Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.6.1 (
sulfatase
)
3,205
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Trembler mice are affected by dominantly inherited neuropathy. Total lipid content and sulfatides were decreased in peripheral nerves from 15-day-old mutants. The proportion of sulfatides in per cent of total lipids was similar in control and Trembler nerves. The specific activity of ceramide galactosyltrnsferase, the enzyme responsible for the synthesis of cerebrosides, was 36 and 13% of controls, in young and adult. Trembler nerves, respectively. In contrast, cerebroside sulfotransferase activities were increased by 257 and 172% in young and adult Trembler sciatic nerves, respectively. No activator or inhibitor effect could be demonstrated. In Trembler
PNS
, Km, Vmax and heat sensitivity of CST differed from controls. Low levels of substrate and high
arylsulfatase A
activity (218% of controls) could explain the lack of sulfatide accumulation. The increased in vivo sulfate and galactose incorporation into non-lipidic material couild reflect the overproduction of endoneurial and perineurial connective tissue, whereas the high turnover rate of sulfatides could be correlated with intense demyelination and remyelination observed in Trembler
PNS
.
...
PMID:Abnormal sulfate metabolism in a hereditary demyelinating neuropathy. 610 27
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of
arylsulfatase A
(
ARSA
) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (
PNS
) and central nervous system (CNS), and early death of MLD patients. The
ARSA
knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the
PNS
and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of
ARSA
knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of
ARSA
knockout mice at a symptomatic stage results in sustained expression of
ARSA
, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.
...
PMID:Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer. 1709 7
Leukodystrophies are rare diseases caused by defects in the genes coding for lysosomal enzymes that degrade several glycosphingolipids. Gene therapy for leukodystrophies requires efficient distribution of the missing enzymes in CNS tissues to prevent demyelination and neurodegeneration. In this work, we targeted the external capsule (EC), a white matter region enriched in neuronal projections, with the aim of obtaining maximal protein distribution from a single injection site. We used bidirectional (bd) lentiviral vectors (LV) (bdLV) to ensure coordinate expression of a therapeutic gene (beta-galactocerebrosidase, GALC;
arylsulfatase A
, ARSA) and of a reporter gene, thus monitoring simultaneously transgene distribution and enzyme reconstitution. A single EC injection of bdLV.GALC in early symptomatic twitcher mice (a murine model of globoid cell leukodystrophy) resulted in rapid and robust expression of a functional GALC protein in the telencephalon, cerebellum, brainstem and spinal cord. This led to global rescue of enzymatic activity, significant reduction of tissue storage and decrease of activated astroglia and microglia. Widespread protein distribution and complete metabolic correction were also observed after EC injection of bdLV.ARSA in a mouse model of metachromatic leukodystrophy. Our data indicated axonal transport, distribution through cerebrospinal fluid flow and cross-correction as the mechanisms contributing to widespread bioavailability of GALC and ARSA proteins in CNS tissues. LV-mediated gene delivery of lysosomal enzymes by targeting highly interconnected CNS regions is a potentially effective strategy that, combined with a treatment able to target the
PNS
and peripheral organs, may provide significant therapeutic benefit to patients affected by leukodystrophies.
...
PMID:Widespread enzymatic correction of CNS tissues by a single intracerebral injection of therapeutic lentiviral vector in leukodystrophy mouse models. 2020 70
