Gene Therapy最新文献_第3页

Correction: Development of an optimized AAV2/5 gene therapy vector for Leber congenital amaurosis owing to defects in RPE65 更正：开发一种优化的 AAV2/5 基因治疗载体，用于治疗因 RPE65 缺陷导致的 Leber 先天性羊角疯。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-07-12 DOI: 10.1038/s41434-024-00463-z

A. Georgiadis, Y. Duran, J. Ribeiro, L. Abelleira-Hervas, S. J. Robbie, B. Sünkel-Laing, S. Fourali, A. Gonzalez-Cordero, E. Cristante, M. Michaelides, J. W. B. Bainbridge, A. J. Smith, R. R. Ali

引用次数: 0

Correction: Dual-targeted NIS polyplexes—a theranostic strategy toward tumors with heterogeneous receptor expression 更正：双靶向 NIS 多聚物--针对受体表达异质性肿瘤的治疗策略。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-07-11 DOI: 10.1038/s41434-024-00464-y

Sarah Urnauer, Kathrin A. Schmohl, Mariella Tutter, Christina Schug, Nathalie Schwenk, Stephan Morys, Sibylle Ziegler, Peter Bartenstein, Dirk-André Clevert, Ernst Wagner, Christine Spitzweg

引用次数: 0

Administration and detection of a multi-target rAAV gene doping vector in horses using multiple matrices and molecular techniques 利用多种基质和分子技术对马体内的多靶点 rAAV 基因兴奋剂载体进行管理和检测。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-07-07 DOI: 10.1038/s41434-024-00462-0

Jillian Maniego, Caitlin Harding, Jocelyn Habershon-Butcher, Pamela Hincks, Edward Ryder

{"title":"Administration and detection of a multi-target rAAV gene doping vector in horses using multiple matrices and molecular techniques","authors":"Jillian Maniego, Caitlin Harding, Jocelyn Habershon-Butcher, Pamela Hincks, Edward Ryder","doi":"10.1038/s41434-024-00462-0","DOIUrl":"10.1038/s41434-024-00462-0","url":null,"abstract":"Gene doping, which includes the non-therapeutic use of genes or genetic elements that have the capacity to enhance athletic performance, is prohibited in horseracing and equestrian sports. To provide a comprehensive assessment of matrix and detection techniques, a custom adeno-associated virus serotype 8 vector was designed to include PCR binding sites for multiple target genes and assay types. The vector was injected via an intramuscular route into two Thoroughbred horses and matrices collected at defined timepoints. DNA was analysed using 3 detection methods: qPCR, digital PCR, and NGS. Overall, there was a strong correlation across the different detection methods employed, although digital PCR was less sensitive at lower concentrations. High concentrations of vector were detected at early timepoints in plasma and whole blood, which rapidly dropped after 0.5 d to trace levels by 4 d and 9 d post-administration respectively, following a similar pattern to previous studies. Vector was detected in dried blood spots at lower levels than whole blood, but with a similar detection time. Detection in hair root bulbs in one horse was observed at over a month post-administration, which opens new avenues for future gene doping testing in humans and animals.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 Note: Optimization of oncolytic effect of Newcastle disease virus Clone30 by selecting sensitive tumor host and constructing more oncolytic viruses 撤稿说明：通过选择敏感的肿瘤宿主和构建更多的溶瘤病毒，优化新城疫病毒克隆30的溶瘤效果。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-07-04 DOI: 10.1038/s41434-024-00459-9

Tianyan Liu, Yu Zhang, Yukai Cao, Shan Jiang, Rui Sun, Jiechao Yin, Zhenqiu Gao, Guiping Ren, Zhenzhong Wang, Qingzhong Yu, Guangchao Sui, Xu Sun, Wenying Sun, Wei Xiao, Deshan Li

引用次数: 0

Stable inhibition of choroidal neovascularization by adeno-associated virus 2/8-vectored bispecific molecules 腺相关病毒 2/8 接种双特异性分子对脉络膜新生血管的稳定抑制。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-07-03 DOI: 10.1038/s41434-024-00461-1

