Abstract:
:Artemis is a hairpin-opening endonuclease involved in nonhomologous end-joining and V(D)J recombination. Deficiency of Artemis results in radiation-sensitive severe combined immunodeficiency (SCID) characterized by complete absence of T and B cells due to an arrest at the receptor recombination stage. We have generated several lentiviral vectors for transduction of the Artemis sequence, intending to complement the deficient phenotype. We found that transduction by a lentiviral vector in which Artemis is regulated by a strong EF-1alpha promoter resulted in a dose-dependent loss of cell viability due to perturbed cell cycle distribution, increased DNA damage, and increased apoptotic cell frequency. This toxic response was not observed in cultures exposed to identical amounts of control vector. Loss of cell viability was also observed in cells transfected with an Artemis expression construct, indicating that toxicity is independent of lentiviral transduction. Reduced toxicity was observed when cells were transduced with a moderate-strength phosphoglycerate kinase promoter to regulate Artemis expression. These results present a novel challenge in the establishment of conditions that support Artemis expression at levels that are nontoxic yet sufficient to correct the T(-)B(-) phenotype, crucial for preclinical studies and clinical application of Artemis gene transfer in the treatment of human SCID-A.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Multhaup M,Karlen AD,Swanson DL,Wilber A,Somia NV,Cowan MJ,McIvor RSdoi
10.1089/hum.2009.162subject
Has Abstractpub_date
2010-07-01 00:00:00pages
865-75issue
7eissn
1043-0342issn
1557-7422journal_volume
21pub_type
杂志文章abstract::Deficiency of glycogen branching enzyme (GBE) causes glycogen storage disease type IV (GSD IV), which is characterized by the accumulation of a less branched, poorly soluble form of glycogen called polyglucosan (PG) in multiple tissues. This study evaluates the efficacy of gene therapy with an adeno-associated viral (...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2016.099
更新日期:2017-03-01 00:00:00
abstract::Glaucoma, a group of optic neuropathies, is the leading cause of irreversible blindness. Neuronal apoptosis in glaucoma is primarily associated with high intraocular pressure caused by chronically impaired outflow of aqueous humor through the trabecular meshwork, a reticulum of mitotically inactive endothelial-like ce...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340152677449
更新日期:2001-11-20 00:00:00
abstract::We evaluated the ability of a replication-deficient, recombinant adenoviral vector to transfer the bifunctional gene GAL-TEK, which expresses a marking/therapeutic gene product, to naturally occurring cat fibrosarcomas in situ. GAL-TEK contains an in-frame fusion of the bacterial LacZ gene for histochemical marking of...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1995.6.9-1215
更新日期:1995-09-01 00:00:00
abstract::We previously reported that spliceosome-mediated RNA trans-splicing (SMaRT), using recombinant adenoviral vectors expressing pre-trans-splicing molecules (PTMs), could partially restore cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activity to polarized human DeltaF508 CF airway epithelia...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.1116
更新日期:2005-09-01 00:00:00
abstract::Although replication-deficient adenoviruses can efficiently transfer genes to the salivary glands, the current vectors precipitate an immediate, transient decrease in salivary function. To study the cause of this salivary hypofunction, 10(6)-10(10) plaque-forming units (pfu) of the vector AdCMV beta gal were delivered...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.9-1085
更新日期:1996-06-10 00:00:00
abstract::Gene transfer for therapeutic angiogenesis represents a novel treatment for patients with chronic angina refractory to standard medical therapy and not amenable to conventional revascularization. We sought to assess the role of intraoperative multiplane transesophageal echocardiography (MPTEE) in guiding injection of ...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/10430349950016951
更新日期:1999-09-20 00:00:00
abstract::DNA-based vaccines able to induce efficient cytotoxic T-cell responses targeting conserved elements (CE) of human immunodeficiency virus type 1 (HIV-1) Gag have been developed. These CE were selected by stringent conservation, the ability to induce T-cell responses with broad human leukocyte antigen coverage, and the ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.065
更新日期:2018-09-01 00:00:00
