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Blood, 1 June 2002, Vol. 99, No. 11, pp. 3923-3930
GENE THERAPY
A new adenoviral helper-dependent vector results in
long-term therapeutic levels of human coagulation factor IX at low
doses in vivo
Anja Ehrhardt and
Mark A. Kay
From the Department of Pediatrics and Genetics, School
of Medicine, Stanford University, CA.
We have developed a new helper-dependent (HD) adenoviral
vector FTC that contains 3 cis-acting
sequences as stuffer DNA: a human fragment of alphoid repeat DNA,
matrix-attachment regions (MARs), and the hepatocyte control
region enhancer. To determine the most robust human coagulation
factor IX (hFIX) expression cassette in an adenovirus, we first tested
different hFIX expression sequences with or without flanking MARs in
first-generation adenoviral vectors. After intravenous infusion of the
vector, serum levels of up to 100 000 ng/mL hFIX (normal level, 5000 ng/mL) were obtained at nontoxic doses. In order to make a direct
comparison, a first-generation and a gene-deleted vector with identical
hFIX expression cassettes were constructed. Both first-generation and
HD adenovirus-treated animals demonstrated a threshold effect in a
dose-response study. With the administration of 2 × 109
transducing particles of either vector, supraphysiological serum levels
of hFIX were obtained, with the highest expression (41 000 ng/mL)
occurring during the first 2 months after injection. The serum factor
IX concentrations, while remaining in the therapeutic range, slowly
declined by 95% over a period of 1 year. At this dose, interleukin-6
and tumor necrosis factor- serum concentrations were elevated in
animals that received the first-generation but not the HD vector. This
study compares the properties of a gene-deleted and first-generation
adenovirus with equivalent expression cassettes and suggests that the
cis-DNA elements contained in the vector and expression
cassette have important effects on gene expression in vivo.
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