Recombinant DNA Advisory Committee - 12/3-4/92 
administration of replication-incompetent adenovirus should not present any apparent 
safety concerns. 
Dr. Crystal addressed the issue of repeat administration that would be proposed for 
future protocols. If a patient developed IgA or IgG antibodies as a result of a single 
administration of this vector, would these immunoglobulins interact with the adenovirus 
and block receptor binding-therefore, interfere with efficacy? Although administration 
of this vector invokes serum anti-AdCFTR immunoglobulins within one week, there are 
two reasons why this response may not present a dilemma for repeat administration 
protocols: (1) the clinical experience is that immunity is not permanent, and (2) the 
mucosal immunity does not correlate with serum immunity. He presented in vivo 
neutralizing antibody titer data derived from rhesus monkeys. These titers were 
determined for both serum sampling and bronchial lavage. No neutralizing antibodies 
were detected in the airways of these animals. Mucosal immunity does not necessarily 
correlate with circulatory immunity. He presented in vivo cotton rat data demonstrating 
the ability to give multiple administrations of the vector, and that long-term gene 
expression is possible. 
Dr. Crystal discussed the patient inclusion and exclusion criteria. Eligible patients will 
be Ela negative in their respiratory epithelium and serum antibody positive. Epithelial 
cell samples will be obtained in order to demonstrate in vitro transduction by the vector 
and that the vector does not replicate. Safety will be demonstrated in the nasal 
epithelium first. If no adverse effects are observed, the vector will be administered to 
the patient's lung. It is probable that efficacy will be observed at the higher vector titer; 
however, the effect will probably be transient over a period of several months. 
What are the risks associated with this treatment? One concern is whether the vector is 
capable of replicating in human airway epithelial cells? Data demonstrates that the 
vector is incapable of replication even at 5 times the MOI of the maximum proposed 
dose. Will there be germ line transfer? Primate data demonstrates that CFTR mRNA 
is expressed only in airway epithelial cells; there was no evidence of expression by PCR 
in any other tissues, including gonads. 
Dr. Crystal agreed with the RAC members' concerns regarding the sterility criteria. 
There is no indication that there will be germ line transfer; therefore, the appropriate 
changes could be incorporated into the informed consent document. However, women 
would be asked to exercise appropriate birth control. 
In regard to the effects of vector administration and bronchial lavage on the patient's 
lung, Dr. Crystal stated that although no damage occurs to the lung, there is an 
inflammatory response to the vector. However, this inflammation is mild and transient 
compared to the endogenous inflammation. 
Recombinant DNA Research, Volume 16 
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