Gene Therapy最新文献_第3页

Suppression of matrigel-induced choroidal neovascularization by AAV delivery of a novel anti-Scg3 antibody 通过 AAV 释放新型抗 Scg3 抗体抑制 matrigel 诱导的脉络膜新生血管。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-27 DOI: 10.1038/s41434-024-00491-9

Chengchi Huang, Avinash Kaur, Liyang Ji, Hong Tian, Keith A. Webster, Wei Li

{"title":"Suppression of matrigel-induced choroidal neovascularization by AAV delivery of a novel anti-Scg3 antibody","authors":"Chengchi Huang, Avinash Kaur, Liyang Ji, Hong Tian, Keith A. Webster, Wei Li","doi":"10.1038/s41434-024-00491-9","DOIUrl":"10.1038/s41434-024-00491-9","url":null,"abstract":"Efforts to develop gene therapy for long-term treatment of neovascular disease are hampered by ongoing concerns that biologics against vascular endothelial growth factor (VEGF) inhibit both physiological and pathological angiogenesis and are therefore at elevated risk of adverse side effects. A potential solution is to develop disease-targeted gene therapy. Secretogranin III (Scg3), a unique disease-restricted angiogenic factor described by our group, contributes significantly to ocular neovascular disease. We have shown that Scg3 blockade with a monoclonal antibody Fab fragment (Fab) stringently inhibits pathological angiogenesis without affecting healthy vessels. Here we tested the therapeutic efficacy of adeno-associated virus (AAV)-anti-Scg3Fab to block choroidal neovascularization (CNV) induced by subretinal injection of Matrigel in a mouse model. Intravitreal AAV-anti-Scg3Fab significantly reduced CNV and suppressed CNV-associated leukocyte infiltration and macrophage activation. The efficacy and anti-inflammatory effects were equivalent to those achieved by positive control AAV-aflibercept against VEGF. Efficacies of AAV-anti-Scg3Fab and AAV-aflibercept were sustained over 4 months post AAV delivery. The findings support development of AAV-anti-Scg3 as an alternative to AAV-anti-VEGF with equivalent efficacy and potentially safer mechanism of action.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"587-593"},"PeriodicalIF":4.6,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345033","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

Gene therapy of Dent disease type 1 in newborn ClC-5 null mice for sustained transgene expression and gene therapy effects 对新生 ClC-5 基因无效小鼠进行 1 型 Dent 病基因治疗，以获得持续的转基因表达和基因治疗效果。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-25 DOI: 10.1038/s41434-024-00490-w

Pin Lyu, Manish Kumar Yadav, Kyung Whan Yoo, Cuili Jiang, Qingqi Li, Anthony Atala, Baisong Lu

{"title":"Gene therapy of Dent disease type 1 in newborn ClC-5 null mice for sustained transgene expression and gene therapy effects","authors":"Pin Lyu, Manish Kumar Yadav, Kyung Whan Yoo, Cuili Jiang, Qingqi Li, Anthony Atala, Baisong Lu","doi":"10.1038/s41434-024-00490-w","DOIUrl":"10.1038/s41434-024-00490-w","url":null,"abstract":"Dent disease type 1 is caused by changes in the chloride voltage-gated channel 5 (CLCN5) gene on chromosome X, resulting in the lack or dysfunction of chloride channel ClC-5. Individuals affected by Dent disease type 1 show proteinuria and hypercalciuria. Previously we found that lentiviral vector-mediated hCLCN5 cDNA supplementary therapy in ClC-5 null mice was effective only for three months following gene delivery, and the therapeutic effects disappeared four months after treatment, most likely due to immune responses to the ClC-5 proteins expressed in the treated cells. Here we tried two strategies to reduce possible immune responses: 1) confining the expression of ClC-5 expression to the tubular cells with tubule-specific Npt2a and Sglt2 promoters, and 2) performing gene therapy in newborn mutant mice whose immune system has not fully developed. We found that although Npt2a and Sglt2 promoters successfully drove ClC-5 expression in the kidneys of the mutant mice, the treatment did not ameliorate the phenotypes. However, gene delivery to the kidneys of newborn Clcn5 mutant mice enabled long-term transgene expression and phenotype improvement. Our data suggest that performing gene therapy on Dent disease affected subjects soon after birth could be a promising strategy to attenuate immune responses in Dent disease type 1 gene therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"563-571"},"PeriodicalIF":4.6,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00490-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345031","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

