We have evaluated n pre-clinical studies a "gutIess" adenoviral vector that expresses the full-length human Factor VIII (hFVIII) cDNA under the control of the human 125-kb albumin promoter.
The vector (MaxAdFVIII) resulted in sustained expression of hFVIII at physiological Ievels (1 00-800 ng/mI) for up to one year n mouse models after a single intravenous injection (Balague et al. Blood, 95: 820-828. 2000). Safety studies with extended observation times were performed in 0578L/6 mice.
Transient decreases in platelet counts and minimal elevation n Iiver transaminase were observed n the highest dose group (1 .6 x 10-13 viral particle per kg).
No significant histopathological findings or other toxicities were associated with the vector. Biodistribution analysis by PCR demonstrated that more than 80% of the vector localized to the Iiver following tau vein administration.
To evaluate the efficacy and safety of the MaxAdFVIII n larger animals, non-human primates and a hemophilic dog were treated with a single intravenous injection of the MaxAdFVIII.
Three vector doses were administered in the non-human primate model (4.3 1011, 1.4 x 1012, and 4.3 x 1012 viral particles per kg).
Therapeutic levels of hFVIII were detected ín aIl three groups and the highest values ranged from 28 to 88 mU/mL.
In the hemophilic dog model, the whole blood clotting time decreased from a pre-treatment value of 24.5 minutes to a normal level of 11 .5 minutes at a dose of 3 x 1012 viral particles per kg.
No significant adverse effects were detected n the two Lower dosage non-human primate groups that resulted in the expression of therapeutic hFVIII levels.
Transient thrombocytopenia and minimal elevation in liver transaminase levels were observed ín the highest dose group similar to those previously observed in mice.
These data from rodents and larger animal models support evaluation of MaxAdFVill in hemophilia A clinical trials.