Abstract：
:There are a number of reasons for choosing ornithine transcarbamylase (OTC) deficiency as a candidate for gene therapy: the gene has been cloned; the disorder is relatively common; the current clinical outcome is poor; and there are authentic animal models. In considering the development of gene therapy for OTC deficiency, we focused on the use of in vivo gene therapy with an adenoviral vector. Using the partially OTC-deficient sparse fur mouse we found transduction and expression could be achieved using an intravenous infusion of a recombinant adenovirus containing the OTC cDNA. The results were transient as a result of immune activation in response to the vector and vector-transduced cells. By modifying the adenoviral construct, creating an E1 deletion-E2 temperature-sensitive mutation, we blunted the cytotoxic T lymphocyte immune response and achieved correction of biochemical abnormalities for 2-3 months. We also found that transduction and expression following gene transfer occurred sufficiently rapidly to protect against acute hyperammonaemia within 24 h. Subsequent preclinical studies in mice and non-human primates demonstrated that E1-E4-deleted vectors had a substantially improved safety profile and similar efficacy. With this evidence of efficacy and safety of adenoviral vectors, we are embarking on a phase I trial of intravascular gene transfer using an E1-E4-deleted vector in adults with partial OTC deficiency.
journal_name
J Inherit Metab Disjournal_title
Journal of inherited metabolic diseaseauthors
Raper SE,Wilson JM,Yudkoff M,Robinson MB,Ye X,Batshaw MLdoi
10.1023/a:1005369926784subject
Has Abstractpub_date
1998-01-01 00:00:00pages
119-37eissn
0141-8955issn
1573-2665journal_volume
21 Suppl 1pub_type
杂志文章abstract：:Diagnostic information is supplied for the early detection of subacute and chronic forms of type I tyrosinaemia. ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01799947
更新日期：1991-01-01 00:00:00
abstract：:Unlike normal human cells, cultured fibroblasts from patients with argininosuccinic aciduria cannot synthesize arginine from citrulline because they have a deficiency of argininosuccinic acid lyase (ASL). We have found that V79, a Chinese hamster cell line, cannot grow on citrulline. Although these cells show a normal...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF02312521
更新日期：1980-01-01 00:00:00
abstract：:Five new patients are reported and the pathogenesis of the hypoglycaemia without ketogenesis is discussed. This report extends a recent review. ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01800058
更新日期：1988-01-01 00:00:00
abstract：:Congenital lactic acidoses form a heterogeneous group of disorders: this paper considers primarily defects of the pyruvate dehydrogenase complex and the respiratory chain. Attempts to treat these disorders are hampered by uncertainty concerning the pathophysiology and by the central role of the enzymes in cellular met...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/BF01799117
更新日期：1996-01-01 00:00:00
abstract：:A 32 year-old asymptomatic male came to our attention with a 21-year history, documented elsewhere, of puzzling increases in his serum transaminase level. At first, very low serum ceruloplasmin level suggested Wilson disease. Two liver biopsies showed mild portal inflammation, steatosis and mild fibrosis. Further inve...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/s10545-008-1004-9
更新日期：2008-12-01 00:00:00
abstract：:Aldolase B is critical for sugar metabolism, and a catalytic deficiency due to mutations in its gene may result in hereditary fructose intolerance (HFI) syndrome, with hypoglycaemia and severe abdominal symptoms. This report describes two cases of HFI, which were identified by intravenous fructose tolerance test and a...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1022043307569
更新日期：2002-11-01 00:00:00
abstract：:Mixed hyperlipidaemia is a common finding in glycogen storage disease type Ia (GSD Ia). Although cross-sectional studies have demonstrated increases in intermediate-density lipoproteins (IDLs) and reductions in lipoprotein lipase activity, no studies have investigated the dynamics of apolipoprotein B-100 (apo B) metab...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1012407609063
更新日期：2001-10-01 00:00:00
