Abstract:
:The management of disorders of the nervous system remains a medical challenge. The key goals are to understand disease mechanisms, to validate therapeutic targets, and to develop new therapeutic strategies. Viral vector-mediated gene transfer can meet these goals and vectors based on lentiviruses have particularly useful features. Lentiviral vectors can deliver 8 kb of sequence, they mediate gene transfer into any neuronal cell type, expression and therapy are sustained, and normal cellular functions in vitro and in vivo are not compromised. After delivery into the nervous system they induce no significant immune responses, there are no unwanted side effects of the vectors per se to date, and manufacturing and safety testing for clinical applications are well advanced. There are now numerous examples of effective long-term treatment of animal models of neurological disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, motor neuron diseases, lysosomal storage diseases, and spinal injury, using a range of therapeutic genes expressed in lentiviral vectors. Significant issues remain in some areas of neural gene therapy including defining the optimum therapeutic gene(s), increasing the specificity of delivery, regulating expression of potentially toxic genes, and designing clinically relevant strategies. We discuss the applications of lentiviral vectors in therapy and research and highlight the essential features that will ensure their translation to the clinic in the near future.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Wong LF,Goodhead L,Prat C,Mitrophanous KA,Kingsman SM,Mazarakis NDdoi
10.1089/hum.2006.17.1keywords:
subject
Has Abstractpub_date
2006-01-01 00:00:00pages
1-9issue
1eissn
1043-0342issn
1557-7422journal_volume
17pub_type
杂志文章,评审abstract::As an alternative to virus-mediated gene transfer, we previously demonstrated a simple, safe, and efficient transfer of foreign gene into the central nervous system using continuous injection of a plasmid DNA-cationic liposome complex. To explore whether this approach can be applied to the treatment of certain neurolo...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.7-1093
更新日期:1998-05-01 00:00:00
abstract::Unlike oncoretroviruses, lentiviral vectors can insert large genes and can target both dividing and nondividing cells; thus they hold unique promise as gene transfer agents. To enhance target range, the native lentiviral envelope glycoprotein is replaced (pseudotyped) with vesicular stomatitis virus G (VSVG), and the ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340360464723
更新日期:2003-01-01 00:00:00
abstract::Following in vivo recombinant adeno-associated virus (rAAV)-based gene transfer, adaptive immune responses specific to the vector or the transgene product have emerged as a potential roadblock to successful clinical translation. The occurrence of such responses depends on several parameters, including the route of vec...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2014.070
更新日期:2015-01-01 00:00:00
abstract::The potential of short interfering RNA (siRNA) to be developed for therapeutic use against cancer depends on the availability of an efficient tumor-specific delivery vehicle. We have previously shown that a nanoscale nonviral liposome-based complex that includes an anti-transferrin receptor single-chain antibody fragm...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.117
更新日期:2006-01-01 00:00:00
abstract::In previous studies we showed that low-dose irradiation and immunosuppression with cyclosporine and mycophenolate mofetil prolonged in vivo persistence of gene-modified T cells but was unable to induce tolerance. We hypothesized that the lack of sustained antigen presentation because of the limited life span of the in...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2007.086
更新日期:2008-01-01 00:00:00
abstract::The T cell co-stimulatory molecule B7-1 was transduced into a poorly immunogenic murine neuroblastoma cell line (Neuro-2a, N-2a) alone or in combination with MHC class II genes to test the ability of these genes to stimulate antitumor immunity. N-2a cells transduced with B7-1 exhibited reduced tumorigenicity, whereas ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.17-2059
更新日期:1996-11-10 00:00:00
abstract::Accurate quantification of gene transfer (or gene correction) is a universal challenge in the field of gene therapy. In developing a clinical trial of lymphocyte gene therapy for Hunter syndrome (mucopolysaccharidosis type II), methods using Southern blot or automated DNA sequencing technology were employed, but found...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950016898
更新日期:1999-10-10 00:00:00
abstract::PhD-trained biomedical scientists are moving into an increasingly diverse variety of careers within the sciences. However, graduate and postdoctoral training programs have historically focused on academic career preparation, and have not sufficiently prepared trainees for transitioning into other scientific careers. A...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2016.154
更新日期:2016-11-01 00:00:00
abstract::CTL lines directed against HIV-1 antigens were generated from infected individuals and were transduced by the HMB-K(b)HuIFNbeta vector, resulting in low, constitutive expression of interferon beta (IFN-beta). The IFN-beta-transduced cells showed markedly increased HIV-1-specific, MHC class I-restricted CTL activity ag...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950017482
更新日期:1999-07-20 00:00:00
abstract::Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Preexisting immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of ge...
