Gene Therapy最新文献_第7页

Gene therapy corrects the neurological deficits of mice with sialidosis 基因疗法可纠正硅烷基糖苷酸沉积症小鼠的神经系统缺陷。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-02-07 DOI: 10.1038/s41434-024-00443-3

Wuh-Liang Hwu, Karine Chang, Yu-Han Liu, Hao-Chun Wang, Ni-Chung Lee, Yin-Hsiu Chien

{"title":"Gene therapy corrects the neurological deficits of mice with sialidosis","authors":"Wuh-Liang Hwu, Karine Chang, Yu-Han Liu, Hao-Chun Wang, Ni-Chung Lee, Yin-Hsiu Chien","doi":"10.1038/s41434-024-00443-3","DOIUrl":"10.1038/s41434-024-00443-3","url":null,"abstract":"Patients with sialidosis (mucolipidosis type I) type I typically present with myoclonus, seizures, ataxia, cherry-red spots, and blindness because of mutations in the neuraminidase 1 (NEU1) gene. Currently, there is no treatment for sialidosis. In this study, we developed an adeno-associated virus (AAV)-mediated gene therapy for a Neu1 knockout (Neu1−/−) mouse model of sialidosis. The vector, AAV9-P3-NP, included the human NEU1 promoter, NEU1 cDNA, IRES, and CTSA cDNA. Untreated Neu1−/− mice showed astrogliosis and microglial LAMP1 accumulation in the nervous system, including brain, spinal cord, and dorsal root ganglion, together with impaired motor function. Coexpression of NEU1 and protective protein/cathepsin A (PPCA) in neonatal Neu1−/− mice by intracerebroventricular injection, and less effective by facial vein injection, decreased astrogliosis and LAMP1 accumulation in the nervous system and improved rotarod performance of the treated mice. Facial vein injection also improved the grip strength and survival of Neu1−/− mice. Therefore, cerebrospinal fluid delivery of AAV9-P3-NP, which corrects the neurological deficits of mice with sialidosis, could be a suitable treatment for patients with sialidosis type I.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 5-6","pages":"263-272"},"PeriodicalIF":5.1,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697264","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

Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/− 临床前剂量反应研究显示，NR2E3 可减轻视网膜色素变性小鼠模型 RhoP23H+/ 的视网膜变性。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-26 DOI: 10.1038/s41434-024-00440-6

Shannon M. McNamee, Natalie P. Chan, Monica Akula, Marielle O. Avola, Maiya Whalen, Kaden Nystuen, Pushpendra Singh, Arun K. Upadhyay, Margaret M. DeAngelis, Neena B. Haider

{"title":"Preclinical dose response study shows NR2E3 can attenuate retinal degeneration in the retinitis pigmentosa mouse model RhoP23H+/−","authors":"Shannon M. McNamee, Natalie P. Chan, Monica Akula, Marielle O. Avola, Maiya Whalen, Kaden Nystuen, Pushpendra Singh, Arun K. Upadhyay, Margaret M. DeAngelis, Neena B. Haider","doi":"10.1038/s41434-024-00440-6","DOIUrl":"10.1038/s41434-024-00440-6","url":null,"abstract":"Retinitis pigmentosa (RP) is a heterogeneous disease and the main cause of vision loss within the group of inherited retinal diseases (IRDs). IRDs are a group of rare disorders caused by mutations in one or more of over 280 genes which ultimately result in blindness. Modifier genes play a key role in modulating disease phenotypes, and mutations in them can affect disease outcomes, rate of progression, and severity. Our previous studies have demonstrated that the nuclear hormone receptor 2 family e, member 3 (Nr2e3) gene reduced disease progression and loss of photoreceptor cell layers in RhoP23H−/− mice. This follow up, pharmacology study evaluates a longitudinal NR2E3 dose response in the clinically relevant heterozygous RhoP23H mouse. Reduced retinal degeneration and improved retinal morphology was observed 6 months following treatment evaluating three different NR2E3 doses. Histological and immunohistochemical analysis revealed regions of photoreceptor rescue in the treated retinas of RhoP23H+/− mice. Functional assessment by electroretinogram (ERG) showed attenuated photoreceptor degeneration with all doses. This study demonstrates the effectiveness of different doses of NR2E3 at reducing retinal degeneration and informs dose selection for clinical trials of RhoP23H-associated RP.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 5-6","pages":"255-262"},"PeriodicalIF":5.1,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-024-00440-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139564014","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 a stable Sf9 insect cell line to produce VSV-G pseudotyped baculoviruses 开发稳定的 Sf9 昆虫细胞系以生产 VSV-G 假型杆状病毒。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-26 DOI: 10.1038/s41434-024-00442-4

