Recombinant DNA Advisory Committee - 03/1-2/93 
that some of these studies have been studied long-term, and that 4 x 10 5 adenovirus 
particles is considered to be a safe dose. Dr. Post commented that this number of 
particles are safe to administer to a normal patient. What would the effect be in CF 
patients? Dr. Wilmott responded that CF patients are exposed to adenovirus particles at 
the same rate as normal individuals. In general, CF patients are hyperimmune and 
demonstrate high levels of gamma globulin, particularly IgG. There is no reason to 
believe that these patients will manifest any problems specifically associated with 
adenovirus infection. 
Presentation--Dr. Whitsett 
Dr. Whitsett responded to Ms. Grossman's concerns about in vivo toxicity. The cotton 
rat was chosen as the in vivo model because of its unique susceptibility to adenovirus. 
Data was presented in which cotton rats were given 3 x 10 11 pfu intratracheally. 
Substantial gene expression was observed out to 7 days. These animals demonstrated 
lymphocyte and macrophage peribronchiolar and perivascular responses in response to 
vector administration. Recently, this same response has been observed in the hamster 
model. Dr. Whitsett explained that rabbit experiments are currently in progress; 3 
animals have been treated to date. These 3 rabbits demonstrated responses similar to 
those observed in the cotton rats and hamsters. The animals did not become ill. They 
did not breath rapidly or have cyanosis. However, pathology demonstrated significant 
lymphocytic and monocytic infiltration by hematoxylin and eosin (H&E) staining. There 
was no evidence of pneumonia or hemorrhage. 
Dr. Whitsett explained that the investigators are concerned about demonstrating the 
safety of multiple administrations, and that they will continue to perform repeat dose 
experiments in large animals. The human protocol will not be initiated until these large 
animal experiments have been completed and evaluated. 
Dr. Whitsett explained that repeat administrations will be necessary because of the 
turnover of the respiratory epithelium. The time frame involved in cell turnover is 
between 80 and 100 days. Conditions will be optimized such that CFTR expression can 
be achieved throughout this entire period. The date chosen for the second 
administration, 56 days, is based on data which demonstrates that this period is where 
one-half of the original mRNA is detectable within the lung. All patients will have 
neutralizing antibodies to the adenovirus which should obviate any concern about an 
aggressive immune response to the vector. 
Dr. Whitsett stated that he is compelled to proceed with this protocol as a feasibility 
study in terms of the repeat administration of the adenovirus vector. The entire strategy 
of CFTR transduction in the lung is dependent on multiple administration of the vector. 
Ms. Grossman said that patients should not be exposed to a second administration of the 
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