Abstract:
:Mutations in the gene encoding the peroxisomal ATP-binding cassette transporter (ABCD1) cause elevations in very long-chain fatty acids (VLCFAs) and the neurodegenerative disease adrenoleukodystrophy (ALD). In most adults, this manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN). A challenge in virus-based gene therapy in AMN is how to achieve functional gene correction to the entire spinal cord while minimizing leakage into the systemic circulation, which could contribute to toxicity. In the present study, we used an osmotic pump to deliver adeno-associated viral (AAV) vector into the lumbar cerebrospinal fluid space in mice. We report that slow intrathecal delivery of recombinant AAV serotype 9 (rAAV9) achieves efficient gene transfer across the spinal cord and dorsal root ganglia as demonstrated with two different transgenes, GFP and ABCD1. In the Abcd1-/- mouse, gene correction after continuous rAAV9-CBA-hABCD1 delivery led to a 20% decrease in VLCFA levels in spinal cord compared with controls. The major cell types transduced were astrocytes, vascular endothelial cells, and neurons. Importantly, rAAV9 delivered intrathecally by osmotic pump, in contrast to bolus injection, reduced systemic leakage into peripheral organs, particularly liver and heart tissue.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Gong Y,Berenson A,Laheji F,Gao G,Wang D,Ng C,Volak A,Kok R,Kreouzis V,Dijkstra IM,Kemp S,Maguire CA,Eichler Fdoi
10.1089/hum.2018.079subject
Has Abstractpub_date
2019-05-01 00:00:00pages
544-555issue
5eissn
1043-0342issn
1557-7422journal_volume
30pub_type
杂志文章abstract::Adenovirus (Ad) vectors used for gene therapy are efficient in entering the infected cell and targeting their genome to the nucleus. To study the mechanism of the interaction between Ad and the nuclear envelope we have established an in vitro assay using rat liver nuclei incubated with serotype 5 Ad vector. Binding of...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950017176
更新日期:1999-09-01 00:00:00
abstract::The clinical success of suicide gene therapy using herpes simplex virus type 1 thymidine kinase (TK) is largely dependent on the capacity of this enzyme to effectively induce the death of bystander cells. We have shown that fusion of TK to an 11-amino acid peptide from the basic domain of the human immunodeficiency vi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.1389
更新日期:2005-12-01 00:00:00
abstract::Recombinant adeno-associated virus serotype 2 (rAAV2)-based human gene therapy for cystic fibrosis has progressed through a series of preclinical studies and phase I and II clinical trials. This agent has shown an encouraging safety profile, consistent levels of DNA transfer, and positive evidence of short-term clinic...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/hum.2005.16.921
更新日期:2005-08-01 00:00:00
abstract::Lentiviral vectors are efficient gene delivery vehicles for therapeutic and research applications. In contrast to oncoretroviral vectors, they are able to infect most nonproliferating cells. In the liver, induction of cell proliferation dramatically improved hepatocyte transduction using all types of retroviral vector...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2011.227
更新日期:2013-02-01 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::In vivo electroporation of plasmid DNA (DNA-EP) is an efficient and safe method for vaccines. It results in increased DNA uptake, enhances protein expression, and augments immune responses to the target antigen in a variety of species. To further improve the efficacy of DNA-EP, we evaluated small interfering RNA (siRN...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2008.210
更新日期:2009-06-01 00:00:00
abstract::Duchenne muscular dystrophy (DMD) typically occurs as a result of truncating mutations in the DMD gene that result in a lack of expression of the dystrophin protein in muscle fibers. Various therapies under development are directed toward restoring dystrophin expression at the subsarcolemmal membrane, including gene t...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2013.092
更新日期:2013-09-01 00:00:00
abstract::Antitumor gene therapy using herpes simplex type 1 thymidine kinase (TKh) and ganciclovir (GCV) treatment has revealed an important intratumoral bystander effect. A whole tumor can be eliminated when only a fraction of its tumor cells express TKh. We now report that the bystander effect not only acts within a tumor, b...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.15-1807
更新日期:1997-10-10 00:00:00
abstract::Recombinant poxviruses expressing immunomodulatory molecules together with specific antigens represent powerful vaccines for cancer immunotherapy. Recently, we and others have demonstrated, in vitro and in vivo, that coexpression of CD80 and CD86 costimulatory molecules enhances the immunogenic capacity of a recombina...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.348
更新日期:2005-03-01 00:00:00
abstract::Gene therapy for Duchenne muscular dystrophy will likely require that the corrective dystrophin gene be delivered to a high fraction of muscle fibers in vivo. Because of the large size of the dystrophin cDNA, adenoviral (Ad) vectors have been developed for this application. However, Ad vectors transduce mature muscle ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.314
更新日期:2006-03-01 00:00:00
abstract::Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). It has been previously shown that ex vivo hepatocyte-directed gene therapy using an integrating lentiviral vector to replace the defective Fah gene can cure liver disease in small- and la...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2017.252
更新日期:2018-11-01 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::The immune response against human immunodeficiency virus type-1 (HIV-1) is believed to play a role in controlling the early stages of disease progression. The cellular immune response, in particular cytotoxic T lymphocyte (CTL) activity, may be important for eliminating virally infected cells in HIV-1-infected individ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1994.5.7-853
