Gene therapy and regulation最新文献_第5页

Engineered Cys 2 His 2 zinc finger DNA-binding domains 设计cys2 His 2锌指dna结合域

Gene therapy and regulation Pub Date : 2004-08-01 DOI: 10.1163/1568558042457479

A. S. Hirsh, J. Joung

引用次数: 3

Method — Intra-bone marrow transplantation of hematopoietic stem cells in non-human primates: long-term engraftment without conditioning 方法-非人灵长类动物造血干细胞骨髓内移植:无条件长期植入

Gene therapy and regulation Pub Date : 2004-08-01 DOI: 10.1163/1568558042457460

Kyoji Ueda, Y. Hanazono, N. Ageyama, H. Shibata, Satoko Ogata, Y. Ueda, T. Tabata, S. Ikehara, M. Taniwaki, M. Hasegawa, K. Terao, K. Ozawa

{"title":"Method — Intra-bone marrow transplantation of hematopoietic stem cells in non-human primates: long-term engraftment without conditioning","authors":"Kyoji Ueda, Y. Hanazono, N. Ageyama, H. Shibata, Satoko Ogata, Y. Ueda, T. Tabata, S. Ikehara, M. Taniwaki, M. Hasegawa, K. Terao, K. Ozawa","doi":"10.1163/1568558042457460","DOIUrl":"https://doi.org/10.1163/1568558042457460","url":null,"abstract":"It has recently been reported that bone marrow cells can efficiently engraft without marrow conditioning when implanted directly into the bone marrow cavity (intra-bone marrow transplantation, iBMT) in mice. We have successfully examined the efficacy of autologous iBMT in a cynomolgus monkey model in conjuction with an in vivo expansion of transplanted cells by a selective amplifier transgene (Ueda et al., 2004) and provide here the detailed parameters of our iBMT method. We injected retrovirally-marked autologous CD34+ cells directly into the non-conditioned marrow cavity of the femur and humerus after gently irrigating the cavity with saline. This transplant procedure was safely performed without pulmonary embolism. Gene-marked cells were not detectable in the peripheral blood at one hour and one day after iBMT as assessed by sensitive PCR, indicating that iBMT hardly generated a systemic delivery of transplanted cells. On the other hand, 2 to 30% of clonogenic hematopoietic colonies produced from the implanted marrow were gene-marked at 6–12 months after iBMT. Our iBMT method for non-human primates is thus discussed in terms of long-lived hematopoietic stem/progenitor cells, bone marrow niche and long-term engraftment after iBMT without myeloablative conditioning.","PeriodicalId":93646,"journal":{"name":"Gene therapy and regulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2004-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1163/1568558042457460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64795901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Cancer gene therapy — current status in the clinics 癌症基因治疗的临床现状

Gene therapy and regulation Pub Date : 2004-08-01 DOI: 10.1163/1568558042457488

K. Pulkkanen, H. Sallinen, K. Tyynelä, S. Ylä-Herttuala

{"title":"Cancer gene therapy — current status in the clinics","authors":"K. Pulkkanen, H. Sallinen, K. Tyynelä, S. Ylä-Herttuala","doi":"10.1163/1568558042457488","DOIUrl":"https://doi.org/10.1163/1568558042457488","url":null,"abstract":"By now, we have seen the dawn of the clinical era of cancer gene therapy. An enormous amount of biological knowledge and experimental data were gathered during a short period of pre-clinical years, and numerous applications proceeded into human trials. The first clinical years have taught us hard lessons, and often forced us to pull back and choose new and alternative courses. However, they have also given sufficient promise that cancer gene therapy will establish its foothold in clinical cancer management in the future. More importantly, pioneering trials have helped us to put things into the right perspective; clinical advance will likely emerge from the combined use of gene therapy with traditional therapies. It also appears that no cancer gene therapy approach can be applied universally, but rather we will see treatments that show effectiveness in only a particular type of tumor. For the last but not the least — while researchers are likely to increase their efforts to find more efficient solutions — scientific rigor and study design should not be jeopardised by potential pressures from investors and drug companies. In this review, we summarize highlights in i) the current approaches and genetic treatment modalities that are available based on pre-clinical studies, and ii) the status of cancer gene therapy in current clinical oncology, with special reference to those cancers where gene therapy has proceeded to human trials.","PeriodicalId":93646,"journal":{"name":"Gene therapy and regulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2004-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1163/1568558042457488","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64795794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Alternative capsid strategies for targeting recombinant AAV gene therapy 靶向重组AAV基因治疗的备选衣壳策略

Gene therapy and regulation Pub Date : 2003-08-01 DOI: 10.1163/156855803322664628

S. Loiler, T. Flotte

引用次数: 1

Stem cell gene therapy: breakthrough culminating in combination of ex vivo protocols with transient topical gene therapy 干细胞基因治疗:突破最终结合体外协议与短暂的局部基因治疗

