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Evaluation of the duration of human factor VIII expression in nonhuman primates after systemic delivery of an

Julie L Andrews¹, Pamela S Shirley, William O Iverson

¹Genetic Therapy, Inc. (A Novartis Company), Gaithersburg, MD 20878, USA.

Human Gene Therapy

|August 7, 2002

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Early adenoviral vectors delivered human factor VIII (FVIII) to monkeys, but expression was short-lived. Immune responses and transient side effects were observed, indicating limitations for long-term FVIII gene therapy.

Area of Science:

Gene Therapy
Viral Vectors
Hemophilia Research

Background:

Adenoviral vectors are explored for gene delivery.
Factor VIII (FVIII) is crucial for blood clotting.
Gene therapy aims to provide long-term FVIII expression for hemophilia.

Purpose of the Study:

To evaluate the efficacy and safety of an adenoviral vector for human FVIII gene delivery in nonhuman primates.
To assess the duration of FVIII expression and potential immune responses.

Main Methods:

Systemic delivery of an E1/E2a/E3-deficient adenoviral vector encoding flagged human FVIII cDNA to cynomolgus monkeys.
Analysis of liver biopsy samples for vector DNA.
Detection of human FVIII in plasma using immunoprecipitation/Western blot.

Related Experiment Videos

Assessment of inhibitor development via Bethesda assays.

Monitoring of liver enzymes, IL-6, and platelet counts.

Main Results:

Vector DNA was detected in liver biopsies, with copy number declining over 56 days.
Human FVIII expression was detected in plasma, persisting for 14-28 days.
Peak FVIII levels ranged from 50-100 ng/ml.
Inhibitors developed in two of four animals.
Transient increases in liver enzymes, IL-6, and decreases in platelets were observed.

Conclusions:

Early generation adenoviral vectors do not support long-term FVIII expression in nonhuman primates.
The study highlights challenges in achieving sustained gene expression and managing immune responses for FVIII gene therapy.