Tinghui Bai, Bohao Cui, Man Xing, Siyue Chen, Yanfang Zhu, Dongxue Lin, Yingying Guo, Mei Du, Xiaohong Wang, Dongming Zhou, Hua Yan

{"title":"Stable inhibition of choroidal neovascularization by adeno-associated virus 2/8-vectored bispecific molecules","authors":"Tinghui Bai, Bohao Cui, Man Xing, Siyue Chen, Yanfang Zhu, Dongxue Lin, Yingying Guo, Mei Du, Xiaohong Wang, Dongming Zhou, Hua Yan","doi":"10.1038/s41434-024-00461-1","DOIUrl":"10.1038/s41434-024-00461-1","url":null,"abstract":"Neovascular age-related macular degeneration (nAMD) causes severe visual impairment. Pigment epithelium-derived factor (PEDF), soluble CD59 (sCD59), and soluble fms-like tyrosine kinase-1 (sFLT-1) are potential therapeutic agents for nAMD, which target angiogenesis and the complement system. Using the AAV2/8 vector, two bi-target gene therapy agents, AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59, were generated, and their therapeutic efficacy was investigated in laser-induced choroidal neovascularization (CNV) and Vldlr−/− mouse models. After a single injection, AAV2/8-mediated gene expression was maintained at high levels in the retina for two months. Both AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 significantly reduced CNV development for an extended period without side effects and provided efficacy similar to two injections of current anti-vascular endothelial growth factor monotherapy. Mechanistically, these agents suppressed the extracellular signal-regulated kinase and nuclear factor-κB pathways, resulting in anti-angiogenic activity. This study demonstrated the safety and long-lasting effects of AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 in CNV treatment, providing a promising therapeutic strategy for nAMD.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00461-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Highly efficient and specific regulation of gene expression using enhanced CRISPR-Cas12f system 利用增强型 CRISPR-Cas12f 系统高效特异地调控基因表达。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-06-25 DOI: 10.1038/s41434-024-00458-w

Yeounsun Oh, Lee Wha Gwon, Hyomin K. Lee, Junho K. Hur, Kwang-Hyun Park, Kee-Pyo Kim, Seung Hwan Lee

{"title":"Highly efficient and specific regulation of gene expression using enhanced CRISPR-Cas12f system","authors":"Yeounsun Oh, Lee Wha Gwon, Hyomin K. Lee, Junho K. Hur, Kwang-Hyun Park, Kee-Pyo Kim, Seung Hwan Lee","doi":"10.1038/s41434-024-00458-w","DOIUrl":"10.1038/s41434-024-00458-w","url":null,"abstract":"The recently developed CRISPR activator (CRISPRa) system uses a CRISPR-Cas effector-based transcriptional activator to effectively control the expression of target genes without causing DNA damage. However, existing CRISPRa systems based on Cas9/Cas12a necessitate improvement in terms of efficacy and accuracy due to limitations associated with the CRISPR-Cas module itself. To overcome these limitations and effectively and accurately regulate gene expression, we developed an efficient CRISPRa system based on the small CRISPR-Cas effector Candidatus Woesearchaeota Cas12f (CWCas12f). By engineering the CRISPR-Cas module, linking activation domains, and using various combinations of linkers and nuclear localization signal sequences, the optimized eCWCas12f-VPR system enabled effective and target-specific regulation of gene expression compared with that using the existing CRISPRa system. The eCWCas12f-VPR system developed in this study has substantial potential for controlling the transcription of endogenous genes in living organisms and serves as a foundation for future gene therapy and biological research.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00458-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene replacement therapy for spinal muscular atrophy: safety and preliminary efficacy in a Brazilian cohort 脊髓性肌萎缩症的基因替代疗法：巴西队列的安全性和初步疗效。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-06-05 DOI: 10.1038/s41434-024-00456-y

Rodrigo Holanda Mendonça, Adriana Banzzatto Ortega, Ciro Matsui Jr, Vanessa van der Linden, Marcelo Kerstenetzky, Luis Fernando Grossklauss, Elizabeth L. Silveira-Lucas, Graziela Jorge Polido, Edmar Zanoteli