abstract：:We report D-2-hydroxyglutaric aciduria in a neonate with intracranial haemorrhage and absence of the corpus callosum. D-2-hydroxyglutaric acid was confirmed by specific chiral derivatization gas chromatography-mass spectrometry. Absence of the corpus callosum and spontaneous neonatal intracranial haemorrhage should ra...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1024000202364
更新日期：2003-01-01 00:00:00
abstract：:There have been few reports of cases missed by expanded newborn screening. Tandem mass spectrometry was introduced in New South Wales, Australia in 1998 to screen for selected disorders of amino acid, organic acid and fatty acid metabolism. Of 1,500,000 babies screened by 2012, 1:2700 were diagnosed with a target diso...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-014-9727-2
更新日期：2014-11-01 00:00:00
abstract：:Studies on fibroblasts from patients with lactic acidosis of different causes showed secondary metabolic changes in pathways of glucose metabolism. These secondary changes may be important clues to the diagnosis of the many different types of hereditary lactic acidosis. ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01805587
更新日期：1978-01-01 00:00:00
abstract：:Defects of the mitochondrial oxidative phosphorylation (OXPHOS) system are frequent causes of neurological disorders in children. Linkage analysis and DNA sequencing identified a new founder p.G250V substitution in the C20ORF7 complex I chaperone in five Ashkenazi Jewish patients from two families with a combined OXPH...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-011-9348-y
更新日期：2012-01-01 00:00:00
abstract：:Understanding the relationship between genotype and clinical phenotype will clearly aid in the prognosis, treatment and counselling of patients with lysosomal storage diseases (LSDs). This, however, will require the establishment of widely accepted indices with which to score the severity of LSDs, as these diseases ar...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1023/a:1012419823739
更新日期：2001-01-01 00:00:00
abstract：:The liver plays an important rôle in protecting the organism from potentially toxic chemical insults through its capacity to convert lipophiles into more water-soluble metabolites which can be efficiently eliminated from the body via the urine. This protective ability of the liver stems from the expression of a wide v...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/BF01797915
更新日期：1991-01-01 00:00:00
abstract：:There is a failure of growth in hypoxanthine guanine phosphoribosyltransferase deficiency; slow weight gain is marked after the second year of age but is apparent in the birth weights of all eight of our patients for whom we have data. However, head growth and bone development are less affected than weight. A partial ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01800063
更新日期：1987-01-01 00:00:00
abstract：:Achieving the goals of newborn screening is, as for any screening, a balancing act: getting the maximum benefit from screening while producing the minimum harm. The advent of "expanded" newborn screening, with a large number of disorders detectable using a single test, has also posed problems, not new, but now more ob...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-010-9106-6
更新日期：2010-10-01 00:00:00
abstract：:Using a human dihydropteridine reductase (DHPR) cDNA, the frequency of restriction fragment length polymorphisms (RFLPs) with restriction endonucleases AvaII, MspI, NcoI and HinfI was estimated in unrelated, unaffected Japanese. The allele frequencies are different from those found in Caucasians, especially with MspI ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF01800212
更新日期：1990-01-01 00:00:00
abstract：:Gaucher disease is a lysosomal storage disorder caused by a deficiency of the enzyme acid beta-glucosidase. The most prevalent mutant genotype in type I Gaucher disease, N370S/N370S, is commonly thought to confer a mild phenotype presenting in adulthood. To characterize a subset of more severely affected N370S homozyg...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-008-0868-z
更新日期：2008-12-01 00:00:00
abstract：:A new French-Canadian family from the province of Quebec is reported, in which a male child was diagnosed as hyperargininaemic after showing positive tests for cystinuria on neonatal screening. The child has no residual activity of erythrocyte arginase, and a plasma arginine level of 633 mumol/l. Both parents have 32-...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/BF02310878
更新日期：1983-01-01 00:00:00
