Gene Therapy最新文献_第10页

Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system 诱导多能干细胞衍生树突状细胞疫苗疗法在泛素-蛋白酶体系统上进行基因修饰

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-03-23 DOI: 10.1038/s41434-023-00388-z

Shinta Tominaga, Toshiyasu Ojima, Motoki Miyazawa, Hiromitsu Iwamoto, Junya Kitadani, Shimpei Maruoka, Keiji Hayata, Hiroki Yamaue

{"title":"Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system","authors":"Shinta Tominaga, Toshiyasu Ojima, Motoki Miyazawa, Hiromitsu Iwamoto, Junya Kitadani, Shimpei Maruoka, Keiji Hayata, Hiroki Yamaue","doi":"10.1038/s41434-023-00388-z","DOIUrl":"10.1038/s41434-023-00388-z","url":null,"abstract":"We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10080264","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: Adjuvant properties of IFN-γ and GM-CSF in the scFv6.C4 DNA vaccine against CEA-expressing tumors 更正：针对 CEA 表达肿瘤的 scFv6.C4 DNA 疫苗中 IFN-γ 和 GM-CSF 的佐剂特性

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-03-20 DOI: 10.1038/s41434-023-00396-z

Bianca Ferrarini Zanetti, Camila Pontes Ferreira, José Ronnie Carvalho Vasconcelos, Sang Won Han

引用次数: 0

Gene augmentation for autosomal dominant retinitis pigmentosa using rhodopsin genomic loci nanoparticles in the P23H+/− knock-in murine model 在 P23H+/- 基因敲入小鼠模型中使用视网膜基因组位点纳米颗粒进行常染色体显性色素性视网膜炎的基因扩增

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-03-20 DOI: 10.1038/s41434-023-00394-1

Simna SP, Rajendra N. Mitra, Min Zheng, Jared D. Chrispell, Kai Wang, Yong-Su Kwon, Ellen R. Weiss, Zongchao Han

{"title":"Gene augmentation for autosomal dominant retinitis pigmentosa using rhodopsin genomic loci nanoparticles in the P23H+/− knock-in murine model","authors":"Simna SP, Rajendra N. Mitra, Min Zheng, Jared D. Chrispell, Kai Wang, Yong-Su Kwon, Ellen R. Weiss, Zongchao Han","doi":"10.1038/s41434-023-00394-1","DOIUrl":"10.1038/s41434-023-00394-1","url":null,"abstract":"Gene therapy for autosomal dominant retinitis pigmentosa (adRP) is challenged by the dominant inheritance of the mutant genes, which would seemingly require a combination of mutant suppression and wild-type replacement of the appropriate gene. We explore the possibility that delivery of a nanoparticle (NP)-mediated full-length mouse genomic rhodopsin (gRho) or human genomic rhodopsin (gRHO) locus can overcome the dominant negative effects of the mutant rhodopsin in the clinically relevant P23H+/−-knock-in heterozygous mouse model. Our results demonstrate that mice in both gRho and gRHO NP-treated groups exhibit significant structural and functional recovery of the rod photoreceptors, which lasted for 3 months post-injection, indicating a promising reduction in photoreceptor degeneration. We performed miRNA transcriptome analysis using next generation sequencing and detected differentially expressed miRNAs as a first step towards identifying miRNAs that could potentially be used as rhodopsin gene expression enhancers or suppressors for sustained photoreceptor rescue. Our results indicate that delivering an intact genomic locus as a transgene has a greater chance of success compared to the use of the cDNA for treatment of this model of adRP, emphasizing the importance of gene augmentation using a gDNA that includes regulatory elements.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10132703","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

Comment on: Premature delivery in the domestic sow in response to in utero delivery of AAV9 to fetal piglets 评论：家养母猪早产对胎儿在子宫内注射 AAV9 的反应

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-03-14 DOI: 10.1038/s41434-023-00395-0

Apeksha Dave, Cara L. Berkowitz, Valerie L. Luks, Brandon M. White, Rohan Palanki, Marco D. Carpenter, John S. Riley, Sourav K. Bose, Haiying Li, Li Li, Pallavi V. Menon, Shiva Teerdhala, Mina Ebrahimi, Philip W. Zoltick, William H. Peranteau

引用次数: 0

Terminal hairpins improve protein expression in IRES-initiated mRNA in the absence of a cap and polyadenylated tail 末端发夹能在没有帽子和多聚腺苷酸尾部的情况下提高 IRES 启动的 mRNA 中蛋白质的表达量

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-02-24 DOI: 10.1038/s41434-023-00391-4

