ASGT Press Release

DENVER (June 1, 2000) - Gene therapy researchers presented groundbreaking findings regarding infectious diseases at a press conference held today in conjunction with the American Society of Gene Therapy's 3^rd Annual Meeting in Denver, Colo. Gene therapy researchers from around the world have converged, making Denver the gene therapy capitol of the world for the next three days.

"Gene therapy is in its infancy as a biomedical discipline," said ASGT President, Savio L. C. Woo, PhD, Professor and Director of the Institute for Gene Therapy and Molecular Medicine at the Mount Sinai School of Medicine, NY. "As the research reported here today illustrates, we are already seeing preliminary results that give us glimpses of hope that we will be able to offer effective treatments for debilitating and often deadly diseases."

Gene therapy is opening doors to new approaches to infectious diseases that have remained resistant to more traditional approaches. At this afternoon's press conference researchers reported on two studies that show tremendous promise for fighting HIV and hepatitis.

Traditional vaccines have been made from killed or attenuated virus too weak to cause disease. They have eradicated smallpox, driven polio to the brink of extinction, as well as held in check a variety of infectious agents. Unfortunately, these tried and true approaches have not been effective against the human immunodeficiency virus (HIV) that causes AIDS. This study represents the first efforts in developing a new kind of HIV vaccine.

The authors have used molecular tools to snip many of the genes from the HIV genome and, in particular, to replace the HIV envelope protein required for infection with that from another virus. The resulting particle or "pseudotyped vector", which can only be made in the laboratory, can infect a cell but will not replicate itself. The latest generation of HIV vectors contains only 3 of the 9 HIV genes.

HIV is a member of the lentivirus family, which is uniquely capable of replicating in nondividing cells. Here we showed that pseudotyped HIV vectors are very effective in introducing HIV genes into specialized white blood cells called dendritic cells, which are the gatekeepers of the immune system. The HIV genes are permanently integrated into the genetic materials of the "transduced" dendritic cells and immediately direct the production of copious amounts of viral proteins. Transduction has no deleterious influence on the immunological characteristics of these cells. Small pieces of the viral proteins (peptides) complexed with particular host cell molecules are transported to the surface of the dendritic cells. In this manner, transduced dendritic cells effectively program naïve T cells or activate previously programmed T cells to kill HIV-infected cells.

The ability to study human liver diseases such as viral hepatitis infection has been hampered by the lack of small animal models that can support the complete infectious life cycle of the viruses. Towards this goal, numerous attempts to make human-mouse chimeric livers have failed. The utility of the well-characterized culture system for human hepatocytes (liver cells) is limited to very short-term studies due to loss of hepatocyte-specific characteristics in culture.

In this report, the authors describe success in developing a mouse that can maintain primary human hepatocytes long-term. To do this, they transplanted the human hepatocytes within an extracellular matrix under the renal capsule. To maintain the hepatocytes in vivo, the animals were given bimonthly injections of anti-cMet antibody. This molecule functions to activate the human receptor for hepatocyte growth factor (c-Met). The transplanted human hepatocytes survived and maintained hepatocyte-specific characteristics at least 6 months in the mouse host.

The investigators went on to show that these animals are susceptible to hepatitis B virus infection and hepatitis delta superinfection, and can sustain the complete viral life cycles. These particular viruses were selected for study because: (1) as many as 400 million people worldwide are suffering from these viral infections; (2) development of therapies against these viruses has been greatly hampered by lack of cell culture and/or small animal models; (3) there was no mouse model system that allowed the study of the complete life cycle of these viruses (i.e infection, replication, and release of infectious virions back into the blood stream).

The investigators plan to use these animals to investigate new therapeutic strategies for eliminating viral infection from the cells in vivo (drug and gene therapy approaches), and to develop the model for Hepititis C infection. Hepatitis C infects an estimated ~2% of the population in the U.S., and is predicted to become a world health problem exceeding even HIV.

In summary, this new transplantation system demonstrates proof-of-principle that human hepatocytes can be engrafted long-term in small animals and thus serves as a tool for investigating and developing multiple aspects of human liver diseases and potential new therapies.

The ASGT is the largest medical professional organization representing researchers and scientists dedicated to discovering new gene therapies. ASGT was established in 1996, and has grown to over 2,400 members. It is committed to promoting and fostering the exchange and dissemination of information and ideas related to gene therapy, encouraging the general field of research involving gene therapy and to promoting professional and public education in all areas of gene therapy.