Viral Safety Studies in Xenotransplantation and Gene Therapy Products

Principal Investigator: Carolyn A. Wilson, PhD
Office / Division / Lab: OCTGT / DCGT / GTIB

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Overview

Public Health Issue: Gammaretroviruses are simple animal retroviruses (related to HIV, the cause of AIDS). Gammaretroviruses may pose risks in several regulated biologics products, both as contaminants and in their use as gene therapy vectors to deliver reparative genes. For example, a derivative of a mouse gammaretrovirus was used for gene therapy given to children in a clinical trial for X-linked Severe Combined Immunodeficiency Disease (more commonly known as the "Bubble Boy Disease"). Although this therapy appeared to be highly effective, some patients developed a serious adverse event, leukemia, demonstrating that these animal viruses may cause disease in humans. In addition, pig gammaretroviruses are potential contaminants in some other products, such as proteins derived from pig plasma, and xenotransplantation products that involve the transfer of pig cells, tissues or organs to humans.

Regulatory Contribution: This research program develops assays and important information that allow the FDA to evaluate and better predict the safety and efficacy of gammaretrovirus exposure in humans.

Research Approach: We study the gammaretrovirus porcine endogenous retrovirus (PERV), an inherited element found in all pigs. We use molecular biology, tissue culture, and animal models to study the conditions that affect virus infection and transmission, with an emphasis on studying the factors that influence the ability of PERV to infect human cells. We also use retroviral vector technology to study a CDC Category A potential agent of bioterrorism, Ebola virus (an agent of viral hemorrhagic fever).

Mission Relevance and Outcomes: These studies provide data and scientific and technical expertise relevant to the evaluation of the safety and efficacy of gene therapy and xenotransplantation products. The work directly informs policy development in these product areas. In addition, our laboratory has developed methods for detection of PERV that have been adapted by sponsors to test their xenotransplantation products.

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Publications

Methods Mol Biol 2009;506:477-488
The US and EU Regulatory Perspectives on the Clinical Use of Hematopoietic Stem/Progenitor Cells Genetically Modified Ex Vivo by Retroviral Vectors.
Wilson CA, Cichutek K

Cell Mol Life Sci 2008 Nov;65(21):3399-3412
Porcine endogenous retroviruses and xenotransplantation.
Wilson CA

J Virol 2008 Aug;82(15):7483-91
Identification of residues outside of the receptor binding domain that influence infectivity and tropism of porcine endogenous retrovirus.
Argaw T, Figueroa M, Salomon DR, Wilson CA

Virology 2008 Jun 5;375(2):637-45
Functional hierarchy of two L domains in porcine endogenous retrovirus (PERV) that influence release and infectivity.
Marcucci KT, Martina Y, Harrison F, Wilson CA, Salomon DR

Xenotransplantation 2007 Jul;14(4):309-15
No evidence of PERV infection in healthcare workers exposed to transgenic porcine liver extracorporeal support.
Levy MF, Argaw T, Wilson CA, Brooks J, Sandstrom P, Merks H, Logan J, Klintmalm G

Virus Res 2006 Nov;121(2):205-14
Identification of two amino acid residues on Ebola virus glycoprotein 1 critical for cell entry.
Mpanju OM, Towner JS, Dover JE, Nichol ST, Wilson CA

J Virol 2006 Apr;80(7):3135-46
Mice transgenic for a human porcine endogenous retrovirus receptor are susceptible to productive viral infection.
Martina Y, Marcucci KT, Cherqui S, Szabo A, Drysdale T, Srinivisan U, Wilson CA, Patience C, Salomon DR

Virology 2006 Mar 5;346(1):108-17
The infectivity and host range of the ecotropic porcine endogenous retrovirus, PERV-C, is modulated by residues in the C-terminal region of its surface envelope protein.
Gemeniano M, Mpanju O, Salomon DR, Eiden MV, Wilson CA

Am J Transplant 2005 Aug;5(8):1837-47
Pseudotyping of porcine endogenous retrovirus by xenotropic murine leukemia virus in a pig islet xenotransplantation model.
Martina Y, Kurian S, Cherqui S, Evanoff G, Wilson C, Salomon DR

Mol Ther 2004 Dec;10(6):976-80
Workshop on long-term follow-up of participants in human gene transfer research.
Nyberg K, Carter BJ, Chen T, Dunbar C, Flotte TR, Rose S, Rosenblum D, Simek SL, Wilson C

J Gen Virol 2004 Jan;85(Pt 1):15-9
Limited infection without evidence of replication by porcine endogenous retrovirus in guinea pigs.
Argaw T, Colon-Moran W, Wilson CA