Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in glial cells and neurons, the result of an inherited deficiency of arylsulfatase A (ARSA; EC 3.1.6.

Safe, efficient, and reproducible gene therapy of the brain in the dog models of Sanfilippo and Hurler syndromes.

Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years.

An unusual homozygous arylsulfatase: a pseudodeficiency in a metachromatic leukodystrophy Tunisian patient.

Metachromatic leukodystrophy is an autosomal recessive neurodegenerative lysosomal disease characterized by a deficiency of the lysosomal enzyme arylsulfatase A and the subsequent accumulation of sulfatide in neuronal and visceral tissues. Clinical diagnosis is usually confirmed by in vitro analysis of arylsulfatase A activity but may be complicated in cases of arylsulfatase A pseudodeficiency and sphingolipid activators protein deficiency. We report the case of a 3-year-old boy who presented a severe form of late infantile metachromatic leukodystrophy.

Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.

Background: In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease.

Methodology/principal Findings: In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88.

Gene therapy of the brain in the dog model of Hurler's syndrome.

Objective: A defect of the lysosomal enzyme alpha-L-iduronidase (IDUA) interrupts the degradation of glycosaminoglycans in mucopolysaccharidosis type I, causing severe neurological manifestations in children with Hurler's syndrome. Delivery of the missing enzyme through stereotactic injection of adeno-associated virus vectors coding for IDUA prevents neuropathology in affected mice. We examined the efficacy and the safety of this approach in enzyme-deficient dogs.

Prevention of neuropathology in the mouse model of Hurler syndrome.

A defect of the lysosomal enzyme alpha-L-iduronidase (IDUA) interrupts heparan and dermatan sulfate degradation and causes neuropathology in children with severe forms of mucopolysaccharidosis type I (MPSI, Hurler syndrome). Enzyme substitution therapy is beneficial but ineffective on the central nervous system. We could deliver the missing enzyme to virtually the entire brain of MPSI mice through a single injection of gene transfer vectors derived from adenoassociated virus serotype 2 (AAV2) or 5 (AAV5) coding for human IDUA.

Expression and distribution of distinct variants of E-MAP-115 during proliferation and differentiation of human intestinal epithelial cells.

Epithelial cell proliferation and differentiation occur concomitant with striking remodeling of the cytoskeleton. Microtubules (MTs) play important roles in these processes, during which the MTs themselves are reorganized and stabilized by microtubule-associated proteins (MAPs). Among the proteins classified as structural MAPs, E-MAP-115 (also named ensconsin) is preferentially expressed in cells of epithelial origin.