1.0 BACKGROUND AND RATIONALE 
1 . 1 Disease Background/Current Treatment 
Fanconi anemia (FA) is an autosomal recessive genetic 
disorder characterized by progressive pancytopenia, 
congenital abnormalities, and a predisposition to 
malignancy ( 1) . Most patients present at age 6-8 and 
die as young adults from complications of severe bone 
marrow aplasia or from the development of acute 
leukemia . 
Therapy is currently limited to allogeneic bone 
marrow transplantation from a normal HLA- identical 
sibling(l). Unfortunately, the majority of FA patients 
will not have a suitable donor. Non-HLA-matched donors 
and HLA-matched unrelated donors could be used, but the 
morbidity and mortality risk is much greater than that 
seen with patients having an HLA-matched sibling donor. 
Somatic cell methods have established that at 
least four different genes can cause FA(2). Recently, 
mutation in a novel gene named FACC (Fanconi anemia C- 
complementing) has been identified as causing one type 
of FA(3) . The gene sequence shares no similarities to 
any known gene and does not possess known functional 
motifs. FACC maps to chromosome 9q and encodes a set 
of cDNAs that share the same coding region but differ 
at both 5' and 3' untranslated regions (2 , 3 ) . The 
protein has a predicted size of 63 kD. FACC mutations, 
which introduce splicing errors or stop codons, have 
been identified in approximately 15% of FA patients (4). 
1 . 2 Stratecry of Gene Therapy 
The hallmark of the FA cell phenotype is extreme 
sensitivity to bifunctional DNA cross-linking agents 
[such as mitomycin C (MMC) and diepoxybutane (DEB) ] 
resulting in chromosomal instability and cell death(5). 
It is thought that this hypersensitivity is a result of 
a defect in the repair of DNA damage. Transfer of a 
normal FACC cDNA corrects the phenotypic defect, 
resulting in normalized cell growth in the presence of 
agents such as MMC. FA hematopoietic stem cells rescued 
by gene therapy should have a selective growth 
advantage within the hypoplastic marrow environment. 
For these reasons, we believe that a gene therapy 
strategy may be an effective treatment strategy for 
FA(C) . 
1 . 3 Description of Viral Vector 
See appendix. 
1 . 4 Preclinical 
Retroviral mediated gene transfer in rodent and large 
animal transplant models 
Extensive preclinical studies have documented the 
ability of retroviral vectors to transfer genes to the 
hematopoietic stem cells of mice(6-7). Since the 
target cells must be cycling to facilitate efficient 
gene transfer, growth factors are included in the 
infection mixture; in particular, stem cell factor 
(SCF) , interleukin- 3 (IL-3) and interleukin- 6 (IL-6) 
have been shown to increase transduction 
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Recombinant DNA Research, Volume 19 
