Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells. Gene Ther 2007 Feb;14(3):256-65
Date
08/25/2006Pubmed ID
16929352DOI
10.1038/sj.gt.3302839Scopus ID
2-s2.0-33846544543 (requires institutional sign-in at Scopus site) 44 CitationsAbstract
A deficiency in alpha-galactosidase A (alpha-gal A) activity causes Fabry disease. Virus-based delivery of genes can correct cells and establish a sustained supply of therapeutic proteins. Recombinant lentiviral vectors (LVs) show promise in this context. We first demonstrate LV-mediated marking of peripheral blood (PB) cells by transduction/transplantation of hematopoietic stem/progenitor cells. Stable enGFP expression was observed in PB for 37 weeks. Next, we transplanted Fabry mice with bone marrow mononuclear cells (BMMNCs) transduced a single time with a LV encoding the human alpha-gal A cDNA. Sustained expression of functional alpha-gal A in Fabry mice was observed over 24 weeks. Plasma alpha-gal A activity from treated Fabry mice was two-fold higher than wild-type controls. Increased alpha-gal A activity, often to supra-normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed. In secondary bone marrow transplantations, Fabry mice showed multilineage marking of PB, splenocytes and BMMNCs, along with therapeutic levels of alpha-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34(+) cells from a Fabry patient and observed corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease.
Author List
Yoshimitsu M, Higuchi K, Ramsubir S, Nonaka T, Rasaiah VI, Siatskas C, Liang SB, Murray GJ, 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
AnimalsB-Lymphocytes
Fabry Disease
Flow Cytometry
Genetic Therapy
Genetic Vectors
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Humans
Lentivirus
Mice
Mice, Knockout
Models, Animal
Transduction, Genetic
alpha-Galactosidase
