CBER Expertise
Safety and efficiency of gene therapy
Principal Investigator: Andrew Byrnes, MD
Office / Division / Lab: OCTGT / DCGT / GTIB
Overview
Public Health Issue: Gene therapy vectors are being developed to treat diseases such as cancer. Vectors derived from viruses such as adenovirus can be designed to deliver anti-tumor proteins or to replicate selectively in tumors and kill them. Intravenous injection of vectors would be an ideal way to target widespread metastatic tumors. However, the liver rapidly clears adenovirus vectors, and these vectors can cause significant liver damage and inflammation. The rapid clearance prevents vectors from reaching the desired targets, and the safety concerns for the liver limit the amount of vector that can safely be used.
Regulatory Contribution: Although many of these products are first studied in animal models, it is unclear how well the toxicities and dose-response data from animal studies can predict the risk to humans, and which animal species are the most appropriate models. It is also uncertain how patients with pre-existing liver disease might react to adenovirus gene therapy. It is important to be able to evaluate and understand these effects so that we can make well-informed decisions about the risk-benefit ratio of gene therapy products.
Research Approach: We aim to understand the underlying reasons for rapid clearance of adenovirus vectors by the liver, and how this leads to liver disease. We are studying the cells in the liver that are responsible for clearing adenovirus vectors, the molecular mechanisms for the clearance, and the subsequent reactions of the immune system. We have also studied how pre-existing liver disease affects the clearance and safety of adenovirus vectors.
Mission Relevance and Outcomes: These studies will help to understand the mechanisms for adenovirus vector clearance and toxicity, as well as the relevance of animal models to the human outcomes. Ultimately, such understanding will provide a rational basis for designing safer and more effective gene therapy vectors.
Publications
Genomics 2006 Apr;87(4):552-9
Quality prediction of cell substrate using gene expression profiling.
Han J, Farnsworth RL, Tiwari JL, Tian J, Lee H, Ikonomi P, Byrnes AP, Goodman JL, Puri RK
Virology 2006 Mar 30;347(1):183-90
Heparin-binding and patterns of virulence for two recombinant strains of Sindbis virus.
Bear JS, Byrnes AP, Griffin DE
IDrugs 2005 Dec;8(12):993-6
Challenges and future prospects in gene therapy.
Byrnes AP
Mol Ther 2006 Jan;13(1):108-17
Rapid Kupffer cell death after intravenous injection of adenovirus vectors.
Manickan E, Smith JS, Tian J, Eggerman TL, Lozier JN, Muller J, Byrnes AP
Mol Ther 2004 Jun;9(6):932-41
Severe pulmonary pathology after intravenous administration of vectors in cirrhotic rats.
Smith JS, Tian J, Lozier JN, Byrnes AP
Arch Virol 2004;(18):21-33
Emergence and virulence of encephalitogenic arboviruses.
Griffin DE, Byrnes AP, Cook SH
Gene Ther 2004 Mar;11(5):431-8
Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease.
Smith JS, Tian J, Muller J, Byrnes AP