12/07/87 
Dr. Anderson responded that he has no evidence from monkeys that he entered totipotent cells. 
From mouse and sheep data, there are several arguments for totipotent cel! infection: (1) new 
dextran culture data exists on bone marrow from a patient; (2) he has repeated sheep studies 
in rhesus monkeys, about six weeks ago. Regarding selective advantage, in most cases there 
has to be some space. It is unclear whether this is a selective advantage of donor cells or just 
filling up space. It is also unclear whether target cells exist in ADA marrow. The pool size may 
be inadequate to fix this. 
Dr. Mulligan stated that a 0.5% expression level is very low. Dr. Parkman said that the number 
of totipotent cells is 1 in 10 5 . Regarding safety issues in the packaging functions, a safe line, 
PA31 7, will be available that will not transfer helper virus. Dr. Anderson will be able to use the 
Mulligan cell line. Dr. Gottesman said that the helper virus safety issue can be avoided by the 
next generation of cell lines. 
Dr. Mulligan asked about viral integration. 
Dr. Anderson believed that individuals face no dangers from the helper virus. He is conducting 
an additional study on this subject. Dr. Mulligan asked if insertion next to an oncogene might 
lead to activation. Dr. Gottesman answered that these are very low probability events. 
Dr. Mulligan turned the discussion to vectors, citing Dr. Temin on the inactivation of transcription. 
He believed that Dr. Anderson’s vector could activate something. 
Two safety issues arose: (1) helper virus; (2) after a cell is infected, whether a sequence could 
be mobilized and transferred and, if so, whether this would matter. 
Dr. Mulligan said that it might be possible to develop a mouse model for ADA. There was, 
however, no evidence of whether it could work. Dr. Anderson agreed that no one could know 
if it would work. Nonetheless, he could learn if a patient could be helped. 
Dr. Mulligan asked if experiments would continue if the first two are failures. Dr. Anderson said 
he changed the request to a "last hope protocol," and desired to get the review process started. 
Dr. Mulligan asked if fixable cells are available. Dr. Anderson believed that such cells exist, but 
are inhibited from dividing. Dr. O’Reilly offered some data on in vitro studies-frequency of gene 
transfer and expression using the Anderson vector looking for new resistance and ADA 
expression. Dr. Anderson said his studies have been unable to detect a replicating cycle for the 
helper virus. 
Mr. Capron returned to the document, stating that two paths are possible: (1) design of standard 
type of protocol, or (2) compassionate use. 
Dr. Mulligan stated that Dr. Anderson wished to treat only two patients, which apparently has not 
changed. Dr. Parkman pointed out that if the patient population is too restricted, the protocol 
will have less efficacy, and safety issues will remain obscure. Moreover, reviewers read the 
protocol as a front line alternative, although it now appears to concern only certain patients. Dr. 
Epstein felt that a continuum existed between a major clinical trial and compassionate use. 
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Recombinant DNA Research, Volume 13 