Precision medicine: toward restoring fat with gene therapy in inherited lipodystrophy 精准医学：利用基因疗法恢复遗传性脂肪营养不良症患者的脂肪。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-24 DOI: 10.1038/s41434-024-00489-3

Xavier Prieur, Lei Cao

引用次数: 0

BRD9 promotes the progression of gallbladder cancer via CST1 upregulation and interaction with FOXP1 through the PI3K/AKT pathway and represents a therapeutic target BRD9 通过 CST1 上调和与 FOXP1 的相互作用，通过 PI3K/AKT 通路促进胆囊癌的进展，是一个治疗靶点。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-21 DOI: 10.1038/s41434-024-00488-4

Jing Qiang, Cheng Zhao, Liu-Qing Shi, Si-Rui Sun, Hua-Kai Wang, Shi-Lei Liu, Zi-Yi Yang, Ping Dong, Shan-Shan Xiang, Jian-Dong Wang, Yi-Jun Shu

{"title":"BRD9 promotes the progression of gallbladder cancer via CST1 upregulation and interaction with FOXP1 through the PI3K/AKT pathway and represents a therapeutic target","authors":"Jing Qiang, Cheng Zhao, Liu-Qing Shi, Si-Rui Sun, Hua-Kai Wang, Shi-Lei Liu, Zi-Yi Yang, Ping Dong, Shan-Shan Xiang, Jian-Dong Wang, Yi-Jun Shu","doi":"10.1038/s41434-024-00488-4","DOIUrl":"10.1038/s41434-024-00488-4","url":null,"abstract":"Gallbladder cancer (GBC) is highly aggressive and has poor prognosis, with most patients only diagnosed at an advanced stage. Furthermore, treatment options are limited, and their effect is unsatisfactory. Bromodomain-containing protein (BRD) is an epigenetic regulator that plays a carcinogenic role in several tumors, including squamous cell lung cancer, acute myeloid leukemia, synovial sarcoma, and malignant rhabdomyosarcoma. However, the expression, biological function, and molecular mechanisms of action of BRD9 in GBC are still unknown. Kaplan–Meier analysis, qRT-PCR, and analysis of clinical features were used to assess the clinical significance of BRD9 in GBC. Cell Counting Kit-8 and colony formation assays were performed to determine the effects of BRD9 on cell growth. The functional role of BRD9 in GBC was explored using qRT-PCR, western blotting, siRNA, and CHIP-qPCR. mRNA sequencing was performed to explore the underlying mechanisms of BRD9, and a nude mouse model of GBC was established to explore the anti-tumor effects of the BRD9 inhibitor I-BRD9 in vivo. BRD9 expression was elevated in GBC tissues compared with adjacent non-tumor tissues, and high BRD9 expression was associated with poor prognosis in patients with GBC. BRD9 knockdown by siRNA significantly decreased cell growth. Targeting BRD9 with I-BRD9 inhibited the proliferation of GBC cells without significant toxic effects. Additionally, I-BRD9 treatment suppressed CST1 expression in GBC cell lines, thereby inhibiting the PI3K-AKT pathway. The transcription factor FOXP1 was found to interact with BRD9 to regulate CST1 expression. Collectively, these results suggest that BRD9 may be a promising biomarker and therapeutic target for GBC.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 11-12","pages":"594-606"},"PeriodicalIF":4.6,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00488-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284337","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: Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa 更正：在多种视网膜色素变性模型中，Nr2e3 是一种能挽救视网膜变性并促进平衡的遗传修饰因子。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-18 DOI: 10.1038/s41434-024-00482-w

Sujun Li, Shyamtanu Datta, Emily Brabbit, Zoe Love, Victoria Woytowicz, Kyle Flattery, Jessica Capri, Katie Yao, Siqi Wu, Michael Imboden, Arun Upadhyay, Rasappa Arumugham, Wallace B. Thoreson, Margaret M. DeAngelis, Neena B. Haider

引用次数: 0

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 4.6 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: Inhibition of microRNA-495 suppresses chondrocyte apoptosis through activation of the NF-κB signaling pathway by regulating CCL4 in osteoarthritis 撤稿说明：抑制microRNA-495可通过调节骨关节炎中的CCL4，激活NF-κB信号通路，从而抑制软骨细胞凋亡。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-09-09 DOI: 10.1038/s41434-024-00475-9

Da-Wei Yang, Gui-Bin Qian, Ming-Jiu Jiang, Peng Wang, Kun-Zheng Wang

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":"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":"31 11-12","pages":"572-579"},"PeriodicalIF":4.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00485-7.pdf","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":"OA","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":"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