María del Pilar Plastine, Sabrina Amalfi, María Gabriela López, María José Gravisaco, Oscar Taboga, Victoria Alfonso

{"title":"Development of a stable Sf9 insect cell line to produce VSV-G pseudotyped baculoviruses","authors":"María del Pilar Plastine, Sabrina Amalfi, María Gabriela López, María José Gravisaco, Oscar Taboga, Victoria Alfonso","doi":"10.1038/s41434-024-00442-4","DOIUrl":"10.1038/s41434-024-00442-4","url":null,"abstract":"Baculoviruses have shown great potential as gene delivery vectors in mammals, although their effectiveness in transferring genes varies across different cell lines. A widely employed strategy to improve transduction efficiency is the pseudotyping of viral vectors. In this study, we aimed to develop a stable Sf9 insect cell line that inducibly expresses the G-protein of the vesicular stomatitis virus to pseudotype budded baculoviruses. It was obtained by inserting the VSV-G gene under the control of the very strong and infection-inducible pXXL promoter and was subsequently diluted to establish oligoclonal lines, which were selected by the fusogenic properties of VSV-G and its expression levels in infected cells and purified budded virions. Next, to enhance the performance of the cell line, the infection conditions under which functional pseudotyped baculoviruses are obtained were optimized. Finally, different baculoviruses were pseudotyped and the expression of the transgene was quantified in mammalian cells of diverse origins using flow cytometry. The transduction efficiency of pseudotyped baculovirus consistently increased across all tested mammalian cell lines compared with control viruses. These findings demonstrate the feasibility and advantages of improving gene delivery performance without the need to insert the pseudotyping gene into the baculoviral genomes.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 3-4","pages":"187-194"},"PeriodicalIF":5.1,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567008","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: Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates 更正：以 SIV 为靶标的 CRISPR 在非人灵长类动物中的临床前安全性和生物分布。

IF 4.6 3区医学

Gene Therapy Pub Date : 2024-01-12 DOI: 10.1038/s41434-023-00438-6

Tricia H. Burdo, Chen Chen, Rafal Kaminski, Ilker K. Sariyer, Pietro Mancuso, Martina Donadoni, Mandy D. Smith, Rahsan Sariyer, Maurizio Caocci, Shuren Liao, Hong Liu, Wenwen Huo, Huaqing Zhao, John Misamore, Mark G. Lewis, Vahan Simonyan, Elaine E. Thompson, Ethan Y. Xu, Thomas J. Cradick, Jennifer Gordon, Kamel Khalili

引用次数: 0

AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes 用于视网膜神经节细胞靶向传递治疗基因的 AAV2 载体优化。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-10 DOI: 10.1038/s41434-023-00436-8

Brahim Chaqour, Thu T. Duong, Jipeng Yue, Tehui Liu, David Camacho, Kimberly E. Dine, Julian Esteve-Rudd, Scott Ellis, Jean Bennett, Kenneth S. Shindler, Ahmara G. Ross

