Gene Therapy最新文献_第3页

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":"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":"31 11-12","pages":"531-540"},"PeriodicalIF":4.6,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00483-9.pdf","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":"OA","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":"31 11-12","pages":"607-613"},"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":"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":"31 11-12","pages":"553-559"},"PeriodicalIF":4.6,"publicationDate":"2024-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00480-y.pdf","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":"OA","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":"31 9-10","pages":"439-444"},"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

The AAV2.7m8 capsid packages a higher degree of heterogeneous vector genomes than AAV2 与 AAV2 相比，AAV2.7m8 的包囊包装异质载体基因组的程度更高。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-12 DOI: 10.1038/s41434-024-00477-7

Mengtian Cui, Qin Su, Mitchell Yip, Jackson McGowan, Claudio Punzo, Guangping Gao, Phillip W. L. Tai

{"title":"The AAV2.7m8 capsid packages a higher degree of heterogeneous vector genomes than AAV2","authors":"Mengtian Cui, Qin Su, Mitchell Yip, Jackson McGowan, Claudio Punzo, Guangping Gao, Phillip W. L. Tai","doi":"10.1038/s41434-024-00477-7","DOIUrl":"10.1038/s41434-024-00477-7","url":null,"abstract":"Recombinant adeno-associated virus (rAAV) vectors are currently the only proven vehicles for treating ophthalmological diseases through gene therapy. A wide range of gene therapy programs that target ocular diseases are currently being pursued. Nearly 20 years of research have gone into enhancing the efficacy of targeting retinal tissues and improving transgene delivery to specific cell types. The engineered AAV capsid, AAV2.7m8 is currently among the best capsids for transducing the retina following intravitreal (IVT) injection. However, adverse effects, including intraocular inflammation, have been reported following retinal administration of AAV2.7m8 vectors in clinical trials. Furthermore, we have consistently observed that AAV2.7m8 exhibits low packaging titers irrespective of the vector construct design. In this report, we found that AAV2.7m8 packages vector genomes with a higher degree of heterogeneity than AAV2. We also found that genome-loaded AAV2.7m8 stimulated the infiltration of microglia in mouse retinas following IVT administration, while the response to genome-loaded AAV2 and empty AAV2.7m8 capsids produced much milder responses. This finding suggests that IVT administration of AAV2.7m8 vectors may stimulate retinal immune responses in part because of its penchant to package and deliver non-unit length genomes.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 9-10","pages":"489-498"},"PeriodicalIF":4.6,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00477-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970988","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

Correction: Andrew C. G. Porter (1955–2023) 更正：安德鲁-波特（1955-2023）。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-07 DOI: 10.1038/s41434-024-00474-w

Rafael J. Yáñez-Muñoz, Jane E. Itzhaki

引用次数: 0

Correction: Limited potential of AAV-mediated gene therapy in transducing human mesenchymal stem cells for bone repair applications 更正：AAV 介导的基因疗法在转导人类间充质干细胞用于骨修复方面的潜力有限。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-08-01 DOI: 10.1038/s41434-024-00472-y

Sofia Bougioukli, Morgan Chateau, Heidy Morales, Venus Vakhshori, Osamu Sugiyama, Daniel Oakes, Donald Longjohn, Paula Cannon, Jay R. Lieberman

引用次数: 0