Gene Therapy最新文献

Activated factor X delivered by adeno-associated virus significantly inhibited bleeding and alleviated hemophilic synovitis in hemophilic mice 通过腺相关病毒递送的活化 X 因子可显著抑制血友病小鼠出血并缓解血友病滑膜炎

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-09-10 DOI: 10.1038/s41434-024-00479-5

Feixu Zhang, Xinyue Zhou, Baolai Hua, Xinyi He, Zhanao Li, Xiao Xiao, Xia Wu

引用次数: 0

Retraction Note: miR-503-5p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A. 撤稿说明：miR-503-5p 通过直接下调 VEGF-A 抑制结肠癌肿瘤发生、血管生成和淋巴管生成。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-06 DOI: 10.1038/s41434-024-00486-6

Linlin Wei, Chaonan Sun, Yaotian Zhang, Ning Han, Shichen Sun

引用次数: 0

AAV dose-dependent transduction efficiency in retinal ganglion cells and functional efficacy of optogenetic vision restoration. 视网膜神经节细胞中 AAV 的剂量依赖性转导效率和光遗传学视力恢复的功能效果。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-05 DOI: 10.1038/s41434-024-00485-7

Qi Lu, Anna Wright, Zhuo-Hua Pan

{"title":"AAV dose-dependent transduction efficiency in retinal ganglion cells and functional efficacy of optogenetic vision restoration.","authors":"Qi Lu, Anna Wright, Zhuo-Hua Pan","doi":"10.1038/s41434-024-00485-7","DOIUrl":"https://doi.org/10.1038/s41434-024-00485-7","url":null,"abstract":"Optogenetics is a promising approach for restoring vision to the blind after photoreceptor degeneration. The ability to restore vision through AAV-mediated delivery of light-sensitive proteins, especially channelrhodopsins, into retinal ganglion cells has been extensively demonstrated in animal models. For clinical application, knowledge of viral dose-dependent functional efficacy is desired. In this study, using a triple-knockout blind mouse model and a highly light-sensitive channelrhodopsin variant, we evaluated viral dose-dependent vision restoration through retinal ganglion cell expression by using optomotor behavioral assays. Our results show that both the restored light sensitivity and visual acuity reached peak levels at a medial viral dose of 108 vg. With increasing dose, transduction efficiency continued to increase while protein expression peaked at the dose of ~109 vg and declined at higher doses. Also, a significant increase in retinal gliosis and inflammatory responses started at the dose of ~109 vg, and a marked increase was observed at the dose of ~1010. These results provide valuable insights into viral dose design for clinical studies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139949","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

CRISPR/Cas9-mediated exon skipping to restore premature translation termination in a DFNB4 mouse model. CRISPR/Cas9介导的外显子跳接可恢复 DFNB4 小鼠模型的过早翻译终止。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-04 DOI: 10.1038/s41434-024-00483-9

Chun-Ying Huang, Yi-Hsiu Tsai, Yi-Fen Cheng, Peng-Yu Wu, Yu-Chi Chuang, Po-Yuan Huang, Jai-Shin Liu, Chen-Chi Wu, Yen-Fu Cheng

{"title":"CRISPR/Cas9-mediated exon skipping to restore premature translation termination in a DFNB4 mouse model.","authors":"Chun-Ying Huang, Yi-Hsiu Tsai, Yi-Fen Cheng, Peng-Yu Wu, Yu-Chi Chuang, Po-Yuan Huang, Jai-Shin Liu, Chen-Chi Wu, Yen-Fu Cheng","doi":"10.1038/s41434-024-00483-9","DOIUrl":"https://doi.org/10.1038/s41434-024-00483-9","url":null,"abstract":"SLC26A4 encodes pendrin, a crucial anion exchanger essential for maintaining hearing function. Mutations in SLC26A4, including the prevalent c.919-2 A > G splice-site mutation among East Asian individuals, can disrupt inner ear electrolyte balance, leading to syndromic and non-syndromic hearing loss, such as Pendred syndrome and DFNB4. To explore potential therapeutic strategies, we utilized CRISPR/Cas9-mediated exon skipping to create a Slc26a4∆E8+E9/∆E8+E9 mouse model. We assessed pendrin expression in the inner ear and evaluated vestibular and auditory functions. The Slc26a4∆E8+E9/∆E8+E9 mice demonstrated reframed pendrin in the inner ear and normal vestibular functions, contrasting with severely abnormal vestibular functions observed in the Slc26a4 c.919-2 A > G splicing mutation mouse model. However, despite these molecular achievements, hearing function did not show the expected improvement, consistent with observed pathology, including cochlear hair cell loss and elevated hearing thresholds. Consequently, our findings highlight the necessity for alternative genetic editing strategies to address hearing loss caused by the SLC26A4 c.919-2 A > G mutation.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132532","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