{"title":"AAV2 vector optimization for retinal ganglion cell-targeted delivery of therapeutic genes","authors":"Brahim Chaqour, Thu T. Duong, Jipeng Yue, Tehui Liu, David Camacho, Kimberly E. Dine, Julian Esteve-Rudd, Scott Ellis, Jean Bennett, Kenneth S. Shindler, Ahmara G. Ross","doi":"10.1038/s41434-023-00436-8","DOIUrl":"10.1038/s41434-023-00436-8","url":null,"abstract":"Recombinant adeno-associated virus (AAV)-2 has significant potential as a delivery vehicle of therapeutic genes to retinal ganglion cells (RGCs), which are key interventional targets in optic neuropathies. Here we show that when injected intravitreally, AAV2 engineered with a reporter gene driven by cytomegalovirus (CMV) enhancer and chicken β-actin (CBA) promoters, displays ubiquitous and high RGC expression, similar to its synthetic derivative AAV8BP2. A novel AAV2 vector combining the promoter of the human RGC-selective γ-synuclein (hSNCG) gene and woodchuck hepatitis post-transcriptional regulatory element (WPRE) inserted upstream and downstream of a reporter gene, respectively, induces widespread transduction and strong transgene expression in RGCs. High transduction efficiency and selectivity to RGCs is further achieved by incorporating in the vector backbone a leading CMV enhancer and an SV40 intron at the 5’ and 3’ ends, respectively, of the reporter gene. As a delivery vehicle of hSIRT1, a 2.2-kb therapeutic gene with anti-apoptotic, anti-inflammatory and anti-oxidative stress properties, this recombinant vector displayed improved transduction efficiency, a strong, widespread and selective RGC expression of hSIRT1, and increased RGC survival following optic nerve crush. Thus, AAV2 vector carrying hSNCG promoter with additional regulatory sequences may offer strong potential for enhanced effects of candidate gene therapies targeting RGCs.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 3-4","pages":"175-186"},"PeriodicalIF":5.1,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139416829","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

Analysis and comparative evaluation of expedited programs for gene therapy products: insights from the United States, the European Union, Japan, and South Korea 基因治疗产品加速计划的分析和比较评估：美国、欧盟、日本和韩国的见解

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-10 DOI: 10.1038/s41434-023-00437-7

Hyeokgyo Jeong, Sujata Purja, Eunyoung Kim

{"title":"Analysis and comparative evaluation of expedited programs for gene therapy products: insights from the United States, the European Union, Japan, and South Korea","authors":"Hyeokgyo Jeong, Sujata Purja, Eunyoung Kim","doi":"10.1038/s41434-023-00437-7","DOIUrl":"10.1038/s41434-023-00437-7","url":null,"abstract":"Gene therapy products (GTPs) used for incurable diseases can be expedited for early commercialization to fulfill unmet needs. This study analyzed the expedited programs available for GTPs in the US, EU, Japan, and South Korea using their regulatory authorities’ websites, related regulations, and documents. In total, there were five expedited programs available for GTPs in the US, four in the EU, and three in both Japan and South Korea, of which four are tailored for GTPs. These programs, sharing similar objectives, can be categorized as those expediting drug development, review, and approval. However, variations are observed in eligibility criteria, specific benefits, and post-marketing study conditions across regulatory authorities. Additionally, the criteria for orphan drug designation for a rare disease differs in prevalence thresholds, incentive offered, and marketing exclusivity period. Overall, 19 GTPs were approved–13 in the US, 14 in the EU, eight in Japan, and three in South Korea–with majority obtaining regulatory approval through at least one expedited program. Therefore, future studies can analyze whether acquiring multiple expedited programs accelerates the drug development and commercialization of GTPs compared with when only one expedited program is processed. Additionally, inter-authority scientific discussion is encouraged for harmonization of expedited program requirements.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 5-6","pages":"242-254"},"PeriodicalIF":5.1,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139415328","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: Long noncoding RNA RBMS3-AS3 acts as a microRNA-4534 sponge to inhibit the progression of prostate cancer by upregulating VASH1 撤稿说明：长非编码 RNA RBMS3-AS3 可作为 microRNA-4534 的海绵，通过上调 VASH1 抑制前列腺癌的进展。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-09 DOI: 10.1038/s41434-023-00439-5

