Successful transduction of oligodendrocytes and restoration of arylsulfatase A deficiency in metachromatic leukodystrophy fibroblasts using an adenovirus vector.
Metachromatic leukodystrophy (MLD) is an inherited metabolic disease which is characterized by deficient activity of arylsulfatase A (ASA). This deficiency causes progressive accumulation of cerebroside sulfate (CS) in oligodendrocytes (OLs) in the brain resulting in dysmyelination. We are developing approaches for treating MLD based on direct delivery of ASA genes to brain. In this paper, we report a recombinant adenovirus (Adex1SRLacZL) that efficiently transduces OLs. Moreover, transduction and expression of the human transgene was efficient in primary fibroblasts from MLD patients exposed to similar recombinant adenovirus carrying the ASA gene (Adex1SRASA) In addition, the expressed ASA protein was correctly targeted to lysosomes and was immunoreactive to anti-ASA antibody. The enzymatic activity of ASA in MLD patient cells is corrected from the deficient state to 2.3 to 5.0 times the activity of normal control cells. These results demonstrate the correction of ASA deficiency by a recombinant adenovirus that is potentially useful for transferring the gene to brain.
Ohashi
T
T
Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.
Watabe
K
K
Sato
Y
Y
Saito
I
I
Barranger
J A
JA
Eto
Y
Y
D000256:Adenoviridae / Q000235:genetics; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000172:deficiency* / Q000235:genetics; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D009836:Oligodendroglia / Q000473:pathology*; D011994:Recombinant Proteins / Q000235:genetics
D011994:Recombinant Proteins; D002553:Cerebroside-Sulfatase