abstract::Huntington's disease (HD) is a fatal neurodegenerative disease caused by a genetic expansion of the CAG repeat region in the huntingtin (HTT) gene. Studies in HD mouse models have shown that artificial miRNAs can reduce mutant HTT, but evidence for their effectiveness and safety in larger animals is lacking. HD transg...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2017.199
更新日期:2018-06-01 00:00:00
abstract::Delivery of plasmid DNA can be enhanced by treatment with ultrasound (US); acoustic cavitation appears to play an important role in the process. Ultrasound contrast agents (UCAs; stabilized microbubbles) nucleate acoustic cavitation, and lower the acoustic pressure threshold for inertial cavitation occurrence. Fifty m...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.893
更新日期:2005-07-01 00:00:00
abstract::Three retroviral constructs containing a full-length human alpha-L-iduronidase (IDUA) cDNA were made. The first, pLIdSN, is designed so that expression of the IDUA cDNA is from the 5' viral long terminal repeat (LTR). The second, pLNCId, is designed to express the IDUA cDNA from the cytomegalovirus (CMV) immediate ear...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1992.3.4-371
更新日期:1992-08-01 00:00:00
abstract::The transfer of a drug resistance gene into hematopoietic cells is an approach being investigated to overcome the problem of myelosuppression produced by anticancer drugs. Chemotherapeutic agents are often given in combination in order to increase their effectiveness. Consequently, there is an advantage in designing v...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.17-2537
更新日期:1998-11-20 00:00:00
abstract::Cotransfer of a therapeutic gene together with the human MDR1 gene provides an opportunity to increase the number of transduced marrow cells, expressing the therapeutic gene, by in vivo selection for MDR1. We have used an Lg-MDR1-IRES-neo (LgMIN) retroviral vector, containing MDR1 and neo genes, separated by the EMCV ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.15-2263
更新日期:1998-10-10 00:00:00
abstract::Recombinant adenoviruses have received much attention as a potential vector for gene therapy because of their ability to transduce many cell types with high efficiencies in vivo. After intravenous infusion, the majority of the vector is found in hepatocytes, but vector DNA is found to varying degrees in other tissues....
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.14-1693
更新日期:1996-09-10 00:00:00
abstract::Adenovirus vectors transduce liver hepatocytes with extreme efficiency; however, transgene expression is eliminated within 2 weeks. Extinction of transgene expression has been attributed to infiltrating cytotoxic T lymphocytes (CTLs) in the liver in a process that resembles a number of human diseases, including viral ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950019048
更新日期:1999-01-20 00:00:00
abstract::Gene-modified replication-competent adenoviruses (Ads) are emerging as a promising new modality for the treatment of cancer. We have previously shown that E1B 19kDa and E1B 55kDa gene-deleted Ad (Ad-DeltaE1B19/55) exhibits improved tumor-specific replication and cell lysis, leading to an enhanced antitumor effect. In ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.167
更新日期:2007-09-01 00:00:00
abstract::Naked plasmid DNA electrotransfer offers advantages over viral-based gene delivery, including being regulatory permissive, but factors influencing expression efficiency and cell fate impact on translational utility. This study compared co-expression of red and green fluorescence reporter plasmids with differing promot...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.062
更新日期:2019-02-01 00:00:00
abstract::Replacement of the p53 tumor suppressor gene is a rational approach to the management of malignant gliomas because p53 is frequently mutated or inactivated in these cancers. Major weaknesses of this approach are that malignant gliomas are mixtures of cells with wild-type and mutant p53, and that tumor cells exhibiting...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.685
更新日期:2005-06-01 00:00:00
abstract::Establishing pharmacological parameters, such as efficacy, routes of administration, and toxicity, for recombinant adeno-associated virus (rAAV) vectors is a prerequisite for gaining acceptance for clinical applications. In fact, even a therapeutic window, that is, the dose range between therapeutic efficacy and toxic...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2009.092
更新日期:2009-08-01 00:00:00
abstract::Recent advances in genome sequencing have greatly improved our ability to understand and identify the causes of genetic diseases. However, there remains an urgent need for innovative, safe, and effective treatments for these diseases. CRISPR-based genome editing systems have become important and powerful tools in the ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2020.111
