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Blood, Vol. 95 No. 3 (February 1), 2000:
pp. 820-828
Sustained high-level expression of full-length human factor VIII
and restoration of clotting activity in hemophilic mice using a minimal
adenovirus vector
Cristina Balagué,
Jiemin Zhou,
Yifan Dai,
Ramón Alemany,
Steven F. Josephs,
Grai Andreason,
Mangala Hariharan,
Erica Sethi,
Elena Prokopenko,
Hsing-yi Jan,
Yan-Chun Lou,
Debbie Hubert-Leslie,
Lulio Ruiz, and
Wei-Wei Zhang
From GenStar Therapeutics Corp, San Diego, CA; and the Gene Therapy
Unit, Baxter Healthcare Corp, Round Lake, IL.
The successful prophylactic treatment of hemophilia A by frequent
infusions of plasma concentrates or recombinant factor VIII (hFVIII)
indicates that gene therapy may be a potential alternative for the
treatment of the disease. For efficient delivery and long-term expression of the hFVIII gene, a novel minimal adenovirus (mini-Ad) vector, MiniAdFVIII, has been developed. The vector is devoid of all
viral genes and carries the full-length hFVIII cDNA under the control
of the human 12.5-kb albumin promoter. The MiniAdFVIII vector was
propagated with the assistance of an ancillary vector in 293 cells and
was purified by CsCl banding. Sustained expression of hFVIII at
physiologic levels (100-800 ng/mL) was achieved in mice after a single
intravenous injection of MiniAdFVIII. The expressed hFVIII had a
structure identical to that of recombinant hFVIII, as determined by
Western blot analysis. The functionality of the protein was confirmed
by the restoration of blood coagulation capacity in MiniAdFVIII-treated
hemophilic mice, as determined by tail clipping observations. Although
antivector or antihuman FVIII antibodies at various levels were
detected, long-term expression of the transgene was observed in the
mice that did not generate antibodies against the transgene product.
The vector DNA persisted in the liver tissues of the mice with
long-term expression. No significant histopathologic findings or
toxicities were observed to be associated with the vector in the
MiniAdFVIII-treated C57BL/6 mice. These results support the further
development of MiniAdFVIII for clinical trials toward the treatment of
hemophilia A.
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