Victor Solodushko, Brian Fouty

引用次数: 0

Novel rAAV vector mediated intrathecal HGF delivery has an impact on neuroimmune modulation in the ALS motor cortex with TDP-43 pathology 新型 rAAV 向量介导的鞘内 HGF 给药对伴有 TDP-43 病理的 ALS 运动皮层的神经免疫调节有影响

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-02-24 DOI: 10.1038/s41434-023-00383-4

Barış Genç, Boram Nho, Hana Seung, Benjamin Helmold, Huiwon Park, Öge Gözütok, Seunghyun Kim, Jinil Park, Sanghyun Ye, Haneul Lee, Nayeon Lee, Seung-Shin Yu, Sunyoung Kim, Junghun Lee, Hande Özdinler

{"title":"Novel rAAV vector mediated intrathecal HGF delivery has an impact on neuroimmune modulation in the ALS motor cortex with TDP-43 pathology","authors":"Barış Genç, Boram Nho, Hana Seung, Benjamin Helmold, Huiwon Park, Öge Gözütok, Seunghyun Kim, Jinil Park, Sanghyun Ye, Haneul Lee, Nayeon Lee, Seung-Shin Yu, Sunyoung Kim, Junghun Lee, Hande Özdinler","doi":"10.1038/s41434-023-00383-4","DOIUrl":"10.1038/s41434-023-00383-4","url":null,"abstract":"Recombinant adeno-associated virus (rAAV)-based gene therapies offer an immense opportunity for rare diseases, such as amyotrophic lateral sclerosis (ALS), which is defined by the loss of the upper and the lower motor neurons. Here, we describe generation, characterization, and utilization of a novel vector system, which enables expression of the active form of hepatocyte growth factor (HGF) under EF-1α promoter with bovine growth hormone (bGH) poly(A) sequence and is effective with intrathecal injections. HGF’s role in promoting motor neuron survival had been vastly reported. Therefore, we investigated whether intrathecal delivery of HGF would have an impact on one of the most common pathologies of ALS: the TDP-43 pathology. Increased astrogliosis, microgliosis and progressive upper motor neuron loss are important consequences of ALS in the motor cortex with TDP-43 pathology. We find that cortex can be modulated via intrathecal injection, and that expression of HGF reduces astrogliosis, microgliosis in the motor cortex, and help restore ongoing UMN degeneration. Our findings not only introduce a novel viral vector for the treatment of ALS, but also demonstrate modulation of motor cortex by intrathecal viral delivery, and that HGF treatment is effective in reducing astrogliosis and microgliosis in the motor cortex of ALS with TDP-43 pathology.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10132690","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

Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9 利用 CjCas9 去除弗里德里希共济失调小鼠模型心脏中的 GAA 重复基因

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-02-14 DOI: 10.1038/s41434-023-00387-0

Pouiré Yaméogo, Catherine Gérard, Nathalie Majeau, Jacques P. Tremblay

引用次数: 1

Sonoselective delivery using ultrasound and microbubbles combined with intravenous rAAV9 CLDN5-GFP does not increase endothelial gene expression 使用超声波和微气泡结合静脉注射 rAAV9 CLDN5-GFP 的声选择性递送不会增加内皮基因的表达。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-02-13 DOI: 10.1038/s41434-023-00389-y

Rikke Hahn Kofoed, Elizabeth M. Simpson, Kullervo Hynynen, Isabelle Aubert

{"title":"Sonoselective delivery using ultrasound and microbubbles combined with intravenous rAAV9 CLDN5-GFP does not increase endothelial gene expression","authors":"Rikke Hahn Kofoed, Elizabeth M. Simpson, Kullervo Hynynen, Isabelle Aubert","doi":"10.1038/s41434-023-00389-y","DOIUrl":"10.1038/s41434-023-00389-y","url":null,"abstract":"Transcranial ultrasound combined with intravenous microbubbles can be used to increase blood-brain barrier permeability or, at lower pressures, to mediate sonoselective gene delivery to endothelial cells. Previously, sonoselective gene delivery with plasmid-coated microbubbles as gene carriers resulted in transient transgene expression in the brain endothelium. We investigated the potential of recombinant adeno-associated virus 9 (rAAV9), a serotype known for its efficient transduction and long-term transgene expression, for sonoselective gene delivery to endothelial cells of the brain. We found that rAAV9 led to gene delivery to brain endothelial cells following intravenous administration at a dosage of 1 × 1011 GC/g. However, the sonoselective gene delivery approach with intravenous rAAV9, using the same parameters as previously used for plasmid delivery, did not increase transgene expression in brain endothelial cells targeted. These results suggest that intravenous rAAV9 are using mechanisms of entry into the cerebrovasculature that are not significantly influenced by sonoselective treatments known to facilitate endothelial cell entry of plasmids coated onto microbubbles.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10698537","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