{"title":"Gene replacement therapy for spinal muscular atrophy: safety and preliminary efficacy in a Brazilian cohort","authors":"Rodrigo Holanda Mendonça, Adriana Banzzatto Ortega, Ciro Matsui Jr, Vanessa van der Linden, Marcelo Kerstenetzky, Luis Fernando Grossklauss, Elizabeth L. Silveira-Lucas, Graziela Jorge Polido, Edmar Zanoteli","doi":"10.1038/s41434-024-00456-y","DOIUrl":"10.1038/s41434-024-00456-y","url":null,"abstract":"Spinal muscular atrophy (SMA) is a motor neuron disease associated with progressive muscle weakness, ventilatory failure, and reduced survival. Onasemnogene abeparvovec is the first gene replacement therapy (GT) approved to treat this condition. An observational retrospective study was conducted to assess adverse events and efficacy of GT in SMA patients. Forty-one patients with SMA (58.5% females and 80.1% SMA type 1) were included. The mean age at GT dosing was 18 (±6.4) months. Thirty-six patients (87.8%) were under previous treatment with nusinersen, and 10 (24.4%) continued nusinersen after GT. Mean CHOP-INTEND increased 13 points after 6 months and this finding did not differ between groups according to nusinersen maintenance after GT (p = 0.949). Among SMA type 1 patients, 14 (46.6%) reached the ability to sit alone. Liver transaminases elevation at least two times higher than the upper limit of normal value occurred in 29 (70.7%) patients. Thrombocytopenia occurred in 13 (31.7%) patients, and one presented thrombotic microangiopathy. Older age (>2 years) was associated with more prolonged use of corticosteroids (p = 0.021). GT is effective in SMA patients, combined nusinersen after GT did not appear to add gain in motor function and older age is associated with prolonged corticosteroid use.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Superoxide dismutase 1-modified dental pulp stem cells alleviate high-altitude pulmonary edema by inhibiting oxidative stress through the Nrf2/HO-1 pathway 超氧化物歧化酶1修饰的牙髓干细胞通过Nrf2/HO-1途径抑制氧化应激，缓解高海拔肺水肿

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-06-04 DOI: 10.1038/s41434-024-00457-x

Zhuang Mao, Changyao Wang, Juanli Liu, Xue Li, Han Duan, Yi Ye, Huifang Liu, Lin Lv, Guanzhen Xue, Zhichao He, Tana Wuren, Hua Wang

{"title":"Superoxide dismutase 1-modified dental pulp stem cells alleviate high-altitude pulmonary edema by inhibiting oxidative stress through the Nrf2/HO-1 pathway","authors":"Zhuang Mao, Changyao Wang, Juanli Liu, Xue Li, Han Duan, Yi Ye, Huifang Liu, Lin Lv, Guanzhen Xue, Zhichao He, Tana Wuren, Hua Wang","doi":"10.1038/s41434-024-00457-x","DOIUrl":"10.1038/s41434-024-00457-x","url":null,"abstract":"High-altitude pulmonary edema (HAPE) is a deadly form of altitude sickness, and there is no effective treatment for HAPE. Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cell isolated from dental pulp tissues and possess various functions, such as anti-inflammatory and anti-oxidative stress. DPSCs have been used to treat a variety of diseases, but there are no studies on treating HAPE. In this study, Sprague-Dawley rats were exposed to acute low-pressure hypoxia to establish the HAPE model, and SOD1-modified DPSCs (DPSCsHiSOD1) were administered through the tail vein. Pulmonary arterial pressure, lung water content (LWC), total lung protein content of bronchoalveolar lavage fluid (BALF) and lung homogenates, oxidative stress, and inflammatory indicators were detected to evaluate the effects of DPSCsHiSOD1 on HAPE. Rat type II alveolar epithelial cells (RLE-6TN) were used to investigate the effects and mechanism of DPSCsHiSOD1 on hypoxia injury. We found that DPSCs could treat HAPE, and the effect was better than that of dexamethasone treatment. SOD1 modification could enhance the function of DPSCs in improving the structure of lung tissue, decreasing pulmonary arterial pressure and LWC, and reducing the total lung protein content of BALF and lung homogenates, through anti-oxidative stress and anti-inflammatory effects. Furthermore, we found that DPSCsHiSOD1 could protect RLE-6TN from hypoxic injury by reducing the accumulation of reactive oxygen species (ROS) and activating the Nrf2/HO-1 pathway. Our findings confirm that SOD1 modification could enhance the anti-oxidative stress ability of DPSCs through the Nrf2/HO-1 signalling pathway. DPSCs, especially DPSCsHiSOD1, could be a potential treatment for HAPE.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD 视黄酸相关孤儿受体α是一种基因修饰因子，能挽救斯塔加特病和干性黄斑变性小鼠模型中的视网膜变性。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-05-16 DOI: 10.1038/s41434-024-00455-z

