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High levels of human glucocerebrosidase activity in macrophages of long-
term reconstituted mice after retroviral infection of hematopoietic stem
cells
PH Correll, S Colilla, HP Dave and S Karlsson
Molecular and Medical Genetics Section, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892.
Gaucher disease is a leading candidate for somatic gene therapy using bone
marrow (BM) cells as target tissue. Towards this end, we have constructed a
retroviral vector (LG) in which the human glucocerebrosidase (GC) cDNA is
driven by the Moloney murine leukemia virus (MoMLV) long terminal repeat
(LTR). Day 12 to 14 colony-forming unit-spleen progenitor cells were
infected by the LG virus with a 100% efficiency, and GC messenger RNA
(mRNA) and protein were detected in the progeny of these cells. Tissues
from long-term reconstituted mice analyzed 8 months posttransplantation
with LG-infected BM contained the intact provirus at greater than 1 copy
per cell, indicating effective infection of hematopoietic stem cells. Human
GC mRNA generated by the viral LTR was detected in macrophages as well as
other hematopoietic cells. Enzyme activity was increased fivefold and
twofold in macrophages from BM and spleen, respectively, and could be
precipitated with an antibody specific for human GC. Immunohistochemical
analysis detected the human GC protein in 81% of the macrophages from five
recipient mice. These data indicate that, after transduction of
hematopoietic stem cells, the LG vector is capable of directing expression
of human GC in the majority of macrophages from long-term reconstituted
mice and producing enzyme levels comparable with endogenous mouse activity,
suggesting that this virus may be useful in the treatment of Gaucher
disease.
Volume 80,
Issue 2,
pp. 331-336,
07/15/1992
Copyright © 1992 by The American Society of Hematology
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