 mice showed white matter abnormalities and changes in transcriptome and sterol profiles, which were partially corrected by normalization of blood Phe.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"228 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295868","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}
{"title":"AAV9-Mediated Gene Supplementation Therapy prevents and Rescues Arrhythmogenic Cardiomyopathy in Pnpla2-mutated Mice.","authors":"Xiulin Zhang,Congrui Wang,Yuan Chang,Hao Jia,Yue Zhang,Yifan Wang,Weiteng Wang,Han Han,Yuhong Hu,Xijia Shao,Shuang Wen,Siyu Tan,Ningning Zhang,Xiumeng Hua,Hao Cui,Xiao Chen,Jiangping Song","doi":"10.1016/j.ymthe.2025.06.023","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.023","url":null,"abstract":"Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder involving ventricular arrhythmias, cardiac dysfunction, and fibrofatty myocardial replacement. Current treatments are largely palliative, with heart transplantation as the only definitive option for advanced ACM. Here we show that, building upon our previous identification of a patient with a PNPLA2c.G245A/c.G245A mutation, we developed a murine model carrying the same mutation, faithfully mimicking key ACM phenotypes such as arrhythmias, lipid accumulation, and fibrosis. Using an adeno-associated virus 9 (AAV9) vector to deliver the human PNPLA2 gene, we demonstrated that early intervention prevented ACM onset, while later treatment reversed established symptoms and extended survival. Treated mice exhibited improved cardiac function, lipid metabolism, and normalized fatty acid pathways, verified by single-nucleus sequencing. These findings highlight the promise of AAV9-mediated PNPLA2 gene supplementation as an effective therapeutic strategy for ACM, supporting further clinical exploration.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"6 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295866","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}
{"title":"AAV-mediated gene therapy for focal epilepsy by expressing neuropeptide Y and Y2 receptor in rodent and non-human primate hippocampus.","authors":"Barbara Terzic,Esbjörn Melin,Pernilla Fagergren,David Dobry,Stefano Cattaneo,Iris Giupponi,Barbara Bettegazzi,Michele Simonato,Karin Agerman,Merab Kokaia,Lawrence Moon,Elizabeth Ramsburg","doi":"10.1016/j.ymthe.2025.06.019","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.019","url":null,"abstract":"Epilepsy affects approximately 50 million people worldwide, and over 30% of patients are considered treatment-resistant to currently available anti-seizure drugs. Neuropeptide Y (NPY) has been shown to inhibit excitatory synaptic transmission in hippocampal slices from human epilepsy patients via Y2 receptors (Y2R), and overexpression of NPY and/or Y2R in the hippocampus reduces seizures in rodent models of epilepsy. In this study, we demonstrate that AAV-mediated delivery of NPY and Y2R using a novel vector (SPK100.NPY-Y2R) inhibits seizures in rodents. SPK100.NPY-Y2R reduced spontaneous neuronal activity in primary rat cortical cultures and attenuated evoked neuronal activity in ex vivo slices of mouse hippocampus. Furthermore, intrahippocampal administration of SPK100.NPY-Y2R reduced the progression and duration of seizures in a rat model of rapid kindling. Parallel experiments confirmed that hippocampal overexpression of NPY and Y2R is also sufficient to reduce spontaneous seizures in a genetic mouse model of epilepsy (synapsin triple knockout). We also demonstrated successful magnetic resonance-guided, convection enhanced delivery of SPK100.NPY-Y2R to the hippocampus of Papio hamadryas (baboon). This approach achieved favorable vector biodistribution and transduction in the hippocampus, with no observed adverse events. These findings support the development of an intrahippocampal AAV.NPY-Y2R therapy for treating seizures in patients with temporal lobe epilepsy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"42 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295869","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}