Gene therapy and regulation Pub Date : 2003-08-01 DOI: 10.1163/156855803322664592

R. Bertolotti

引用次数: 2

The pros and cons of using the mechanism of AAV site-specific recombination in gene delivery 利用AAV位点特异性重组机制进行基因传递的利弊

Gene therapy and regulation Pub Date : 2003-08-01 DOI: 10.1163/156855803322664619

N. A. Allen, R. Samulski

{"title":"The pros and cons of using the mechanism of AAV site-specific recombination in gene delivery","authors":"N. A. Allen, R. Samulski","doi":"10.1163/156855803322664619","DOIUrl":"https://doi.org/10.1163/156855803322664619","url":null,"abstract":"The field of gene therapy is progressing with continuous improvements in vector development and regulated transgene expression. These contributions will eventually allow matching the best vector system for the specific disease indication. However one essential component of gene delivery that may be more retractile to this type of development and critical to all methods of delivery relates to the molecular fate of the therapeutic nucleic acids after successful in vivo delivery. The importance of this was illustrated in the clinic when leukemias were a result of insertional mutagenesis after attempting to achieve long-term gene expression via retroviral vectors. These results echo the fact that safer methods of achieving long-term gene expression are needed for successful gene therapy vectors. One mechanism to be considered to obtain the desired gene therapy results of safe long-term gene expression is that of the targeted integration. A number of recombination systems both eukaryotic and prokaryotic are being evaluated for this purpose. Included in this list is the targeted recombination of the Adeno-Associated Virus (AAV). AAV is a unique virus in that it can establish latency in human cells by targeting the recombination of its genome to a specific locus on chromosome 19. This review discusses the current understanding of the cis and trans requirements for AAV site-specific recombination and the mechanism involved. The risks of AAV-based site-specific recombination are also addressed as well as the current state of gene delivery vectors based on the site-specific integration of AAV.","PeriodicalId":93646,"journal":{"name":"Gene therapy and regulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2003-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1163/156855803322664619","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64795351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Phage φC31 integrase-mediated site-specific integration for gene therapy 噬菌体φC31整合酶介导的基因治疗位点特异性整合

Gene therapy and regulation Pub Date : 2003-08-01 DOI: 10.1163/156855803322664600

Eric C. Olivares, M. Calos

{"title":"Phage φC31 integrase-mediated site-specific integration for gene therapy","authors":"Eric C. Olivares, M. Calos","doi":"10.1163/156855803322664600","DOIUrl":"https://doi.org/10.1163/156855803322664600","url":null,"abstract":"For most genetic disorders, long-term correction is necessary. Integration of a therapeutic gene into a patient's genome is an obvious route to achieving such permanent correction. Several technologies have been applied to the goal of achieving integration, including viruses and transposases. While these techniques are effective at some level, they each have drawbacks that can be improved upon. A novel integration system based on a phage integrase can address some of the previous limitations. The integrase from the Streptomyces bacteriophage C31 catalyzes site-specific, unidirectional integration into the genomes of higher eukaryotes. This integrase has the ability to recognize a limited number of native genomic sequences and integrate introduced plasmid DNA into them. These native sequences, termed pseudo att sites, resemble the wild-type phage attachment site enough to support integrase-mediated integration. Molecular evolution holds the promise of creating custom integrases that preferentially recombine at particular pseudo att sites. Furthermore, the system has no apparent size limit on carrying capacity. These features make the C31 integrase system extremely appealing for gene therapy applications. The system has been successfully employed in several model gene therapy studies to date. Here we review the development of this novel integration system and its current and potential applications to gene therapy.","PeriodicalId":93646,"journal":{"name":"Gene therapy and regulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2003-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1163/156855803322664600","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64795143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Globin gene transfer: a paradigm for transgene regulation and vector safety 珠蛋白基因转移:转基因调控和载体安全的范例

Gene therapy and regulation Pub Date : 2003-08-01 DOI: 10.1163/156855803322664637

S. Rivella, L. Lisowski, M. Sadelain

{"title":"Globin gene transfer: a paradigm for transgene regulation and vector safety","authors":"S. Rivella, L. Lisowski, M. Sadelain","doi":"10.1163/156855803322664637","DOIUrl":"https://doi.org/10.1163/156855803322664637","url":null,"abstract":"The β-thalassemias and sickle cell disease are severe congenital anemias that are caused by the defective synthesis of the β chain of hemoglobin. Allogeneic hematopoietic stem cell (HSC) transplantation is curative, but this therapeutic option is not available to the majority of patients. The transfer of a regulated β-globin gene in autologous HCSs thus represents a highly attractive alternative treatment. This strategy, simple in principle, raises major challenges in terms of controlling transgene expression, which ideally should be erythroid-specific, differentiation stage-restricted, elevated, position-independent, and sustained over time. Using lentiviral vectors, we recently demonstrated that an optimized combination of proximal and distal transcriptional control elements permits lineage-specific and elevated expression of the β-globin gene, resulting in therapeutic hemoglobin production and correction of anemia in β-thalassemic mice. Several groups have now confirmed and extended these findings in various mouse models of severe hemoglobinopathies, thus generating enthusiasm for a genetic treatment based on globin gene transfer. Furthermore, globin vectors provide a paradigm for improving vector safety by restricting transgene expression to the differentiated progeny within a single lineage, thereby reducing the risk of activating oncogenes in hematopoietic progenitors. Here we review the principles underlying the genesis of regulated vectors for stem cell therapy.","PeriodicalId":93646,"journal":{"name":"Gene therapy and regulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2003-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1163/156855803322664637","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64795432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

