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A functionally active retrovirus vector for gene therapy in Fanconi anemia
group C
CE Walsh, M Grompe, E Vanin, M Buchwald, NS Young, AW Nienhuis and JM Liu
Hematology Branch, NHLBI, National Institutes of Health, Bethesda, MD
20892.
Fanconi anemia (FA) is a rare genetic disorder characterized by progressive
pancytopenia, congenital abnormalities, and a predisposition to malignancy.
Recently, mutation in a novel gene named FACC (Fanconi anemia C
complementing) has been identified as causing one type of FA. Here, we
report successful functional complementation of four FA(C) cell lines using
a retroviral vector to transfer a copy of the normal FACC gene. The
hallmark of the FA cell phenotype is extreme sensitivity to cross-linking
agents such as mitomycin C (MMC). Cell lines transduced by FACC viral
vectors were distinguished by their ability to grow at concentrations of
MMC several orders of magnitude higher than those concentrations inhibitory
of parental controls. The genetically corrected cell lines were analyzed
for susceptibility to MMC-induced chromosomal breakage and were found to
have been normalized. These two different assays confirmed that our
retroviral vectors were capable of transferring a functional FACC gene to
lymphoid cell lines established from FA(C) patients. We next analyzed the
ability of our viral vectors to functionally correct hematopoietic
progenitor cells from a patient bearing a splice donor mutation. Progenitor
cells were purified by an immunoaffinity column to enrich for cells with
high CD34 expression. Similar to FA lymphoid cell lines, this patient's
CD34-enriched cells were extremely sensitive to MMC. After infection of
these progenitor cells with viral vectors bearing normal FACC, increased
numbers of colonies formed both in the absence and presence of < or = 5
nmol/L MMC, but no colonies formed from uninfected cells, even in the
absence of MMC. Polymerase chain amplification was used to confirm proviral
DNA integration. Thus, retroviral vectors can be engineered to transfer a
normal FACC gene to lymphoid cell lines and primary hematopoietic cells
bearing four different FACC mutations. FA stem cells rescued by gene
transduction should have a selective growth advantage within the
hypoplastic FA marrow environment in vivo. These experiments suggest that
gene therapy may be an effective treatment strategy for FA.
Volume 84,
Issue 2,
pp. 453-459,
07/15/1994
Copyright © 1994 by The American Society of Hematology
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