Progress in the management of gynecologic cancer: consensus summary statement.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
Laura King
Publications and source records attributed to Laura King.
Third International Conference on the Management of Erectile Dysfunction: Linking Pathophysiology and Therapeutic Response.
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Erectile Dysfunction↗
Evaluation of the duration of human factor VIII expression in nonhuman primates after systemic delivery of an adenoviral vector.
An E1/E2a/E3-deficient adenoviral vector encoding an epitope-tagged (flagged) human factor VIII (FVIII) cDNA was delivered systemically to four cynomolgus monkeys. Analysis of liver biopsy samples revealed the presence of vector DNA at all points in the study (day 7, 28, and 56), with vector copy number declining approximately 10-fold between day 7 and day 56. Immunoprecipitation/Western analyses detected human flagged FVIII in the plasma of all monkeys and expression persisted for 14-28 days. Peak plasma FVIII levels ranged from 50 to 100 ng/ml. Bethesda assays revealed no inhibitor in two animals, the development of a low-level transient inhibitor in one animal, and an inhibitor titer that continued to increase for the duration of the study in one animal. Other treatment-related changes included modest increases in liver enzymes, an increase in interleukin-6 (IL-6) levels, and a transient decrease in platelets in all four animals. These data indicate that early generation adenoviral vectors do not support the long-term expression of FVIII in nonhuman primates.
Adenoviruses, Human↗
In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor.
Systemic administration of adenoviral vectors leads to a widespread distribution of vector. Therefore, targeting of adenoviral vectors to specific tissues or cell types will require methods to ablate the normal tropism of the vector simultaneously with the introduction of new receptor specificities. To inhibit native receptor binding, we mutated residues in the AB loop of the adenovirus type 5 (Ad5) fiber. We genetically incorporated the S408E-P409A mutation, referred to as KO1, into the adenoviral genome alone or in combination with an RGD-targeting ligand in the HI loop of fiber. Transduction experiments confirmed that the KO1 mutation results in a significant reduction in fiber-dependent gene transfer on A549 and primary fibroblast cells that could be restored via the RGD-targeting ligand. Competition transduction experiments verified the receptor-binding properties of each vector on A549 and hepatocytes in vitro. Unexpectedly, in mice systemic delivery of the vector containing the KO1 mutation resulted in efficient liver transduction that was localized specifically to hepatocytes. We confirmed these results in three different mouse strains, indicating that hepatic adenoviral gene transfer may be independent of the coxsackievirus-adenovirus receptor and that in vivo retargeting will require further viral capsid modifications to generate a fully detargeted adenoviral vector upon which to introduce new tropisms.
Adenoviruses, Human↗