The SCID-Hu mouse model has several deficiencies and resembles primary HIV infection 
rather than AIDS; these mice are also devoid of human macrophages (33,34,35). 
Nevertheless, in studies that are currently ongoing, we are studying the acute and 
subacute toxicities and effects of the ribozyme in an in vivo setting by using the SCID-Hu 
model in collaboration with D. Mosier (35). Human PBLs are transduced in vitro as in 
our prior studies and subsequently tested for resistance to viral challenge in vivo in the 
mice. The status of these experiments will be summarized at the time of the RAC meeting. 
Finally, we note that our ribozyme project collaborator, Dr. Jay Rapapport (NIH) has 
found no evident toxicity of this ribozyme in transgenic mice (Rapapport J, personal 
communication). 
D. Previous Human Gene Therapy Trials . We have designed this human trial with the 
benefit of a great wealth of data acquired in the past three to five years by other groups 
of investigators that support not only the general safety of retroviral vector-based gene 
therapy in humans but also the particular vector and packaging system we will use 
(2,10, 21-25,37,42, 46,47, 55). Most human gene transfer trials approved by the 
RAC and all of its subcommittees to date have employed retroviral vectors for ex vivo 
gene transfer (2, 55). 
LNL6, the vector we are employing to deliver the ribozyme gene, was used in the first 
human gene transfer trial (37) to transfer the NeoR marker gene to tumor-infiltrating 
lymphocytes. The first actual human gene therapy trial (i.e. not solely a gene-marking 
trial) began in September, 1990 and involved retroviral vector-mediated transfer (by 
LASN, a modified LNL6-based vector) of the adenosine deaminase (ADA) gene into the 
lymphocytes of a patient with ADA deficiency (2). Toxicity referable to the vector or the 
packaging line was searched for and was not observed in these or subsequent trials (2, 
55). 
Furthermore, all approved studies have used the packaging line we will use, PA317 
(2,23). In the human trials to date, none of the production batches of retroviral vectors 
and none of the human patients have tested positive for replication-competent helper 
virus (2). We are aware that thymic lymphoma has developed in three of eight rhesus 
monkeys given bone marrow infected with a retroviral stock known to be heavily 
contaminated with replication-competent virus (2, 38,39). Although the disease 
observed in these monkeys was not observed in previous studies of infection of 
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