Bioluminescent imaging of a marking transgene and correction of Fabry mice by neonatal injection of recombinant lentiviral vectors. Proc Natl Acad Sci U S A 2004 Nov 30;101(48):16909-14
Date
11/20/2004Pubmed ID
15550536Pubmed Central ID
PMC534735DOI
10.1073/pnas.0407572101Scopus ID
2-s2.0-10044223213 (requires institutional sign-in at Scopus site) 79 CitationsAbstract
Successful therapy for many inherited disorders could be improved if the intervention were initiated early. This is especially true for lysosomal storage disorders. Earlier intervention may allow metabolic correction to occur before lipid buildup has irreversible consequences and/or before the immune system mounts limiting responses. We have been developing gene therapy to treat lysosomal storage disorders, especially Fabry disease. We describe studies directed toward metabolic correction in neonatal animals mediated by recombinant lentiviral vectors. To develop this method, we first injected a marking lentiviral vector that engineers expression of luciferase into the temporal vein of recipient neonatal animals. The use of a cooled charged-coupled device camera allowed us to track transgene expression over time in live animals. We observed intense luciferase expression in many tissues, including the brain, that did not diminish over 24 weeks. Next, we injected neonatal Fabry mice a single time with a therapeutic lentiviral vector engineered to express human alpha-galactosidase A. The injection procedure was well tolerated. We observed increased plasma levels of alpha-galactosidase A activity starting at our first plasma collection point (4 weeks). Levels of alpha-galactosidase A activity were found to be significantly elevated in many tissues even after 28 weeks. No immune response was observed against the corrective transgene product. Increased levels of enzyme activity also led to significant reduction of globotriaosylceramide in the liver, spleen, and heart. This approach provides a method to treat lysosomal storage disorders and other disorders before destructive manifestations occur.
Author List
Yoshimitsu M, Sato T, Tao K, Walia JS, Rasaiah VI, Sleep GT, Murray GJ, Poeppl AG, Underwood J, West L, Brady RO, Medin JAAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Cell Line
Chromatography, High Pressure Liquid
Enzyme-Linked Immunosorbent Assay
Fabry Disease
Genetic Vectors
Humans
Immunohistochemistry
Lentivirus
Mice
Transgenes
