Molecular Therapy最新文献

Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 high-pathogenicity avian influenza virus with reduced adverse reactions.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-17 DOI: 10.1016/j.ymthe.2024.12.032

Atsushi Kawai, Taro Shimizu, Hiroki Tanaka, Shintaro Shichinohe, Jessica Anindita, Mika Hirose, Eigo Kawahara, Kota Senpuku, Makoto Shimooka, Le Thi Quynh Mai, Ryo Suzuki, Takuto Nogimori, Takuya Yamamoto, Toshiro Hirai, Takayuki Kato, Tokiko Watanabe, Hidetaka Akita, Yasuo Yoshioka

{"title":"Low-inflammatory lipid nanoparticle-based mRNA vaccine elicits protective immunity against H5N1 high-pathogenicity avian influenza virus with reduced adverse reactions.","authors":"Atsushi Kawai, Taro Shimizu, Hiroki Tanaka, Shintaro Shichinohe, Jessica Anindita, Mika Hirose, Eigo Kawahara, Kota Senpuku, Makoto Shimooka, Le Thi Quynh Mai, Ryo Suzuki, Takuto Nogimori, Takuya Yamamoto, Toshiro Hirai, Takayuki Kato, Tokiko Watanabe, Hidetaka Akita, Yasuo Yoshioka","doi":"10.1016/j.ymthe.2024.12.032","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.032","url":null,"abstract":"Messenger RNA vaccines based on lipid nanoparticles (mRNA-LNPs) are promising vaccine modalities. However, mRNA-LNP vaccines frequently cause adverse reactions such as swelling and fever in humans, partly due to the inflammatory nature of LNP. Modification of the ionizable lipids used in LNP is one approach to avoid these adverse reactions. Herein, we report the development of mRNA-LNP vaccines with better protective immunity and reduced adverse reactions using LNP, which contains a disulfide (SS)-cleavable bond and pH-activated lipid-like materials with oleic acid (ssPalmO) as an ionizable lipid (LNPssPalmO). We used mRNA expressing H5N1 subtype high-pathogenicity avian influenza virus-derived hemagglutinin or neuraminidase to generate mRNA-LNP vaccines against H5N1 influenza. Compared with conventional LNP, mRNA-LNPssPalmO induced comparable antigen-specific antibodies and better interferon-gamma (IFN-γ)-producing T-helper type-1 (Th1) responses in mice. Both mRNA-LNPssPalmO and conventional mRNA-LNP conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNPssPalmO showed better cross-protection against heterologous H5N1 virus challenge compared with conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNPssPalmO induced less inflammatory responses (e.g., inflammatory cytokine production and vascular hyperpermeability) and fewer adverse reactions (e.g., weight loss and fever) compared with conventional mRNA-LNP. These results suggest that mRNA-LNPssPalmO would be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847122","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

In situ blockade of TNF-TNFR2 axis via oncolytic adenovirus improves antitumor efficacy in solid tumors. 通过溶瘤腺病毒原位阻断 TNF-TNFR2 轴可提高实体瘤的抗肿瘤疗效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-16 DOI: 10.1016/j.ymthe.2024.12.011

Xiaozhen Kang, Yifeng Han, Mengdi Wu, Yuxin Li, Peng Qian, Chuning Xu, Zhengyun Zou, Jie Dong, Jiwu Wei

{"title":"In situ blockade of TNF-TNFR2 axis via oncolytic adenovirus improves antitumor efficacy in solid tumors.","authors":"Xiaozhen Kang, Yifeng Han, Mengdi Wu, Yuxin Li, Peng Qian, Chuning Xu, Zhengyun Zou, Jie Dong, Jiwu Wei","doi":"10.1016/j.ymthe.2024.12.011","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.011","url":null,"abstract":"Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8+ T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4+ T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma, and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847121","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

Retraction Notice to: Inhibition of Hepatitis C Virus Replication by Intracellular Delivery of Multiple siRNAs by Nanosomes. 撤稿通知：通过纳米体在细胞内输送多种 siRNA 抑制丙型肝炎病毒复制

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-14 DOI: 10.1016/j.ymthe.2024.11.036