{"title":"RNA-DNA hybrid binding domain broadens the editing window of base editors.","authors":"Yue Yang,Zihao Fu,Shengcheng Deng,Guanglan Wu,Chuanle Wang,Xiao Luo,Rui Kang,Yuxi Chen,Chengxiang Peng,Pengfei Zhang,Kaixin Cui,Fen Wan,Junhua Wang,Qin Zhou,Wei Chen,Yuanyan Xiong,Wenbin Ma,Zhou Songyang,Puping Liang","doi":"10.1016/j.ymthe.2025.06.024","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.024","url":null,"abstract":"Adenine base editors (ABEs) and cytosine base editors (CBEs) are prominent tools for precise genome editing but are hindered by limited editing activity at positions proximal to the protospacer adjacent motif (PAM). This study investigates the potential of enhancing base editors editing activity by fusing them with RNA-DNA hybrid binding domains (RHBDs). Specifically, fusing ABE8e with the RHBD of Homo sapiens RNaseH1 (RHBD1) significantly increased A-to-G editing efficiency in the PAM-proximal region (A9-A15) by up to 3.5-fold, while reducing off-target cytosine editing. Additionally, RHBD1 is compatible with ABEmax, BE4max, and dual base editor (eA&C-BEmax), enhancing their editing activity at the PAM-proximal bases. Notably, RHBD1-fused BE4max led to a 3.1-fold improvement in C-to-T editing efficiency at PAM-proximal region (C9-C12). Furthermore, we demonstrated that RHBD1-fused ABE8e could effectively edit disease-related single nucleotide variations (SNVs) in human cells, and validated its efficacy in adult mouse liver. These findings highlight the significance of the RHBD in expanding editing window and the applicability of base editors for gene therapy and disease modeling.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"10 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295867","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}
Molecular TherapyPub Date : 2025-06-14DOI: 10.1016/j.ymthe.2025.06.022
David D Fuller, Sabhya Rana, Prajwal P Thakre, Ethan S Benevides, Megan K Pope, Adrian G Todd, Victoria N Jensen, Lauren Vaught, Denise A Cloutier, Roberto A Ribas, Reece C Larson, Matthew S Gentry, Ramon C Sun, Vijay Chandran, Manuela Corti, Darin J Falk, Barry J Byrne
{"title":"Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease.","authors":"David D Fuller, Sabhya Rana, Prajwal P Thakre, Ethan S Benevides, Megan K Pope, Adrian G Todd, Victoria N Jensen, Lauren Vaught, Denise A Cloutier, Roberto A Ribas, Reece C Larson, Matthew S Gentry, Ramon C Sun, Vijay Chandran, Manuela Corti, Darin J Falk, Barry J Byrne","doi":"10.1016/j.ymthe.2025.06.022","DOIUrl":"10.1016/j.ymthe.2025.06.022","url":null,"abstract":"<p><p>Absence of functional acid-α-glucosidase (GAA) leads to early onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model (Gaa<sup>-/-</sup>) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline) injection was done on postnatal day 1; rats were studied at 6-12 months old. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI) revealed that AAV-GAA treatment normalized diaphragm muscle glycogen as well as glycans. In vivo magnetic resonance imaging demonstrated that impaired cardiac volumes in Gaa<sup>-/-</sup> rats were corrected by AAV-GAA treatment. Biochemical assays showed that AAV treatment increased GAA activity in the heart, diaphragm, quadriceps, and spinal cord. Inspiratory tidal volume and minute ventilation were increased in AAV-GAA-treated vs. saline-treated Pompe rats. Neurophysiological phrenic nerve recordings and spinal histological evaluation indicated that AAV-GAA treatment drove functional neuronal GAA expression. We conclude that neonatal AAV9-DES-GAA therapy drives sustained, functional GAA expression and improved cardiorespiratory function in the Gaa<sup>-/-</sup> rat model of Pompe disease.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302567","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}
Molecular TherapyPub Date : 2025-06-14DOI: 10.1016/j.ymthe.2025.06.017