journal_title:Human gene therapy
pub_type: 杂志文章,多中心研究
doi:10.1089/hum.2014.109
更新日期:2015-03-01 00:00:00
abstract::Previously, we described a nonviral cytoplasmic gene therapy vector system based on the T7 autogene concept. This system has been shown to achieve rapid and high levels of gene expression in a variety of animal cells and tissues. To test the utility of the system in vivo tumor ablation, a T7 cancer gene therapy plasmi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.5-729
更新日期:1998-03-20 00:00:00
abstract::Lentiviral vectors are promising tools for gene transfer into the central nervous system. We have characterized in detail transduction with human immunodeficiency virus type 1 (HIV-1)-derived vectors encoding enhanced green fluorescent protein (eGFP) in the adult mouse brain. Different brain regions such as the striat...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340252899019
更新日期:2002-05-01 00:00:00
abstract::When transferring the human multidrug resistance 1 (MDR1) cDNA, FMEV retroviral vectors mediate high-dose multidrug resistance and, thus, background-free selection in primary human hematopoietic progenitor cells. Here, we analyzed strategies for co-expression of a second gene from an FMEV:MDR1 vector. When linking the...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.1-33
更新日期:1998-01-01 00:00:00
abstract::Replication-competent adenoviruses may provide a highly efficient means of delivering therapeutic genes to tumors. Previously, we evaluated in vitro a replication-competent adenovirus (Ad5-CD/TKrep) containing a cytosine deaminase (CD)/herpes simplex type 1 thymidine kinase (HSV-1 TK) fusion gene that allows lytic vir...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050016166
更新日期:2000-01-01 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::One of the major obstacles to pulmonary-directed gene therapy using adenoviral vectors is the induction of inflammation. We investigated whether the adenoviral particles that constitute the initial inoculum can serve as an inflammatory stimulus, independent of their ability to express genes that they contain. Viral pa...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1995.6.12-1553
更新日期:1995-12-01 00:00:00
abstract::Gene electrotransfer is gaining momentum as an efficient methodology for nonviral gene transfer. In skeletal muscle, data suggest that electric pulses play two roles: structurally permeabilizing the muscle fibers and electrophoretically supporting the migration of DNA toward or across the permeabilized membrane. To in...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hgt.2008.060
更新日期:2008-11-01 00:00:00
abstract::Genetic immunization has been widely applied in efforts to find novel and efficient mechanisms of stimulating the immune response. An effective attack against viral pathogens or tumors often requires activation of T cell-mediated immunity and the generation of cytotoxic T cells. Intramuscular immunization with plasmid...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.3-325
更新日期:1998-02-10 00:00:00
abstract::If established cultured cell lines genetically modified to secrete desired gene products could be implanted in different allogeneic recipients without immune rejection, novel gene products would be delivered more cost effectively. We tested this strategy by encapsulating mouse Ltk- cells transfected with the human gro...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1993.4.4-433
更新日期:1993-08-01 00:00:00
abstract::Cell-based gene transfer using a stent platform would provide a significant advantage in terms of site-specific gene expression in the vasculature. The current study presents a novel stent design that allows stable in vivo transgene expression over a 4-week period in the vasculature. A mesh-stent coated with fibronect...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340252792567
更新日期:2002-02-10 00:00:00
abstract::Targeted delivery of intravenously administered genetically altered cells or stem cells is still in an early stage of investigation. We developed a method of delivering iron oxide (ferumoxide)-labeled mesenchymal stem cells (MSCs) to a targeted area in an animal model by applying an external magnet. Rats with or witho...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303404322959506
更新日期:2004-04-01 00:00:00
abstract::Adoptive cellular therapy provides the promise of a potentially powerful general treatment for cancer. Although this is a complex and challenging field, there have been major advances in basic and translational research resulting in clinical trial activity that is now beginning to confirm this promise. However, these ...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2010.086
更新日期:2010-06-01 00:00:00
abstract::Deoxyribozymes, or DNA enzymes (DNAzymes), are novel nucleic acids that have the ability to bind to specific sequences of RNA, and to cleave the target site catalytically. DNAzymes are smaller and more efficient enzymatically than ribozymes (RZs), which are catalytic nucleic acids synthesized from ribonucleotides. We ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950016573
更新日期:1999-11-20 00:00:00
abstract::Immunoisolation of allogeneic cells within a membrane-bound device is a unique approach for gene therapy. We employed an immunoisolation device that protects allograft, but not xenograft, cells from destruction, to implant a human fibroblast line (MSU 1.2) in athymic rodents. Cells, transduced with the MFG-human facto...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.6-879
更新日期:1998-04-10 00:00:00
abstract::Eleven patients with moderate to severe erectile dysfunction (ED) were given a single-dose corpus cavernosum injection of hMaxi-K, a "naked" DNA plasmid carrying the human cDNA encoding hSlo (for human slow-poke), the gene for the alpha, or pore-forming, subunit of the human smooth muscle Maxi-K channel. Three patient...
journal_title:Human gene therapy
pub_type: 杂志文章,多中心研究
doi:10.1089/hum.2006.17.1165
更新日期:2006-12-01 00:00:00
abstract::The recombinant adenoviral (Ad) vector is being considered as a cancer vaccine platform because it efficiently induces immune responses to tumor antigens by intradermal immunization. The aims of this study were to evaluate the potential toxicities and biodistribution after a single dose or six weekly intradermal doses...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.705
更新日期:2006-07-01 00:00:00
abstract::Mice bearing breast tumors were treated with a single dose of an adenovirus expressing interleukin-12 (AdmIL-12.1) injected intratumorally, which produced regressions in greater than 75% of the treated tumors; approximately one-third of the animals remained tumor free. Complete regression was associated with immunity ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.16-1995
更新日期:1996-10-20 00:00:00
abstract::Cell therapies are treatments in which stem or progenitor cells are stimulated to differentiate into specialized cells able to home to and repair damaged tissues. After their discovery, endothelial progenitor cells (EPCs) stimulated worldwide interest as possible vehicles to perform autologous cell therapy of tumors. ...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2016.066
更新日期:2016-10-01 00:00:00
abstract::Blood vessels are among the easiest targets for gene therapy. However, no data are available about the safety and feasibility of intracoronary gene transfer in humans. We studied the safety and efficacy of catheter-mediated vascular endothelial growth factor (VEGF) plasmid/liposome (P/L) gene transfer in human coronar...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1089/10430340050016003
更新日期:2000-01-20 00:00:00
abstract::This Phase I study, "Ribozyme Gene Therapy of HIV-1 Infection" (UCSD HSC #971072, FDA BB-IND 6405), is a prospective, open-label trial of infusion of autologous gene-altered cells into asymptomatic HIV-1 seropositive individuals. The objectives of this trial are to test the safety, feasibility, and potential efficacy ...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/hum.1998.9.16-2407
更新日期:1998-11-01 00:00:00