Partha K Chandra, Anup K Kundu, Sidhartha Hazari, Sruti Chandra, Lili Bao, Tara Ooms, Gilbert F Morris, Tong Wu, Tarun K Mandal, Srikanta Dash

引用次数: 0

Antiviral and immunomodulatory effects of ouabain against Congenital Zika Syndrome model. 乌巴因对先天性寨卡综合征模型的抗病毒和免疫调节作用

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-13 DOI: 10.1016/j.ymthe.2024.12.021

Deyse Cristina Madruga Carvalho, Tiffany Dunn, Rafael Kroon Campos, Jessica A Tierney, Florence Onyoni, Luiz Henrique Agra Cavalcante-Silva, Lindomar José Pena, Sandra Rodrigues-Mascarenhas, Ping Wu, Scott C Weaver

{"title":"Antiviral and immunomodulatory effects of ouabain against Congenital Zika Syndrome model.","authors":"Deyse Cristina Madruga Carvalho, Tiffany Dunn, Rafael Kroon Campos, Jessica A Tierney, Florence Onyoni, Luiz Henrique Agra Cavalcante-Silva, Lindomar José Pena, Sandra Rodrigues-Mascarenhas, Ping Wu, Scott C Weaver","doi":"10.1016/j.ymthe.2024.12.021","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.021","url":null,"abstract":"Zika virus (ZIKV) is an arbovirus associated with neurological disorders accompanying congenital infections. With no vaccine or antiviral approved, there is an urgent need for the development of effective antiviral agents against ZIKV infection. We evaluated the anti-ZIKV and immunomodulatory activity of ouabain, a Na+/K+-ATPase inhibitor known to have immunomodulatory and antiviral activities, using human neural stem/progenitor cells (hNS/PCs) and a murine model of congenital Zika syndrome (CZS). Our data demonstrated that ouabain reduces ZIKV infection in hNS/PCs, mouse placenta, yolk sac, and the fetal head. Ouabain mitigated neurogenesis impairment triggered by ZIKV in hNS/PCs, and prevented ZIKV-mediated reduction of fetus and head sizes. In addition, ouabain decreased TNF and IL-1β levels in the placenta, highlighting its immunomodulatory activity in the murine model. Our findings indicate that ouabain possesses anti-ZIKV and immunomodulatory activities, suggesting that it should be further investigated as a promising treatment for CZS.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829443","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

Single-cell data-driven design of armed oncolytic virus and combination therapy to activate a cooperative innate-adaptive immunity against cancer. 以单细胞数据为驱动设计武装溶瘤病毒和联合疗法，以激活对抗癌症的先天适应性合作免疫。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-13 DOI: 10.1016/j.ymthe.2024.12.017

Jiliang Zhao, Han Wang, Chunlei Wang, Fan Li, Jingru Chen, Feilong Zhou, Yiping Zhu, Jinhua Chen, Jinming Liu, Hao Zheng, Nanxin Gong, Yazhuo Du, Yufan Zhang, Li Deng, Yuyao Du, Yanqin Liu, Yuanke Li, Na Li, Hongru Zhang, Dan Ding, Shouzhi Yu, Cuizhu Zhang, Yingbin Yan, Wei Wang, Youjia Cao, Yuntao Zhang, Hongkai Zhang