Unbin Chae,Hae-Jun Yang,Hanseop Kim,Seung Hwan Lee,Dong Gil Lee,Jeong Young Koo,Seung-Min Ha,Seo-Jong Bak,Mina Joo,Hyun Hee Nam,Kyung-Seob Lim,Philyong Kang,Hee-Chang Son,You Jeong An,Young-Hyun Kim,In-Sung Song,Sang-Hee Lee,Hae Rim Kim,Sang-Mi Cho,Eun-Kyoung Kim,Ki-Hoan Nam,Kyung-Sook Chung,Jae-Yoon Kim,Seon-Yeop Kim,Seon-Kyu Kim,Seon-Young Kim,Dong-Seok Lee,Jin-Man Kim,Young-Ho Park,Sun-Uk Kim
{"title":"Precise Progerin Targeting Using RfxCas13d: A Therapeutic Avenue for Hutchinson-Gilford Progeria Syndrome.","authors":"Unbin Chae,Hae-Jun Yang,Hanseop Kim,Seung Hwan Lee,Dong Gil Lee,Jeong Young Koo,Seung-Min Ha,Seo-Jong Bak,Mina Joo,Hyun Hee Nam,Kyung-Seob Lim,Philyong Kang,Hee-Chang Son,You Jeong An,Young-Hyun Kim,In-Sung Song,Sang-Hee Lee,Hae Rim Kim,Sang-Mi Cho,Eun-Kyoung Kim,Ki-Hoan Nam,Kyung-Sook Chung,Jae-Yoon Kim,Seon-Yeop Kim,Seon-Kyu Kim,Seon-Young Kim,Dong-Seok Lee,Jin-Man Kim,Young-Ho Park,Sun-Uk Kim","doi":"10.1016/j.ymthe.2025.06.017","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.017","url":null,"abstract":"Hutchinson-Gilford progeria syndrome (HGPS), an extremely rare progressive genetic disorder, is caused by a point mutation in LMNA that induces progerin production, which disrupts cellular function and triggers premature aging and mortality. Despite extensive efforts, HPGS remains incurable. We successfully implemented a strategy using RfxCas13d to selectively target progerin mRNA at specific junction regions, without unintended cleavage and reduce its expression. This technique discriminated between normal lamin A and progerin, thus providing a safe and targeted therapeutic avenue to treat HGPS. Our approach effectively restored aberrant gene expression and progerin-induced cellular phenotypes, including senescence, mitochondrial dysfunction, and DNA damage in cells with HGPS and LMNAG608G/G608G mice. Notably, LMNAG608G/G608G mice exhibited improved progeroid phenotypes, suggesting a potential therapeutic application of this approach for other diseases resulting from abnormal RNA splicing.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"44 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295865","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}
{"title":"A single dose of a vectorized mAb targeting TDP-43 potently inhibits the neuropathology in a model of ALS/FTD.","authors":"Greg Del Val,Florence Gauye,Mickaël Audrain,Sébastien Menant,Monisha Ratnam,Elodie Chevalier,Romain Ollier,Daisy Bhatia,Tamara Seredenina,Tariq Afroz,Andrea Pfeifer,Marie Kosco-Vilbois,Damien Nevoltris","doi":"10.1016/j.ymthe.2025.06.026","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.026","url":null,"abstract":"TAR DNA binding protein-43 (TDP-43)-mediated pathology is a hallmark of devastating neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Thus, monoclonal antibodies (mAbs) are being developed to target the pathological forms of this protein. To improve mAb exposure within the central nervous system, a potent anti-TDP-43 mAb, ACI-5891, was generated as a vectorized full-length antibody (vmAb) and evaluated for brain delivery using adeno-associated virus 9 (AAV9). Among the expression cassettes explored, the selected construct utilized an internal ribosome entry site (IRES), which produced high expression yields in vitro (>200 mg/L) with comparable quality, binding and functional properties to the conventionally produced mAb. A single intracisternal administration of vmAb ACI-5891 demonstrated a broad brain distribution and sustained expression (i.e., months) in the serum, cerebrospinal fluid and brain of mice. In a mouse model of ALS/FTD, treatment with a vmAb reduced the amount of pathological phospho-TDP-43 in neurons by 58% and 68% when expressed either using a ubiquitous promoter or a brain-selective promoter, respectively. This innovative approach sufficiently delivers effective immunotherapy with a single dose and illustrates the enormous potential of using vectorized antibodies to target neuropathology, including TDP-43 in patients suffering from ALS, FTD and other TDP-43 proteinopathies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295860","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}
Molecular TherapyPub Date : 2025-06-14DOI: 10.1016/j.ymthe.2025.06.025
