Partial correction of the α-galactosidase A deficiency and reduction of glycolipid storage in Fabry mice using synthetic vectors

• Published in: The journal of gene medicine Vol. 6; no. 1; pp. 85 - 92
• Main Authors: Przybylska, Malgorzata, Wu, I-Huan, Zhao, Hongmei, Ziegler, Robin J., Tousignant, Jennifer D., Desnick, Robert J., Scheule, Ronald K., Cheng, Seng H., Yew, Nelson S.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2004
• Subjects: alpha-Galactosidase - biosynthesis; alpha-Galactosidase - genetics; Animals; Disease Models, Animal; Fabry disease; Fabry Disease - genetics; Fabry Disease - therapy; Female; Gene Expression; gene therapy; Genetic Therapy; Genetic Vectors; glycolipids; Lipids; liposomes; lysosomal storage diseases; Mice; Mice, Inbred BALB C; plasmids; Plasmids - genetics; systemic delivery; Trihexosylceramides - metabolism
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.468

Background Fabry disease is a recessive, X‐linked disorder caused by a deficiency of the lysosomal enzyme α‐galactosidase A, leading to an accumulation of the glycosphingolipid globotriaosylceramide (GL‐3) in most tissues of the body. The goal of this study was to determine if systemic delivery of a nonviral vector could correct the enzyme deficiency and reduce the levels of GL‐3 in different tissues of a transgenic knockout mouse model of the disease. Methods Cationic lipid was complexed with a CpG‐depleted plasmid DNA vector and then injected intravenously into Fabry mice. The levels of α‐galactosidase A and GL‐3 in different tissues were assayed at various time points after injection. Results Expression of α‐galactosidase A was detected in the different tissues of Fabry mice for up to 3 months after complex administration, but resulted in minimal reductions in GL‐3 levels. However, the use of the anti‐inflammatory drug dexamethasone and multiple dosing increased α‐galactosidase A expression and resulted in significant reductions of GL‐3 in all the organs with the exception of the kidney. In addition, injecting complex into young Fabry mice partially prevented the normal accumulation of GL‐3 in the heart, lung, and liver. Conclusions Systemic delivery of a cationic lipid–pDNA complex partially corrected the enzyme deficiency and reduced glycolipid storage in a mouse model of Fabry disease. The results are one of the few demonstrations of long‐term efficacy in a genetic disease model using nonviral vectors. However, substantial improvements in expression, especially in critical organs such as the kidney, are required before these vectors can become a viable approach to treat Fabry disease and other lysosomal storage disorders. Copyright © 2003 John Wiley & Sons, Ltd.