abstract：BACKGROUND:Hearing loss (HL) is a well-known feature of Fabry disease (FD). Its presence and characteristics have mainly been studied in adult patients, while only limited data are available on the presence and degree of HL in children with FD. This prompted us to study hearing sensitivity in pediatric FD patients. ME...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-017-0051-5
更新日期：2017-09-01 00:00:00
abstract：BACKGROUND:Recent decades have unravelled the molecular background of a number of inborn errors of metabolism (IEM) causing vitamin B6-dependent epilepsy. As these defects interfere with vitamin B6 metabolism by different mechanisms, the plasma vitamin B6 profile can give important clues for further molecular work-up. ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-016-9955-8
更新日期：2016-09-01 00:00:00
abstract：BACKGROUND:Methylmalonic acidemia and intracellular cobalamin metabolism disorders represent a heterogeneous group of inborn errors of metabolism. Most patients will require diagnostic and/or therapeutic procedures frequently requiring sedation or anesthetic management due to neurological and neurocognitive impairments...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/s10545-015-9816-x
更新日期：2015-09-01 00:00:00
abstract：:Spastic paraparesis is a general term describing progressive stiffness and weakness in the lower limbs caused by pyramidal tract lesions. This clinical situation is frequently encountered in adult neurology. The diagnostic survey is usually limited to searching for acquired causes (spinal cord compression, inflammator...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/s10545-007-0745-1
更新日期：2007-11-01 00:00:00
abstract：:This study reports three novel mutations of the methionine adenosyltransferase (MAT) lA gene and confirms that hyperhomocysteinaemia may be a characteristic finding in MAT I/III deficiency. Thus, MAT I/III deficiency is important in the differential diagnoses of hyperhomocysteinaemia, which may lead to clinical compli...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-005-4497-5
更新日期：2005-01-01 00:00:00
abstract：:A battery of self-report psychosocial measures was mailed to 116 patients who had been referred for clinical management (clinic attenders) or laboratory diagnosis (non-clinic attenders) to the London Supraregional Assay Service Centre for Porphyria over the past decade and who tested positive for porphyria. Usable rep...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1012901607040
更新日期：2001-12-01 00:00:00
abstract：:Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. Thi...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-017-0132-5
更新日期：2018-07-01 00:00:00
abstract：:Patients with an inborn error of metabolism (IEM) are deficient of an enzyme involved in metabolism, and as a consequence metabolism reprograms itself to reach a new steady state. This new steady state underlies the clinical phenotype associated with the deficiency. Hence, we need to know the flux of metabolites throu...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1007/s10545-017-0124-5
更新日期：2018-05-01 00:00:00
abstract：:Even early-treated phenylketonuric patients suffer from phenylalanine-associated (mild) neuropsychological impairment. To date it is still unclear whether patients' deficits show a progression on ageing. This unsolved question seems to be an important aspect in the still ongoing debate about how long and how strictly ...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1023/a:1005587915468
更新日期：1999-08-01 00:00:00
abstract：BACKGROUND:Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiolo...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-016-9928-y
更新日期：2016-05-01 00:00:00
abstract：:What next? The Human Genome Project signifies complexity rather than simplification in the relationship between genotype and phenotype. Genotypes are embedded in genomes. Individuality in phenotypes is embedded in components of the phenome (transcriptome, metabolome, proteome, etc.). The phenome, its layers, and its n...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章,评审
doi：10.1023/B:BOLI.0000031100.26546.6e
更新日期：2004-01-01 00:00:00
abstract：:We report a Brazilian girl who was diagnosed as having galactosialidosis (deficiency of protective protein/cathepsin A; PPCA deficiency; GS) at the age of 2 years 6 months during an extensive investigation for renal failure. She was found to have low levels of both β-galactosidase and α-neuraminidase in fibroblasts an...
journal_title：Journal of inherited metabolic disease
pub_type： 杂志文章
doi：10.1007/s10545-008-0730-3
更新日期：2008-12-01 00:00:00