更新日期:1994-07-01 00:00:00
abstract::Recombinant adeno-associated virus (rAAV) is a prototypical gene therapy vector characterized by excellent safety profiles, wide host range, and the ability to transduce differentiated cells. Numerous rAAV-based vectors providing efficient and sustained expression of transgenes in target tissues have been developed fo...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2005.16.551
更新日期:2005-05-01 00:00:00
abstract::Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) offer great hope for in vitro modeling of Parkinson's disease (PD), as well as for designing cell-replacement therapies. To realize these opportunities, there is an urgent need to develop efficient protocols for the directed differentiation of...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2011.054
更新日期:2012-01-01 00:00:00
abstract::Successful gene transfer into articular cartilage is a prerequisite for gene therapy of articular joint disorders. In the present study we tested the hypothesis that recombinant adeno-associated virus (rAAV) vectors are capable of effecting gene transfer in isolated articular chondrocytes in vitro, articular cartilage...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303403321208998
更新日期:2003-03-01 00:00:00
abstract::Glycogen storage disease type II (GSDII) is a lysosomal storage disease caused by a deficiency in acid alpha-glucosidase (GAA), and leads to cardiorespiratory failure by the age of 2 years. In this study, we investigate the impact of anti-GAA antibody formation on cross-correction of the heart, diaphragm, and hind-lim...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2005.16.68
更新日期:2005-01-01 00:00:00
abstract::Advances in cell and gene therapy are opening up new avenues for regenerative medicine. Because of their acquired pluripotency, human induced pluripotent stem cells (hiPSCs) are a promising source of autologous cells for regenerative medicine. They show unlimited self-renewal while retaining the ability, in principle,...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2012.251
更新日期:2013-06-01 00:00:00
abstract::Expression of a gene encoding the diphtheria toxin A (DT-A) fragment, controlled by tissue specific regulatory elements, has previously been used to kill selected cell populations. Here, we have examined the feasibility of controlling DT-A expression using regulatory systems from the human immunodeficiency virus (HIV-...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1991.2.1-53
更新日期:1991-04-01 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::Administration of plasmid/lipid complexes to the lung airways for the treatment of metastatic pulmonary diseases represents a new strategy of gene therapy. In this study we present evidence that intratracheal administration of a plasmid encoding murine IL-12 complexed with N-[1-(2,3-dioleyloxy)propyl)-N,N,N-trimethyla...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950018481
更新日期:1999-03-20 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::Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrogenesis. Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are key profibrotic cytokines that regulate HSC activation and proliferation with functional convergence. Dual RNA interference against their ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.047
更新日期:2019-02-01 00:00:00
abstract::Mutations in the alpha-chain of lysosomal hexosaminidase (EC 3.2.1.52) underlie two distinct biochemical phenotypes known as variant B and variant B1 of G(M2) gangliosidosis. This paper shows that the transduction of human B1-type fibroblasts (producing catalytically inactive alpha-chains) with a retroviral vector enc...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401750476267
更新日期:2001-09-20 00:00:00
abstract::Pulmonary edema is cleared via active Na(+) transport by alveolar epithelial Na(+)/K(+)-ATPases and Na(+) channels. Rats exposed to acute hyperoxia have a high mortality rate, decreased Na(+)/K(+)-ATPase function, and decreased alveolar fluid clearance (AFC). We hypothesized that Na(+)/K(+)-ATPase subunit gene overexp...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303400750035753
更新日期:2000-11-01 00:00:00
abstract::Here we show potent inhibition of HIV-1 replication in a human T cell line and primary human CD4(+) cells by expressing a single antiviral protein. Nullbasic is a mutant form of the HIV-1 Tat protein that was previously shown to strongly inhibit HIV-1 replication in nonhematopoietic cell lines by targeting three steps...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2012.176
更新日期:2013-03-01 00:00:00
abstract::Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that has been considered as a model for liver-directed gene therapy. Current treatment has failed to avert a high mortality or morbidity from hyperammonemic coma. Restoration of enzyme activity in the liver should suffice to normalize me...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340152712719
更新日期:2002-01-01 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::Glycogen storage disease type II (GSD-II) is a lethal, autosomal recessive metabolic myopathy caused by a lack of acid-alpha-glucosidase (GAA) activity in the cardiac and skeletal muscles. Absence of adequate intralysosomal GAA activity results in massive amounts of glycogen accumulation in multiple muscle groups, res...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401750195917
更新日期:2001-05-20 00:00:00
abstract::Trans-dominant mutants of human immunodeficiency virus type 1 (HIV-1) Tat and Rev are attractive candidates for use in gene therapy in the treatment of HIV-1 infections because both are essential for viral replication. Retroviral vectors were constructed to allow either Tat-inducible or Tat- and Rev-inducible expressi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1993.4.5-625
更新日期:1993-10-01 00:00:00