{"title":"Single-cell data-driven design of armed oncolytic virus and combination therapy to activate a cooperative innate-adaptive immunity against cancer.","authors":"Jiliang Zhao, Han Wang, Chunlei Wang, Fan Li, Jingru Chen, Feilong Zhou, Yiping Zhu, Jinhua Chen, Jinming Liu, Hao Zheng, Nanxin Gong, Yazhuo Du, Yufan Zhang, Li Deng, Yuyao Du, Yanqin Liu, Yuanke Li, Na Li, Hongru Zhang, Dan Ding, Shouzhi Yu, Cuizhu Zhang, Yingbin Yan, Wei Wang, Youjia Cao, Yuntao Zhang, Hongkai Zhang","doi":"10.1016/j.ymthe.2024.12.017","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.017","url":null,"abstract":"Oncolytic viruses have been considered promising cancer immunotherapies. However, oncovirotherapy agents impart durable responses in only a subset of cancer patients. Thus, exploring the cellular and molecular mechanisms underlying the heterogeneous responses in patients can provide guidance to develop more effective oncolytic virus therapies. Single-cell RNA sequencing (scRNA-seq) analysis of tumors responsive and non-responsive to oncovirotherapy revealed signatures of the tumor immune microenvironment associated with immune response. Thus, we designed and constructed an armed oncolytic virus OV-5A that expressed five genes with non-redundant functions. OV-5A treatment exhibits robust immune response against various tumors in multiple mouse models, peripheral blood mononuclear cell (PBMC)-patient derived xenograft (PDX) model, organoid-immune cell co-culture systems and patient tissue sections by activating a cooperative innate-adaptive immune response against tumor cells. scRNA-seq analysis of complete responder and partial responder to OV-5A treatment guided the design of combination therapy of OV-5A. This data-driven approach paves a innovative way to rationalize the design of oncolytic virus and multi-agent combination therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829452","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

Potentiating CAR-T-cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal. 通过逆转 TGF-β 信号，增强 CAR-T 细胞在免疫抑制肿瘤微环境中的功能。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-13 DOI: 10.1016/j.ymthe.2024.12.014

Shen Zheng, Xuan Che, Kai Zhang, Yun Bai, Hongkui Deng

{"title":"Potentiating CAR-T-cell function in the immunosuppressive tumor microenvironment by inverting the TGF-β signal.","authors":"Shen Zheng, Xuan Che, Kai Zhang, Yun Bai, Hongkui Deng","doi":"10.1016/j.ymthe.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.014","url":null,"abstract":"The immunosuppressive tumor microenvironment represents a key challenge for chimeric antigen receptor (CAR) T cells in solid tumors and includes the production of the inhibitory cytokine transforming growth factor-β (TGF-β), which limits CAR-T-cell persistence and function. Current strategies involving the blockade of TGF-β signaling have little benefit for solid tumor treatment. Here, we demonstrate a novel inverted cytokine receptor (ICR)-modified CAR-T-cell strategy not only TGF-β signal blockade but also antitumor efficacy enhancement. The newly designed T cells carry an ICR construct that fuses the TGF-β receptor II extracellular domain to the interleukin-15 (IL-15) receptor α cytoplasmic domain (named TB15) and is directed to the tumor antigen epidermal growth factor receptor by a CAR construct. In mice with high-TGF-β solid tumors, our signal-inverted CAR/TB15 T cells effectively treat tumors by blocking TGF-β and repurposing IL-15 stimulative signaling, resulting in enhanced CAR-T-cell persistence and function. As a proof of concept, our study results extend synthetic receptor signaling beyond CAR-directed killing, which could endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumors by using a chimeric inverted cytokine receptor.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824099","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

Tailoring capsid directed evolution technology for improved AAV-mediated CAR-T generation. 定制囊壳定向进化技术，改进 AAV 介导的 CAR-T 生成。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-12 DOI: 10.1016/j.ymthe.2024.12.012

Adrian Westhaus, Elena Barba-Sarasua, Yuyan Chen, Kenneth Hsu, Suzanne Scott, Maddison Knight, Florencia Haase, Santiago Mesa Mora, Benjamin C Houghton, Ramon Roca-Pinilla, Predrag Kalajdzic, Geraldine O'Neill, Adrian J Thrasher, Giorgia Santilli, Leszek Lisowski

