Naked plasmid DNA-based alpha-galactosidase A gene transfer partially reduces systemic accumulation of globotriaosylceramide in Fabry mice.
Fabry disease is an X-linked recessive inborn metabolic disorder in which a deficiency in lysosomal enzyme alpha-galactosidase A (Gal A) causes the systemic accumulation of globotriaosylceramide (Gb3). Although many investigators have attempted to treat alpha-Gal A knock-out mice (Fabry mice) with gene therapy, no report has demonstrated therapeutic effects by the retrograde renal vein injection of naked DNA. We recently developed a naked plasmid vector-mediated kidney-targeted gene transfer technique. A solution containing naked plasmid DNA encoding human alpha-Gal A (pKSCX-alpha-Gal A) was rapidly injected into the left kidney of Fabry mice (pKSCX-alpha-Gal A mice). pKSCX was used for mock transfections (pKSCX mice). We confirmed that vector-derived human alpha-Gal A mRNA was present in the left kidney but not in other tissues, by reverse transcriptase polymerase chain reaction. Compared with the pKSCX mice, the pKSCX-alpha-Gal A mice showed partial therapeutic effects: increased alpha-Gal A activity in the injected kidney and in the liver, heart, and plasma, and decreased Gb3 in the injected kidney, contralateral kidney, liver, heart, and spleen. Our results demonstrated that, although further studies are needed to improve the outcome, this method has promise as a potential treatment option for Fabry disease.
Nakamura
Gen
G
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan .
Maruyama
Hiroki
H
Ishii
Satoshi
S
Shimotori
Masaaki
M
Kameda
Shigemi
S
Kono
Toru
T
Miyazaki
Jun-ichi
J
Kulkarni
Ashok B
AB
Gejyo
Fumitake
F
D000818:Animals; D000906:Antibodies / Q000276:immunology; D001835:Body Weight; D019556:COS Cells; D002522:Chlorocebus aethiops; D004247:DNA / Q000235:genetics*; D000795:Fabry Disease / Q000201:enzymology* / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D009928:Organ Specificity; D010957:Plasmids / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D019076:Transgenes / Q000235:genetics*; D014281:Trihexosylceramides / Q000378:metabolism*; D000519:alpha-Galactosidase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; D012333:RNA, Messenger; D014281:Trihexosylceramides; C018549:globotriaosylceramide; D004247:DNA; D000519:alpha-Galactosidase