Positron-emission-tomography monitoring of anti-glioblastoma HSV-1-tk gene therapy 抗胶质母细胞瘤HSV-1-tk基因治疗的正电子发射断层扫描监测

Gene therapy and regulation Pub Date : 2003-03-01 DOI: 10.1163/156855803762295422

A. Jacobs, A. Winkeler, C. Dittmar, S. Vollmar, K. Wienhard, J. Voges, W. Heiss

{"title":"Positron-emission-tomography monitoring of anti-glioblastoma HSV-1-tk gene therapy","authors":"A. Jacobs, A. Winkeler, C. Dittmar, S. Vollmar, K. Wienhard, J. Voges, W. Heiss","doi":"10.1163/156855803762295422","DOIUrl":"https://doi.org/10.1163/156855803762295422","url":null,"abstract":"A phase I/II clinical trial of gene therapy for recurrent glioblastoma has been initiated in which non-invasive monitoring of the critical steps is performed by a combination of standard clinical positron-emission tomography (PET) for metabolic identification/evaluation of malignant lesions with pioneering PET imaging of HSV-1- tk transgene expression. Localization, characterization and trial follow-up of target tumors rely on multitracer PET brain imaging probed with radiolabeled 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG), methyl-[ 11 C]-L-methionine (MET) and 3´-deoxy-3´-[ 18 F]fluoro-L-thymidine (FLT) while the location, magnitude and duration of therapeutic HSV-1- tk transgene expression is monitored with 2´-fluoro-2´-deoxy-1-β-D-arabinofuranosyl-5-[ 124 I]iod ([ 124 I]-FIAU). In addition, in order to improve the distribution of the vector within the tumor tissue, a stereotactically guided convection-enhanced delivery (CED) protocol was devised in which the transfection of the HSV-1- tk gene into brain tumor cells is mediated by a liposome-DNA complex. Preliminary findings on a first group of five patients demonstrated that FIAU-PET imaging of HSV-1- tk expression in patients with glioblastoma is feasible and that vector-mediated gene expression may predict the therapeutic effect of ganciclovir prodrug activation. In addition, they showed that integration of magnetic resonance (MR) and PET imaging data into a 3D stereotaxic coordinate system results in an efficient non-invasive spatio-temporal monitoring of a brain gene therapy trial. Such a non-invasive imaging provides the means to identify potential critical parameters and to implement dosing/ routing adjustments that will have a critical impact on the development of standardized gene therapy protocols.","PeriodicalId":93646,"journal":{"name":"Gene therapy and regulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2003-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1163/156855803762295422","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64795216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

Non-viral methods of gene transfer to airway epithelium 气道上皮基因转移的非病毒方法

Gene therapy and regulation Pub Date : 2003-03-01 DOI: 10.1163/156855803762295440

P. Davis, A. Ziady

{"title":"Non-viral methods of gene transfer to airway epithelium","authors":"P. Davis, A. Ziady","doi":"10.1163/156855803762295440","DOIUrl":"https://doi.org/10.1163/156855803762295440","url":null,"abstract":"The airway epithelium has been an important target for gene therapy in the last decade. This route of administration is readily accessible and the airway is affected by a number of disorders for which gene therapy may be useful. Viral vectors were first used to transfer genes to the airway of cystic fibrosis patients a decade ago. However, in vivo results have been disappointing, with substantial inflammation and toxicity occurring at doses that do not produce significant gene transfer. More recently researchers have used plasmid DNA based technologies as an alternative. DNA alone can transfect cells in culture and in vivo, though it is inefficient. Complexing DNA with cationic molecules improves efficiency. Nonviral gene transfer with lipid-DNA complexes has showed promise in cell culture and animals, but is much less efficacious in humans, and inflammation occurs at doses below those required for therapeutic effect. Trans-nuclear membrane delivery appears to be the limiting factor of current liposome-DNA complex efficiency in vivo. DNA compacted with polycations has also been used with good success in animal models, with minimal toxicity and is currently being tested in human trials. In this review, we will discuss the advances and limitations of these nonviral vectors in gene delivery, particularly to airway epithelial cells.","PeriodicalId":93646,"journal":{"name":"Gene therapy and regulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2003-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1163/156855803762295440","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64795837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4