{"title":"Tailoring capsid directed evolution technology for improved AAV-mediated CAR-T generation.","authors":"Adrian Westhaus, Elena Barba-Sarasua, Yuyan Chen, Kenneth Hsu, Suzanne Scott, Maddison Knight, Florencia Haase, Santiago Mesa Mora, Benjamin C Houghton, Ramon Roca-Pinilla, Predrag Kalajdzic, Geraldine O'Neill, Adrian J Thrasher, Giorgia Santilli, Leszek Lisowski","doi":"10.1016/j.ymthe.2024.12.012","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.012","url":null,"abstract":"Chimeric antigen receptor (CAR) T-cell (CAR-T) therapies present options for patients diagnosed with certain leukemias. Recent advances of the technology included a method to integrate the CAR into the T-cell receptor alpha constant (TRAC) locus to take advantage of the endogenous promoter and regulatory elements for CAR expression. This method used adeno-associated viral (AAV) vectors based on AAV6 to deliver the donor template encoding the CAR construct. Since the original publication, improvements have been made to this targeted CAR integration technique, however, none of those techniques focused on improving the AAV vector used to deliver the therapeutic cargo. The herein presented study developed a novel AAV capsid directed evolution platform that allows to specifically select for novel AAV capsid variants that enable more efficient targeted gene editing-mediated CAR construct integration into the TRAC locus in primary T-cells. Using this new platform, we selected several novel AAVs that enable more efficient editing in T-cells than AAV6. Two novel capsids, AAV-T1 and AAV-T2, were able to mediate five-fold improvement for on-target knock-in, which resulted in five-fold reduction of the vector dose to produce highly cytolytic T-cells against a brain tumor cell line.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824321","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

In vivo evolution of env in SHIV-AD8_EO-infected rhesus macaques after AAV-vectored delivery of eCD4-Ig. 通过 AAV 传播 eCD4-Ig 后，SHIV-AD8EO 感染的猕猴体内 env 的演变。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-12 DOI: 10.1016/j.ymthe.2024.12.015

Daniel O'Hagan, Siddhartha Shandilya, Lincoln J Hopkins, Patricia A Hahn, Sebastian P Fuchs, Jose M Martinez-Navio, Michael D Alpert, Mathew R Gardner, Ronald C Desrosiers, Guangping Gao, Jeffrey D Lifson, Michael Farzan, Amir Ardeshir, Mauricio A Martins

{"title":"In vivo evolution of env in SHIV-AD8EO-infected rhesus macaques after AAV-vectored delivery of eCD4-Ig.","authors":"Daniel O'Hagan, Siddhartha Shandilya, Lincoln J Hopkins, Patricia A Hahn, Sebastian P Fuchs, Jose M Martinez-Navio, Michael D Alpert, Mathew R Gardner, Ronald C Desrosiers, Guangping Gao, Jeffrey D Lifson, Michael Farzan, Amir Ardeshir, Mauricio A Martins","doi":"10.1016/j.ymthe.2024.12.015","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.015","url":null,"abstract":"eCD4-Ig is an entry inhibitor of the human immunodeficiency virus (HIV) that mimics the engagement of both CD4 and CCR5 with the HIV Envelope (Env) protein, a property which imbues it with remarkable potency and breadth. However, env is exceptionally genetically malleable and can evolve to escape a wide variety of entry inhibitors. Here we document the evolution of partial eCD4-Ig resistance in simian-HIV (SHIV)-AD8EO-infected rhesus macaques (RMs) treated with adeno-associated vectors (AAV) encoding eCD4-Ig. In one RM, setpoint viremia plateaued at 1,000 vRNA copies/ml, despite concomitant serum concentrations of eCD4-Ig in the 60-110 μg/ml range, implying that the virus had gained partial eCD4-Ig resistance. Env mutations occurring prominently in this animal were cloned and further characterized. Three of these mutations (R315G, A436T, G471E) were sufficient to confer substantial resistance to eCD4-Ig-mediated neutralization onto the parental Env, accompanied by a marked loss of viral fitness. This resistance was not driven by decreased CD4 affinity, subverted sulfopeptide mimicry, changes to coreceptor tropism, or by a gain of CD4 independence. Rather, our data argue that the Env evolving in this animal attained eCD4-Ig resistance by decreasing triggerability, stabilizing state-2, and changing the nature of its relationship to the host CD4.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823933","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

Self-amplifying mRNA vaccines protect elderly BALB/c mice against a lethal respiratory syncytial virus infection.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-12 DOI: 10.1016/j.ymthe.2024.12.013

Lulu Zuo, Qixing Liu, Ke Zhang, Lu Zhao, Siyu Lin, You Dai, Yun Sun, Yingwen Li, Pingping Zhang, Huyan Shen, Dongmei He, Shuang Ma, Xianhua Long, Yanhua Chen, Yusi Luo, Gary Wong

