Abstract:
:Deficiencies in different steps of purine metabolism give rise to a number of human inherited disorders. Lesch-Nyhan syndrome is a severe neurological disorder, caused by a deficiency in the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). HPRT-deficient mice have been generated, but have proved to be an unsuccessful model of the human disease. We have suggested that this may be due to a greater dependency in rodents on the other purine salvage enzyme, adenine phosphoribosyltransferase (APRT). We have generated an APRT-deficient mouse line by gene targeting, with a phenotype that closely resembled the symptoms of APRT deficiency in man. APRT null mice were viable, but 90% died prematurely before 6 months of age, displaying highly abnormal kidney morphology, with pathology characteristic of tubule obstruction. These mice have elevated urinary levels of adenine and 2,8-dihydroxyadenine, a highly insoluble adenine derivative, plus birefringent crystalline deposits and calculi within tubules throughout the kidney. A standard therapy for APRT-deficient human patients is the administration of the xanthine oxidase inhibitor, allopurinol. This has proved an effective therapy for APRT null mice, preventing accumulation of 2,8-dihydroxyadenine and much of the resultant renal obstruction, allowing us to establish a breeding line. We believe that these mice should provide a useful model for further study of APRT deficiency in humans. Furthermore, by generating APRT and HPRT double mutants, we will be able to test our hypothesis that both genes must be inactivated in mice before a model for Lesch-Nyhan syndrome can be obtained.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Redhead NJ,Selfridge J,Wu CL,Melton DWdoi
10.1089/hum.1996.7.13-1491subject
Has Abstractpub_date
1996-08-20 00:00:00pages
1491-502issue
13eissn
1043-0342issn
1557-7422journal_volume
7pub_type
杂志文章abstract::Rat myoblast primary cultures were tested as a model for proinsulin synthesis and processing and unregulated insulin delivery for insulin-dependent diabetes mellitus (IDDM) gene therapy. Three human proinsulin cDNA constructs containing genetically engineered furin endoprotease cleavage sites between the B-chain and C...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.1-71
更新日期:1996-01-01 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::Low in vivo transduction efficiency and safety concerns have been hurdles for effective hematopoietic stem cell (HSC) gene therapy. Here, we investigate whether the safety and efficiency of retroviral gene transfer into HSCs can be improved by using human allogeneic umbilical cord blood (UCB)-derived supplements inste...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2007.123
更新日期:2008-07-01 00:00:00
abstract::Adeno-associated viral vectors are showing great promise as gene therapy vectors for a wide range of retinal disorders. To date, evaluation of therapeutic approaches has depended almost exclusively on the use of animal models. With recent advances in human stem cell technology, stem cell-derived retina now offers the ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.027
更新日期:2018-10-01 00:00:00
abstract::Laminin-5 is composed of three distinct polypeptides, alpha3, beta3, and gamma2, which are encoded by three different genes, LAMA3, LAMB3, and LAMC2, respectively. We have isolated epidermal keratinocytes from a patient presenting with a lethal form of junctional epidermolysis bullosa characterized by a homozygous mut...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.9-1359
更新日期:1998-06-10 00:00:00
abstract::Production of clinical-grade gammaretroviral vectors for ex vivo gene delivery requires a scalable process that can rapidly generate large amounts of vector supernatant, clear large numbers of residual packaging cells with minimal decreases in vector titer, and satisfy all current regulatory guidelines regarding produ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2010.064
更新日期:2011-01-01 00:00:00
abstract::Protein transduction domains (PTD), which can transport proteins or peptides across biological membranes, have been identified in several proteins of viral, invertebrate, and vertebrate origin. Here, we evaluate the immunological and biological consequences of including PTD in synthetic peptides and in DNA vaccines th...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303401753153938
更新日期:2001-10-10 00:00:00
abstract::With the aim of developing new gene transfer tools for treating CF with gene therapy, we have synthesized a novel family of molecules named cationic phosphonolipids. The most efficient among them were selected by in vitro screening to compare their activities in vivo in mouse lungs. We used a reporter gene whose activ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.16-2309
更新日期:1998-11-01 00:00:00
abstract::This study focuses on the design, construction, and evaluation of a chimeric promoter for gene therapy applications where it is desirable to have low-level basal expression of the newly transferred gene, which can be induced to higher levels of expression by the administration of pharmacologic agents that can be safel...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.15-1883
更新日期:1996-10-01 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::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::Gene therapy has evolved into a tempting strategy for the management of cancer and other life-threatening diseases. Various approaches employ retroviral vectors to deliver the therapeutic gene. The profound knowledge about retrovirus biology allows the generation of increasingly advanced vector systems as well as an a...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2007.071
更新日期:2008-01-01 00:00:00
abstract::The hepatocarcinoma-intestine-pancreas (HIP) gene, also called pancreatitis-associated protein-1 (PAP1) or Reg IIIalpha, is activated in most human hepatocellular carcinomas (HCCs) but not in normal liver, which suggests that HIP regulatory sequence could be used as efficient liver tumor-specific promoters to express ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2007.153
