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Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2536-2542
Improved muscle-derived expression of human coagulation factor
IX from a skeletal actin/CMV hybrid enhancer/promoter
J. Nathan Hagstrom,
Linda B. Couto,
Ciaran Scallan,
Melissa Burton,
Mark L. McCleland,
Paul A. Fields,
Valder R. Arruda,
Roland W. Herzog, and
Katherine A. High
From the Departments of Pediatrics and Pathology, University of
Pennsylvania Medical Center and The Children's Hospital of
Philadelphia, Philadelphia, PA; Avigen Inc, Alameda, CA; and Institute
for Human Gene Therapy, University of Pennsylvania, Philadelphia, PA.
Hemophilia B is caused by the absence of functional coagulation
factor IX (F.IX) and represents an important model for treatment of
genetic diseases by gene therapy. Recent studies have shown that
intramuscular injection of an adeno-associated viral (AAV) vector into
mice and hemophilia B dogs results in vector dose-dependent, long-term
expression of biologically active F.IX at therapeutic levels. In this
study, we demonstrate that levels of expression of approximately 300 ng/mL (6% of normal human F.IX levels) can be reached by intramuscular
injection of mice using a 2- to 4-fold lower vector dose
(1 × 1011 vector genomes/mouse, injected into 4 intramuscular sites) than previously described. This was accomplished
through the use of an improved expression cassette that uses the
cytomegalovirus (CMV) immediate early enhancer/promoter in combination
with a 1.2-kilobase portion of human skeletal actin promoter. These
results correlated with enhanced levels of F.IX transcript and secreted F.IX protein in transduced murine C2C12 myotubes. Systemic F.IX expression from constructs containing the CMV enhancer/promoter alone
was 120 to 200 ng/mL in mice injected with 1 × 1011
vector genomes. Muscle-specific promoters performed poorly for F.IX
transgene expression in vitro and in vivo. However, the incorporation of a sequence from the  -skeletal actin promoter containing at least
1 muscle-specific enhancer and 1 enhancer-like element further improved
muscle-derived expression of F.IX from a CMV enhancer/promoter-driven expression cassette over previously published results. These findings will allow the design of a clinical protocol for therapeutic levels of
F.IX expression with lower vector doses, thus enhancing efficacy and
safety of the protocol.
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