Intravesical nerve growth factor antisense therapy for bladder hypersensitivity induced by psychological stress. 膀胱内神经生长因子反义疗法治疗心理压力引起的膀胱超敏反应。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-03 DOI: 10.1038/s41434-024-00484-8

Tetsuichi Saito, Pradeep Tyagi, Tomonori Minagawa, Teruyuki Ogawa, Osamu Ishizuka, Naoki Yoshimura

{"title":"Intravesical nerve growth factor antisense therapy for bladder hypersensitivity induced by psychological stress.","authors":"Tetsuichi Saito, Pradeep Tyagi, Tomonori Minagawa, Teruyuki Ogawa, Osamu Ishizuka, Naoki Yoshimura","doi":"10.1038/s41434-024-00484-8","DOIUrl":"10.1038/s41434-024-00484-8","url":null,"abstract":"This study assessed the relationship between NGF expression in the bladder and bladder hypersensitivity caused by psychological stress using water avoidance stress (WAS) in rats by modulating the NGF expression using intravesical liposome-complexed NGF antisense oligonucleotide (OND) therapy on WAS-induced bladder dysfunction. Female Wistar rats were divided into control and WAS groups, the latter of which received WAS sessions for 10 days with or without the OND pretreatment. Rats underwent cystometry with or without intravesical application of low-dose protamine sulfate (LD-PS), or pain behavior measurements after LD-PS application. After functional evaluations, the bladder was harvested for histology and molecular studies. WAS rats with or without LD-PS showed shortened intercontraction intervals and increased pain behaviors compared to control rats, which was improved by OND-treatment. Histological studies revealed that LD-PS provoked urothelial exfoliation in WAS rats. Compared to controls, protein assay showed increased NGF levels, and RT-PCR showed increases of TRPV1 and TRPA1 and a decrease in Cx43 in WAS rat bladders, which were improved by OND-treatment. WAS caused bladder hypersensitivity, which was improved by NGF antisense OND treatment. NGF upregulation in the bladder may be a therapeutic target for the treatment of psychological stress-induced bladder dysfunction.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119529","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

Correction: AAV2-VEGF-B gene therapy failed to induce angiogenesis in ischemic porcine myocardium due to inflammatory responses. 更正：由于炎症反应，AAV2-VEGF-B 基因疗法未能诱导缺血猪心肌的血管生成。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-26 DOI: 10.1038/s41434-024-00481-x

Henna Korpela, Jaakko Lampela, Jonna Airaksinen, Niko Järveläinen, Satu Siimes, Kaisa Valli, Tiina Nieminen, Minttu Turunen, Maria Grönman, Antti Saraste, Juhani Knuuti, Mikko Hakulinen, Pekka Poutiainen, Vesa Kärjä, Jussi Nurro, Seppo Ylä-Herttuala

引用次数: 0

Lentiviral vector gene therapy and CFTR modulators show comparable effectiveness in cystic fibrosis rat airway models. 慢病毒载体基因疗法和 CFTR 调节剂在囊性纤维化大鼠气道模型中显示出相当的疗效。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-25 DOI: 10.1038/s41434-024-00480-y

Alexandra McCarron, Kak-Ming Ling, Samuel T Montgomery, Kelly M Martinovich, Patricia Cmielewski, Nathan Rout-Pitt, Anthony Kicic, David Parsons, Martin Donnelley