M. Akula, S. M. McNamee, Z. Love, N. Nasraty, N. P. M. Chan, M. Whalen, M. O. Avola, A. M. Olivares, B. D. Leehy, A. S. Jelcick, P. Singh, A. K. Upadhyay, D. F. Chen, N. B. Haider

{"title":"Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD","authors":"M. Akula, S. M. McNamee, Z. Love, N. Nasraty, N. P. M. Chan, M. Whalen, M. O. Avola, A. M. Olivares, B. D. Leehy, A. S. Jelcick, P. Singh, A. K. Upadhyay, D. F. Chen, N. B. Haider","doi":"10.1038/s41434-024-00455-z","DOIUrl":"10.1038/s41434-024-00455-z","url":null,"abstract":"Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4−/−) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00455-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140957146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of KoRV-pseudotyped lentiviral vectors for efficient gene transfer into freshly isolated immune cells 开发用于向新鲜分离的免疫细胞进行高效基因转移的 KoRV 伪型慢病毒载体

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-04-29 DOI: 10.1038/s41434-024-00454-0

Alexander Renner, Anika Stahringer, Katharina Eva Ruppel, Stephan Fricke, Ulrike Koehl, Dominik Schmiedel

{"title":"Development of KoRV-pseudotyped lentiviral vectors for efficient gene transfer into freshly isolated immune cells","authors":"Alexander Renner, Anika Stahringer, Katharina Eva Ruppel, Stephan Fricke, Ulrike Koehl, Dominik Schmiedel","doi":"10.1038/s41434-024-00454-0","DOIUrl":"10.1038/s41434-024-00454-0","url":null,"abstract":"Allogeneic cell therapies, such as those involving macrophages or Natural Killer (NK) cells, are of increasing interest for cancer immunotherapy. However, the current techniques for genetically modifying these cell types using lenti- or gamma-retroviral vectors present challenges, such as required cell pre-activation and inefficiency in transduction, which hinder the assessment of preclinical efficacy and clinical translation. In our study, we describe a novel lentiviral pseudotype based on the Koala Retrovirus (KoRV) envelope protein, which we identified based on homology to existing pseudotypes used in cell therapy. Unlike other pseudotyped viral vectors, this KoRV-based envelope demonstrates remarkable efficiency in transducing freshly isolated primary human NK cells directly from blood, as well as freshly obtained monocytes, which were differentiated to M1 macrophages as well as B cells from multiple donors, achieving up to 80% reporter gene expression within three days post-transduction. Importantly, KoRV-based transduction does not compromise the expression of crucial immune cell receptors, nor does it impair immune cell functionality, including NK cell viability, proliferation, cytotoxicity as well as phagocytosis of differentiated macrophages. Preserving immune cell functionality is pivotal for the success of cell-based therapeutics in treating various malignancies. By achieving high transduction rates of freshly isolated immune cells before expansion, our approach enables a streamlined and cost-effective automated production of off-the-shelf cell therapeutics, requiring fewer viral particles and less manufacturing steps. This breakthrough holds the potential to significantly reduce the time and resources required for producing e.g. NK cell therapeutics, expediting their availability to patients in need.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00454-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140832819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0