更新日期:2020-08-01 00:00:00
abstract::Retroviral vectors encoding glucose-responsive promoters driving furin expression may provide an amplified, glucose-regulated secretion of insulin. We constructed LhI*TFSN virus to encode a glucose-regulatable transforming growth factor alpha promoter controlling furin expression with a viral LTR promoter driving cons...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401750061195
更新日期:2001-01-20 00:00:00
abstract::Herpes simplex virus thymidine kinase (HSV-tk) gene therapy for brain tumors depends on ganciclovir (GCV) and its transport across the blood-brain tumor barrier (BBTB). We examined whether RMP-7, the bradykinin analog and potent BBTB permeabilizer, could enhance the efficacy of GCV treatment of brain tumors by increas...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.7-989
更新日期:1998-05-01 00:00:00
abstract::Combining chemotherapy and immunotherapy is problematic because chemotherapy can ablate the immune responses initiated by modulators of the immune system. We hypothesized that protection of immunocompetent cells from the toxic effects of chemotherapy, using drug resistance gene therapy strategies, would allow the comb...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.798
更新日期:2006-08-01 00:00:00
abstract::Autoimmune destruction of islets in the pancreas leads to the development of insulin-dependent diabetes mellitus (IDDM). Replacement of insulin-producing tissue by transplantation of islets provides a cure to disease but requires immunosuppression or a means of controlling anti-graft immune responses. To promote islet...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.18-2717
更新日期:1998-12-10 00:00:00
abstract::Transferring therapeutic genes into the nociceptive system, including dorsal root ganglia (DRGs) and the spinal cord, is potentially a powerful approach for the treatment of chronic pain in humans. Adeno-associated viral vectors (AAVs) are particularly useful in delivering foreign genes to targeted tissues because the...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303403765701187
更新日期:2003-06-10 00:00:00
abstract::Pancreatic cancer is the fourth leading cause of cancer-related death in the United States, and even under optimal therapy these patients face a poor prognosis. Here we report a novel gene therapy-based strategy to battle this disease. We show that the majority of pancreatic tumors overexpress c-erb-B2, which therefor...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2009.083
更新日期:2010-02-01 00:00:00
abstract::Subcutaneous vaccination therapy with glioma cells, which are retrovirally transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), has previously proven effective in C57BL/6 mice harboring intracerebral GL261 gliomas. However, clinical ex vivo gene therapy for human gliomas would be difficult,...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050057503
更新日期:2000-07-01 00:00:00
abstract::The purpose of this study was to determine the safety and antitumor activity of IFN-gamma retroviral vector in patients with advanced melanoma. Seventeen patients (9 single courses, 8 multiple courses) received a total of 363 intratumor injections of IFN-gamma retroviral vector (1 x 10(7) PFU/ml administered at 0.3, 0...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/10430349950017978
更新日期:1999-05-20 00:00:00
abstract::Gene therapy studies in primates can provide important information regarding vector tropism, specific cellular expression, biodistribution, and safety prior to clinical trials. In this study, we report the assessment of transduction efficiency of recombinant adeno-associated virus (rAAV) vectors using human postmortem...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2010.157
更新日期:2011-05-01 00:00:00
abstract::Gyrate atrophy is a progressive blindness associated with deficiency of ornithine aminotransferase (OAT). The strategy of using an autologous keratinocyte graft, modified to express high levels of OAT as an ornithine-catabolizing skin-based enzyme sink, is investigated. Two OAT-containing retroviral vectors were const...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.17-2125
更新日期:1997-11-20 00:00:00
abstract::The therapeutic use of neurotrophic factors for neurodegenerative diseases is promising, however, optimal methods for continuous delivery of these substances to the human central nervous system (CNS) remains problematic. One approach would be to graft genetically engineered human cells that continuously secrete high l...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.3-331
更新日期:1997-02-10 00:00:00