Homology-directed repair of an MYBPC3 gene mutation in a rat model of hypertrophic cardiomyopathy 肥厚型心肌病大鼠模型中 MYBPC3 基因突变的同源定向修复

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-02-10 DOI: 10.1038/s41434-023-00384-3

Jiali Nie, Yu Han, Zhiyuan Jin, Weijian Hang, Hongyang Shu, Zheng Wen, Li Ni, Dao Wen Wang

{"title":"Homology-directed repair of an MYBPC3 gene mutation in a rat model of hypertrophic cardiomyopathy","authors":"Jiali Nie, Yu Han, Zhiyuan Jin, Weijian Hang, Hongyang Shu, Zheng Wen, Li Ni, Dao Wen Wang","doi":"10.1038/s41434-023-00384-3","DOIUrl":"10.1038/s41434-023-00384-3","url":null,"abstract":"Variants in myosin-binding protein C3 (MYBPC3) gene are a main cause of hypertrophic cardiomyopathy (HCM), accounting for 30% to 40% of the total number of HCM mutations. Gene editing represents a potential permanent cure for HCM. The aim of this study was to investigate whether genome editing of MYBPC3 using the CRISPR/Cas9 system in vivo could rescue the phenotype of rats with HCM. We generated a rat model of HCM (“1098hom”) that carried an Mybpc3 premature termination codon mutation (p.W1098x) discovered in a human HCM pedigree. On postnatal day 3, the CRISPR/Cas9 system was introduced into rat pups by a single dose of AAV9 particles to correct the variant using homology-directed repair (HDR). Analysis was performed 6 months after AAV9 injection. The 1098hom rats didn’t express MYBPC3 protein and developed an HCM phenotype with increased ventricular wall thickness and diminished cardiac function. Importantly, CRISPR HDR genome editing corrected 3.56% of total mutations, restored MYBPC3 protein expression by 2.12%, and normalized the HCM phenotype of 1098hom rats. Our work demonstrates that the HDR strategy is a promising approach for treating HCM associated with MYBPC3 mutation, and that CRISPR technology has great potential for treating hereditary heart diseases.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9675211","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: 2

Reversible stabilization of DNA/PEI complexes by reducible click-linkage between DNA and polymer. A new polyplex concept for lowering polymer quantity 通过 DNA 与聚合物之间的还原性点击连接，实现 DNA/PEI 复合物的可逆稳定。降低聚合物数量的新型多聚物概念。

IF 5.1 3区医学

Gene Therapy Pub Date : 2023-02-09 DOI: 10.1038/s41434-023-00386-1

Delphine Maze, Chantal Pichon, Patrick Midoux

{"title":"Reversible stabilization of DNA/PEI complexes by reducible click-linkage between DNA and polymer. A new polyplex concept for lowering polymer quantity","authors":"Delphine Maze, Chantal Pichon, Patrick Midoux","doi":"10.1038/s41434-023-00386-1","DOIUrl":"10.1038/s41434-023-00386-1","url":null,"abstract":"Nonviral transfection of mammalian cells can be performed with electrostatic complexes (polyplexes) between a plasmid DNA (pDNA) encoding a foreign gene and a cationic polymer. However, an excess of the cationic polymer is required for pDNA condensation and polyplexes formation, which generate in vivo toxicity. Here, we present a new concept of polyplexes preparation aiming to reduce the polymer quantity. pDNA was functionalized with 3,6,9-trioxaundecan-1- {4 - [(2-chloroethyl) ethylamino)] - benzylamino}, 11-azide, and polyethyleneimine (lPEI) with reducible dibenzocyclooctyl (SS-DBCO) groups allowing azide-alkyne cycloaddition between pDNA and lPEI after condensation. The size of polyplexes with DBCO-SS-lPEI was smaller than with lPEI due to a stronger DNA condensation thanks to linkages between polymer and pDNA preventing dissociation until disulfide bridges reduction. In vitro transfection showed that the amount of DBCO-SS-lPEI leading to the most efficient polyplexes was three times lower than lPEI. As expected, toxicity in mice was significantly reduced upon intravenous injection of DBCO-SS-lPEI polyplexes at doses where the lPEI polyplexes killed mice. This is probably due to the high stability of the DBCO-SS-lPEI polyplexes which prevented their aggregation in the pulmonary capillaries. Overall, this new concept of polyplexes with DBCO-SS-lPEI offering the possibility of administering higher doses of polyplexes than lPEI and their ability to pass the pulmonary barrier could be favorably exploited for transfection of distant organs or tissues, such as tumors.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2023-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10681101","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