Joint Fellowship Training Program

Mentor:

Andrew P. Byrnes, PhD

Organizational Affiliation and Position:
Principle Investigator, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research

Email:
andrew.byrnes@fda.hhs.gov

Telephone:
(301) 827-1786

Title of Research Program:
Adenovirus vector gene therapy

Research Project Summary (if applicable):
Adenovirus vectors are a new class of drugs that are currently being tested in many dozens of clinical trials in the US. The vast majority of these trials are for the treatment of cancer. These include adenovirus vaccine vectors which immunize against tumor antigens, oncolytic adenovirus vectors which selectively replicate in tumor cells, and adenovirus vectors which express anti-oncogenes, cytokines, or chemotherapy sensitizers. For tumors that are not easily accessible or have metastasized, the ideal route of administration would be intravascular, and adenovirus virions could be engineered to specifically target tumor cells. The major obstacle to intravascular delivery is the reticuloendothelial system, which consists of macrophages and dendritic cells in the liver and spleen. After intravascular injection, adenovirus vectors are recognized by these cells and removed from the circulation within minutes, preventing them from reaching other organs. In addition to being wasteful, this is dangerous. Cells of the reticuloendothelial system recognize the vector as foreign and rapidly release inflammatory mediators. This contributes to hepatotoxicity, which is a major limiting factor in using adenovirus vectors clinically.

The Byrnes lab is studying how adenovirus vectors are recognized and taken up by macrophages and dendritic cells and why these vectors stimulate harmful inflammatory and hepatotoxic responses. We use a variety of molecular and protein techniques to investigate the behavior of adenovirus vectors in cultured cells and, more importantly, in rodent models. We aim to understand how adenovirus vectors interact with the reticuloendothelial system and how to engineer vectors to mitigate this.

Proposed Project for IOTF Fellow:
Fellows will study the tropism and toxicity of normal and retargeted adenovirus vectors after intravenous delivery. Goals are to understand the reasons for the behavior of these vectors, to develop techniques for targeted gene therapy, to decrease dangerous inflammatory responses to vectors, and to evaluate whether certain patient populations have special risks for adverse reactions to adenovirus vector gene therapy.

Regulatory Activity:
Dr. Byrnes has significant responsibilities at the FDA as a product reviewer who regulates clinical trials with adenovirus vectors, mostly for the treatment of cancer. He also regulates a number of other viruses which are used as experimental therapies for cancer. Under the mentorship of Dr. Byrnes, fellows will gain experience by working as part of an interdisciplinary team to evaluate the manufacturing and safety of novel anti-cancer gene therapies.

Reference(s):
Manickan, E., J.S. Smith, J. Tian, J.N. Lozier, T.L. Eggerman, J. Muller and A.P. Byrnes (2006). Rapid Kupffer cell death after intravenous injection of adenovirus vectors. Molecular Therapy (in press)

Smith, J.S., J. Tian, J.N. Lozier and A.P. Byrnes (2004) Severe pulmonary pathology after intravenous administration of adenovirus vectors in cirrhotic rats. Molecular Therapy 9: 932-941.

Smith, J.S., J. Tian, J. Muller and A.P. Byrnes (2004). Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease. Gene Therapy 11: 431-438.