Zhenming Jiang, Yuxi Zhang, Xi Chen, Pingeng Wu, Dong Chen

引用次数: 0

Ghrelin mediated cardioprotection using in vitro models of oxidative stress 利用体外氧化应激模型研究胃泌素介导的心脏保护作用

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-04 DOI: 10.1038/s41434-023-00435-9

Cindy Y. Kok, George Ghossein, Sindhu Igoor, Renuka Rao, Tracy Titus, Shinya Tsurusaki, James JH. Chong, Eddy Kizana

{"title":"Ghrelin mediated cardioprotection using in vitro models of oxidative stress","authors":"Cindy Y. Kok, George Ghossein, Sindhu Igoor, Renuka Rao, Tracy Titus, Shinya Tsurusaki, James JH. Chong, Eddy Kizana","doi":"10.1038/s41434-023-00435-9","DOIUrl":"10.1038/s41434-023-00435-9","url":null,"abstract":"Ghrelin is commonly known as the ‘hunger hormone’ due to its role in stimulating food intake in humans. However, the roles of ghrelin extend beyond regulating hunger. Our aim was to investigate the ability of ghrelin to protect against hydrogen peroxide (H2O2), a reactive oxygen species commonly associated with cardiac injury. An in vitro model of oxidative stress was developed using H2O2 injured H9c2 cells. Despite lentiviral ghrelin overexpression, H9c2 cell viability and mitochondrial function were not protected following H2O2 injury. We found that H9c2 cells lack expression of the preproghrelin cleavage enzyme prohormone convertase 1 (encoded by PCSK1), required to convert ghrelin to its active form. In contrast, we found that primary rat cardiomyocytes do express PCSK1 and were protected from H2O2 injury by lentiviral ghrelin overexpression. In conclusion, we have shown that ghrelin expression can protect primary rat cardiomyocytes against H2O2, though this effect was not observed in other cell types tested.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 3-4","pages":"165-174"},"PeriodicalIF":5.1,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00435-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139093662","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: Cost of gene therapy 更正：基因治疗的成本。

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-04 DOI: 10.1038/s41434-023-00432-y

Patrick T. Harrison, Theodore Friedmann

引用次数: 0

CRISPR/Cas9-mediated base editors and their prospects for mitochondrial genome engineering CRISPR/Cas9 介导的碱基编辑器及其在线粒体基因组工程中的应用前景

IF 5.1 3区医学

Gene Therapy Pub Date : 2024-01-04 DOI: 10.1038/s41434-023-00434-w

Shahin Eghbalsaied, Clancy Lawler, Björn Petersen, Raul A. Hajiyev, Steve R. Bischoff, Stephen Frankenberg

{"title":"CRISPR/Cas9-mediated base editors and their prospects for mitochondrial genome engineering","authors":"Shahin Eghbalsaied, Clancy Lawler, Björn Petersen, Raul A. Hajiyev, Steve R. Bischoff, Stephen Frankenberg","doi":"10.1038/s41434-023-00434-w","DOIUrl":"10.1038/s41434-023-00434-w","url":null,"abstract":"Base editors are a type of double-stranded break (DSB)-free gene editing technology that has opened up new possibilities for precise manipulation of mitochondrial DNA (mtDNA). This includes cytosine and adenosine base editors and more recently guanosine base editors. Because of having low off-target and indel rates, there is a growing interest in developing and evolving this research field. Here, we provide a detailed update on DNA base editors. While base editing has widely been used for nuclear genome engineering, the growing interest in applying this technology to mitochondrial DNA has been faced with several challenges. While Cas9 protein has been shown to enter mitochondria, use of smaller Cas proteins, such as Cas12a, has higher import efficiency. However, sgRNA transfer into mitochondria is the most challenging step. sgRNA structure and ratio of Cas protein to sgRNA are both important factors for efficient sgRNA entry into mitochondria. In conclusion, while there are still several challenges to be addressed, ongoing research in this field holds the potential for new treatments and therapies for mitochondrial disorders.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"31 5-6","pages":"209-223"},"PeriodicalIF":5.1,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41434-023-00434-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139093507","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