Joint Fellowship Training Program
Mentor:
Andrew P. Byrnes, PhD
Organizational Affiliation and Position:
Acting Chief, Gene Transfer and Immunogenicity Branch
Division of Cellular and Gene Therapies
Center for Biologics Evaluation and Research
Contact Information (email/phone):
andrew.byrnes@fda.hhs.gov
(301) 827-1786
Running Title of Program:
Adenovirus vector gene therapy
Research Project Summary:
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 that immunize against tumor antigens, oncolytic adenovirus vectors that selectively replicate in tumor cells, and adenovirus vectors that 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 innate immune response contributes to hepatotoxicity, which is a major limiting factor in using adenovirus vectors clinically.
The Byrnes lab is studying why adenovirus vectors are cleared so rapidly from the circulation and how 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 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 adenovirus vectors after intravenous delivery in rodents. Active areas of investigation include adenovirus receptors, mechanisms of liver transduction, pro-inflammatory signal transduction cascades, and innate responses by cytokines, complement and other mediators, Goals are to develop techniques for targeted gene therapy, to decrease dangerous innate immune responses to vectors, and to evaluate whether certain patient populations have special risks for adverse reactions to adenovirus vector gene therapy. Fellows will gain first-hand experience and expertise in adenovirus vectors that is directly relevant to regulatory issues.
Regulatory Activity:
Dr. Byrnes has significant responsibilities at the FDA as a product reviewer who primarily regulates clinical trials with adenovirus vectors, mostly for the treatment of 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.
References (2-3) (in applicable):
Xu, Z., J. Tian, J.S. Smith and A.P. Byrnes (2008). Clearance of adenovirus by Kupffer cells is mediated by scavenger receptors, natural antibodies and complement. Journal of Virology 82: 11705-11713.
Smith, J.S., Z. Xu, J. Tian, S.C. Stevenson and A.P. Byrnes (2008). Interaction of systemically-delivered adenoviral vectors with Kupffer cells in mouse liver. Human Gene Therapy 19: 547-554.
Tian, J., Z. Xu, J.S. Smith, S.E. Hofherr, M.A. Barry and A.P. Byrnes (2009). Adenovirus activates complement by distinctly different mechanisms in vitro and in vivo: indirect complement activation by virions in vivo. Journal of Virology 83: 5648-5658.