{"title":"Self-amplifying mRNA vaccines protect elderly BALB/c mice against a lethal respiratory syncytial virus infection.","authors":"Lulu Zuo, Qixing Liu, Ke Zhang, Lu Zhao, Siyu Lin, You Dai, Yun Sun, Yingwen Li, Pingping Zhang, Huyan Shen, Dongmei He, Shuang Ma, Xianhua Long, Yanhua Chen, Yusi Luo, Gary Wong","doi":"10.1016/j.ymthe.2024.12.013","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.013","url":null,"abstract":"Respiratory Syncytial Virus (RSV) represents a significant threat, being a primary cause of critical lower respiratory tract infections and fatalities among infants and the elderly worldwide, and poses a challenge to global public health. This urgent public health challenge necessitates the swift development of safe and effective vaccines capable of eliciting robust immune responses at low doses. Addressing this need, our study investigated five self-amplifying RNA (sa-mRNA) candidate vaccines that encode the various pre-fusion conformations of the RSV fusion protein. When administered via low-dose intramuscular injection to 8-month-old elderly mice, these vaccines triggered potent humoral reactions and Th1-biased cellular immunity. A prime-boost strategy followed by challenge with a lethal, mouse-adapted RSV strain showed that three of these sa-mRNA candidates achieved over 80% survival rates. An immune correlates of protection (CoP) analysis contrasting immunized survivors with non-survivors suggest that the titers of IgG and neutralizing antibody are associated with vaccine-mediated protection from RSV infection. Our results highlight the utility of sa-mRNA vaccines to play a crucial role in forging an effective defense against RSV, addressing a critical need in protecting vulnerable populations against this virus.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824174","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

Preclinical development of lentiviral vector gene therapy for Diamond-Blackfan anemia syndrome.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-12 DOI: 10.1016/j.ymthe.2024.12.020

Senthil Velan Bhoopalan, Thiyagaraj Mayuranathan, Nana Liu, Kalin Mayberry, Yu Yao, Jingjing Zhang, Jean-Yves Métais, Koon-Kiu Yan, Robert E Throm, Steven R Ellis, Yan Ju, Lei Han, Shruthi Suryaprakash, Lance E Palmer, Sheng Zhou, Jiyang Yu, Yong Cheng, Jonathan S Yen, Stephen Gottschalk, Mitchell J Weiss

{"title":"Preclinical development of lentiviral vector gene therapy for Diamond-Blackfan anemia syndrome.","authors":"Senthil Velan Bhoopalan, Thiyagaraj Mayuranathan, Nana Liu, Kalin Mayberry, Yu Yao, Jingjing Zhang, Jean-Yves Métais, Koon-Kiu Yan, Robert E Throm, Steven R Ellis, Yan Ju, Lei Han, Shruthi Suryaprakash, Lance E Palmer, Sheng Zhou, Jiyang Yu, Yong Cheng, Jonathan S Yen, Stephen Gottschalk, Mitchell J Weiss","doi":"10.1016/j.ymthe.2024.12.020","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.020","url":null,"abstract":"Diamond-Blackfan anemia syndrome (DBAS) is an inherited bone marrow failure disorder caused by haploinsufficiency of ribosomal protein genes, most commonly RPS19. Limited access to patient hematopoietic stem/progenitor cells (HSPCs) is a major roadblock to developing novel therapies for DBAS. We developed a novel self-inactivating third-generation RPS19-encoding lentiviral vector (LV), termed \"SJEFS-S19\", for DBAS gene therapy. To facilitate LV design, optimize transduction and assess potential therapeutic efficacy, we leveraged a human cellular model of DBAS based on heterozygous disruption of RPS19 in healthy donor CD34+ HSPCs. We show that SJEFS-S19 LV can rescue DBAS-associated defects in ribosomal RNA processing, erythropoiesis and competitive bone marrow repopulation. Transduction of RPS19+/- CD34+ HSPCs with SJEFS-S19 LV followed by xenotransplantation into immunodeficient mice generated a polyclonal HSPC population with normal multi-lineage differentiation and a diverse integration site profile resembling that of clinically proven LVs. Overall, these preclinical studies demonstrate the safety and efficacy of SJEFS-S19, a novel LV for future DBAS gene therapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824157","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