{"title":"Lentiviral vector gene therapy and CFTR modulators show comparable effectiveness in cystic fibrosis rat airway models.","authors":"Alexandra McCarron, Kak-Ming Ling, Samuel T Montgomery, Kelly M Martinovich, Patricia Cmielewski, Nathan Rout-Pitt, Anthony Kicic, David Parsons, Martin Donnelley","doi":"10.1038/s41434-024-00480-y","DOIUrl":"https://doi.org/10.1038/s41434-024-00480-y","url":null,"abstract":"Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures. Phe508del rat ALIs were treated with the modulator combination, elexacaftor-tezacaftor-ivacaftor (ETI), and separate groups of Phe508del and KO tracheal epithelial cells were treated with LV-CFTR followed by differentiation at ALI. Ussing chamber measurements were performed to assess CFTR function. ETI-treated Phe508del ALI cultures demonstrated CFTR function that was 59% of wild-type level, while gene-addition therapy restored Phe508del to 68% and KO to 47% of wild-type level, respectively. Our findings show that rat Phe508del-CFTR protein can be successfully rescued with ETI treatment, and that CFTR gene-addition therapy provides significant CFTR correction in Phe508del and KO ALI cultures to levels that were comparable to ETI. These findings highlight the potential of an LV vector-based gene therapy for the treatment of CF lung disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142055383","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: Oncolysis of pancreatic tumour cells by a γ34.5-deleted HSV-1 does not rely upon Ras-activation, but on the PI 3-kinase pathway 撤稿说明：删除了γ34.5的HSV-1对胰腺肿瘤细胞的肿瘤溶解不依赖于Ras激活，而是依赖于PI 3-激酶途径。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-16 DOI: 10.1038/s41434-024-00478-6

F. Sarinella, A. Calistri, P. Sette, G. Palù, C. Parolin

引用次数: 0

Correction: Alternative oxidase encoded by sequence-optimized and chemically-modified RNA transfected into mammalian cells is catalytically active 更正：转染到哺乳动物细胞中的经过序列优化和化学修饰的 RNA 所编码的替代氧化酶具有催化活性。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-15 DOI: 10.1038/s41434-024-00473-x

Luca Giordano, Manish K. Aneja, Natascha Sommer, Nasim Alebrahimdehkordi, Alireza Seraji, Norbert Weissmann, Carsten Rudolph, Christian Plank, Howard T. Jacobs, Marten Szibor

引用次数: 0

Efficacy of an AAV vector encoding a thermostable form of glucocerebrosidase in alleviating symptoms in a Gaucher disease mouse model 编码恒温型葡萄糖脑苷脂酶的 AAV 载体在减轻戈谢病小鼠模型症状方面的功效

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-15 DOI: 10.1038/s41434-024-00476-8

Ivan Milenkovic, Shani Blumenreich, Ariel Hochfelder, Aviya Azulay, Inbal E. Biton, Mirie Zerbib, Roni Oren, Michael Tsoory, Tammar Joseph, Sarel J. Fleishman, Anthony H. Futerman

{"title":"Efficacy of an AAV vector encoding a thermostable form of glucocerebrosidase in alleviating symptoms in a Gaucher disease mouse model","authors":"Ivan Milenkovic, Shani Blumenreich, Ariel Hochfelder, Aviya Azulay, Inbal E. Biton, Mirie Zerbib, Roni Oren, Michael Tsoory, Tammar Joseph, Sarel J. Fleishman, Anthony H. Futerman","doi":"10.1038/s41434-024-00476-8","DOIUrl":"10.1038/s41434-024-00476-8","url":null,"abstract":"Almost all attempts to date at gene therapy approaches for monogenetic disease have used the amino acid sequences of the natural protein. In the current study, we use a designed, thermostable form of glucocerebrosidase (GCase), the enzyme defective in Gaucher disease (GD), to attempt to alleviate neurological symptoms in a GD mouse that models type 3 disease, i.e. the chronic neuronopathic juvenile subtype. Upon injection of an AAVrh10 (adeno-associated virus, serotype rh10) vector containing the designed GCase (dGCase) into the left lateral ventricle of Gba−/−;Gbatg mice, a significant improvement in body weight and life-span was observed, compared to injection of the same mouse with the wild type enzyme (wtGCase). Moreover, a reduction in levels of glucosylceramide (GlcCer), and an increase in levels of GCase activity were seen in the right hemisphere of Gba−/−;Gbatg mice, concomitantly with a significant improvement in motor function, reduction of neuroinflammation and a reduction in mRNA levels of various genes shown previously to be elevated in the brain of mouse models of neurological forms of GD. Together, these data pave the way for the possible use of modified proteins in gene therapy for lysosomal storage diseases and other monogenetic disorders.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00476-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987784","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