In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors.
Serious adverse events in some human gene therapy clinical trials have raised safety concerns when retroviral or lentiviral vectors are used for gene transfer. We evaluated the potential for generating replication-competent retrovirus (RCR) and assessed the risk of occurrence of adverse events in an in vivo system. Human hematopoietic stem and progenitor cells (HSCs) and mesenchymal stem cells (MSCs) transduced with two different Moloney murine leukemia virus (MoMuLV)-based vectors were cotransplanted into a total of 481 immune-deficient mice (that are unable to reject cells that become transformed), and the animals were monitored for 18 months. Animals with any signs of illness were immediately killed, autopsied, and subjected to a range of biosafety studies. There was no detectable evidence of insertional mutagenesis leading to human leukemias or solid tumors in the 18 months during which the animals were studied. In 117 serum samples analyzed by vector rescue assay there was no detectable RCR. An additional 149 mice received HSCs transduced with lentiviral vectors, and were followed for 2-6 months. No vector-associated adverse events were observed, and none of the mice had detectable human immunodeficiency virus (HIV) p24 antigen in their sera. Our in vivo system, therefore, helps to provide an assessment of the risks involved when retroviral or lentiviral vectors are considered for use in clinical gene therapy applications.
Bauer
Gerhard
G
Stem Cell Program, Department of Internal Medicine, University of California, Davis, Sacramento, California 95817, USA.
Dao
Mo A
MA
Case
Scott S
SS
Meyerrose
Todd
T
Wirthlin
Louisa
L
Zhou
Ping
P
Wang
Xiuli
X
Herrbrich
Phillip
P
Arevalo
Jesusa
J
Csik
Susie
S
Skelton
Dianne C
DC
Walker
Jon
J
Pepper
Karen
K
Kohn
Donald B
DB
Nolta
Jan A
JA
D000818:Animals; D001681:Biological Assay; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000009:adverse effects*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000821:virology; D016086:Lentivirus; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000821:virology; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D008979:Moloney murine leukemia virus; D012190:Retroviridae; D012306:Risk; D014161:Transduction, Genetic