Rebecca M Legere,Jeannine A Ott,Cristina Poveda,Daryll Vanover,Karin E R Borba,Cameron L Martin,Bibiana P da Silveira,Jocelyne M Bray,Kerstin Landrock,Gus A Wright,J Chistensen Blazier,Andrew E Hillhouse,Ashley L Benham-Duret,Brandon Mistretta,Rafaela L Klein,Sarah M Thompson,Amelia R Woolums,Michael F Criscitiello,Luc R Berghman,Angela I Bordin,Phillip J Santangelo,Jeroen Pollet,Noah D Cohen
{"title":"Nebulization of a mRNA-encoded monoclonal antibody for passive immunization of foals against Rhodococcus equi.","authors":"Rebecca M Legere,Jeannine A Ott,Cristina Poveda,Daryll Vanover,Karin E R Borba,Cameron L Martin,Bibiana P da Silveira,Jocelyne M Bray,Kerstin Landrock,Gus A Wright,J Chistensen Blazier,Andrew E Hillhouse,Ashley L Benham-Duret,Brandon Mistretta,Rafaela L Klein,Sarah M Thompson,Amelia R Woolums,Michael F Criscitiello,Luc R Berghman,Angela I Bordin,Phillip J Santangelo,Jeroen Pollet,Noah D Cohen","doi":"10.1016/j.ymthe.2025.06.025","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.06.025","url":null,"abstract":"Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against the virulence associated protein A (VapA) directly into the lungs. VapA-specific memory B-cells from an immunized horse were used to identify and select the sequence for an equine IgG1 mAb. In vitro transcribed mRNA encoding this sequence expressed full-length, VapA-specific mAbs in vitro, and safely and effectively produced intrapulmonary mAb in foals for at least 5 days following nebulization. These findings establish a platform to generate mRNA-encoded mAbs for immunotherapeutic and immunoprophylactic applications in horses and demonstrate the feasibility of delivering nebulized mRNA-mAb for intrapulmonary mAb expression in neonates.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"228 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295806","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}
Molecular TherapyPub Date : 2025-06-14DOI: 10.1016/j.ymthe.2025.06.027
María José Limeres, Rocio Gambaro, Malin Svensson, Silvia Fraude-El Ghazi, Leah Pretsch, Daniel Frank, German A Islan, Ignacio Rivero Berti, Matthias Bros, Ying K Tam, Hiromi Muramatsu, Norbert Pardi, Stephan Gehring, Maximiliano L Cacicedo
{"title":"mRNA-LNP vaccines against hepatitis B virus induce protective immune responses in preventive and chronic mouse challenge models.","authors":"María José Limeres, Rocio Gambaro, Malin Svensson, Silvia Fraude-El Ghazi, Leah Pretsch, Daniel Frank, German A Islan, Ignacio Rivero Berti, Matthias Bros, Ying K Tam, Hiromi Muramatsu, Norbert Pardi, Stephan Gehring, Maximiliano L Cacicedo","doi":"10.1016/j.ymthe.2025.06.027","DOIUrl":"10.1016/j.ymthe.2025.06.027","url":null,"abstract":"<p><p>Over 300 million people worldwide suffer from chronic hepatitis B virus (HBV) infections that can cause serious liver damage and hepatocellular carcinoma. Ineffective innate and adaptive immune responses characterize these chronic infections, making the development of a therapeutic vaccine an urgent medical need. While current vaccines can prevent HBV infections, they are ineffective in treating chronic disease. This study investigated lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines encoding hepatitis B surface antigen (HBsAg) for prophylactic and therapeutic applications. We found that HBsAg mRNA-LNP vaccines induced robust humoral and cellular immune responses, outperforming the protein-based vaccine approved for human use. The incorporation of a major histocompatibility complex class I (MHC class I) signal peptide further enhanced Th1-biased responses preventing HBV infections in a mouse model. Importantly, mRNA-LNP vaccination led to seroconversion, HBsAg clearance, and strong T cell responses in a chronically infected mouse model. These findings highlight the potential of mRNA-LNP as an alternative and effective vaccine modality for HBV prophylaxis and therapeutic use in treating chronic infections.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302566","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}
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