更新日期:2008-09-01 00:00:00
abstract::Murine skeletal muscle cells transduced with foreign genes and tissue engineered in vitro into bioartificial muscles (BAMs) are capable of long-term delivery of soluble growth factors when implanted into syngeneic mice (Vandenburgh et al., 1996b). With the goal of developing a therapeutic cell-based protein delivery s...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950018643
更新日期:1999-03-01 00:00:00
abstract::The objective of this phase II investigation is to assess the safety and efficacy of a plasmid mediated approach to induce angiogenesis/arteriogenesis with the angiomatrix protein Del-1 (developmentally regulated endothelial locus 1), in subjects with intermittent claudication (IC) secondary to peripheral arterial dis...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1089/104303404323142060
更新日期:2004-06-01 00:00:00
abstract::Evaluation of the potential role of dendritic cells (DCs) as adjuvants for tumor vaccination has focused primarily on techniques that load DCs with peptide tumor antigens. Our aim has been to optimize the induction of antitumor immunity by enhancing the ability of DCs to present tumor-associated antigens endogenously ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.11-1355
更新日期:1997-07-20 00:00:00
abstract::Vectors based on lentiviruses have become potent tools for efficient gene transfer to multiple cell types both in vitro and in vivo. In part this is attributable to the stability of transduction afforded by integration into the target cell genome. However, evidence indicates that episomal forms of the vector can also ...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2007.013
更新日期:2007-06-01 00:00:00
abstract::Heme oxygenase 1 (HO-1) is an inducible enzyme that catalyzes heme to generate bilirubin, ferritin, and carbon monoxide. Because enhanced expression of HO-1 confers protection against many types of cell and tissue damage by modulating apoptotic cell death or cytokine expression profiles, we hypothesized that adenoviru...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340260355356
更新日期:2002-11-01 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::Interleukin (IL)-12 has been reported to induce cellular immune responses for protection against tumor formation. Here we investigate the utility of adenoviral delivery of IL-12 as an adjuvant for a human papillomavirus E7 subunit vaccine in a mouse tumor challenge model. Direct intratumoral injection of AdIL-12 resul...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303403769211619
更新日期:2003-10-10 00:00:00
abstract::The use of viral thymidine kinase (TK) gene coupled with the administration of ganciclovir to render cancer cell death has been studied extensively. Many of these experiments utilized retrovirus to transfer the TK gene under the control of a nonspecific promoter. Because nonspecific expression of the viral TK gene may...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.4-463
更新日期:1996-03-01 00:00:00
abstract::CRISPR-based technology has been adapted to achieve a wide range of genome modifications including transcription regulation. The focus of this review is on the application of CRISPR-based platforms such as nuclease-deficient Cas9 and Cas12a, to achieve targeted gene activation. We review studies to date that have empl...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2020.241
更新日期:2021-01-15 00:00:00
abstract::Recombinant adeno-associated virus (AAV)-based vectors expressing therapeutic gene products have shown great potential for human gene therapy. One major challenge for translation of promising research to clinical development is the manufacture of sufficient quantities of AAV vectors that meet stringent standards for p...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2009.064
更新日期:2009-07-01 00:00:00
abstract::The bystander effect is an important part of tumor kill using gene-directed enzyme prodrug therapy (GDEPT). Recently, we have described a novel enzyme prodrug system using bacterial nitroreductase and the prodrug CB1954 (NTR/CB1954). We demonstrate here the presence of a cell-permeable cytotoxic activity in the condit...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.6-709
更新日期:1997-04-10 00:00:00
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-b...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.079
更新日期:2019-05-01 00:00:00
abstract::Metabolic myopathies are a diverse group of rare diseases in which impaired breakdown of stored energy leads to profound muscle dysfunction ranging from exercise intolerance to severe muscle wasting. Metabolic myopathies are largely caused by functional deficiency of a single gene and are generally subcategorized into...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2013.2514
更新日期:2013-11-01 00:00:00
abstract::Current clinical gene therapy protocols for the treatment of human immunodeficiency virus type 1 (HIV-1) infection often involve the ex vivo transduction and expansion of CD4+ T cells derived from HIV-positive patients at a late stage in their disease (CD4 count <400). These protocols involve the transduction of T cel...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.4-487
更新日期:1998-03-01 00:00:00
abstract::Adult T cell leukemia/lymphoma (ATL) is derived from CD4+ T cells and has a poor prognosis because of its resistance to chemotherapy. To evaluate the effectiveness of gene therapy for ATL, the effect of ganciclovir on ATL cell lines transfected with the thymidine kinase gene of herpes simplex virus type 1 (HSV-TK) was...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.18-2203
更新日期:1996-12-01 00:00:00
abstract::Classical gene therapy for cystic fibrosis has had limited success because of immune response against viral vectors and short-term expression of cDNA-based transgenes. These limitations could be overcome by delivering the complete genomic CFTR gene on nonintegrating human artificial chromosomes (HACs). Here, we report...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2009.225
更新日期:2010-09-01 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