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Blood, 1 January 2001, Vol. 97, No. 1, pp. 107-113
GENE THERAPY
Systemic delivery of an adenoviral vector encoding canine factor
VIII results in short-term phenotypic correction, inhibitor
development, and biphasic liver toxicity in hemophilia A
dogs
Angela M. Gallo-Penn,
Pamela S. Shirley,
Julie L. Andrews,
Shawn Tinlin,
Sandy Webster,
Cherie Cameron,
Christine Hough,
Colleen Notley,
David Lillicrap,
Michael Kaleko, and
Sheila Connelly
From Queen's University, Kingston, Ontario, Canada,
and Genetic Therapy, Inc, a Novartis Company, Gaithersburg, MD.
Canine hemophilia A closely mimics the human disease and has been
used previously in the development of factor VIII (FVIII) protein
replacement products. FVIII-deficient dogs were studied to evaluate an
in vivo gene therapy approach using an E1/E2a/E3-deficient adenoviral
vector encoding canine FVIII. Results demonstrated a high level of
expression of the canine protein and complete phenotypic correction of
the coagulation defect in all 4 treated animals. However, FVIII
expression was short-term, lasting 5 to 10 days following vector
infusion. All 4 dogs displayed a biphasic liver toxicity, a transient
drop in platelets, and development of anticanine FVIII antibody. Canine
FVIII inhibitor development was transient in 2 of the 4 treated
animals. These data demonstrate that systemic delivery of attenuated
adenoviral vectors resulted in liver toxicity and hematologic changes.
Therefore, the development of further attenuated adenoviral vectors
encoding canine FVIII will be required to improve vector safety and
reduce the risk of immunologic sequelae, and may allow achievement of
sustained phenotypic correction of canine hemophilia A.
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