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Recombinant adeno-associated virus-mediated gene transfer into
hematopoietic progenitor cells [published erratum appears in Blood 1995 Feb
1;85(3):862]
S Goodman, X Xiao, RE Donahue, A Moulton, J Miller, C Walsh, NS Young, RJ Samulski and AW Nienhuis
Clinical Hematology Branch, National Heart, Lung and Blood Institute,
Bethesda, MD.
Recombinant adeno-associated viruses (rAAV) containing only the inverted
terminal repeats (ITR) from the wild-type virus are capable of stable
integration into the host cell genome, and expression of inserted genes in
cultured cells. We have now defined the ability of rAAV to introduce genes
into primary hematopoietic progenitors. A vector was constructed containing
the coding sequences for beta- galactosidase (beta-gal), including a
nuclear localization signal, under the control of a strong viral promotor.
Infectious vector particles were prepared by cotransfection of the vector
plasmid with a second plasmid that contained the coding sequences for AAV
proteins into adenovirus-infected human embryonic kidney cells. These
vector preparations transferred and expressed the beta-gal gene in human
K562 erythroleukemia and Detroit 6 cells. Positive immunoselection yielded
a population of enriched CD34+ cells that were transduced with the rAAV
beta-gal vector. Nuclear localized enzyme expression was documented in 60%
to 70% of infected cells. Progenitor-derived colonies that developed after
2 weeks in clonogenic cultures were shown to have viral- associated DNA at
an estimated copy number of 1 to 2 per cell using a semiquantitative
polymerase chain reaction (PCR) method. Integration of AAV into
hematopoietic progenitors was documented using wild-type virus, as its
genome may integrate at a preferred site on chromosome 19. Our data suggest
that rAAV will transfer and express genes in primitive hematopoietic
progenitors with high frequency, and support the development of this vector
system for therapeutic gene transfer.
Volume 84,
Issue 5,
pp. 1492-1500,
09/01/1994
Copyright © 1994 by The American Society of Hematology
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