5 . Human Protocol 
5.1 General Design 
The purpose of the protocol is to evaluate the safety and biological efficacy 
of administration of the recombinant adenovirus AdCFTR to the respiratory 
epithelium of individuals with cystic fibrosis. The overall design is that of 
a combined ascending dose toxicity study and biologic efficacy study with the 
patients serving as their own controls (prior to the administration of AdCFTR 
compared to after therapy, as well as during the therapy period by comparing 
the treated to the untreated side of the respiratory tract) . At the completion 
of the study, the following questions will be answered: 
(1) Is it safe to administer an Ela - , (most of) Elb~, E3~ replication 
deficient recombinant adenovirus containing the normal human CFTR cDNA 
to the respiratory epithelium of individuals with CF? 
(2) Will such a recombinant adenovirus transfer the exogenous normal CFTR 
cDNA to respiratory epithelial cells in such a fashion to permit 
expression of the exogenous CFTR mRNA transcripts and CFTR protein, 
and to correct the biologic CF phenotype (i.e., convey to the cells 
the ability to secrete Cl - in response to elevations of cAMP)? 
(3) How long does the biologic correction last? 
(4) Is the biologic correction sufficient to correct the abnormal 
electrical potential difference of the airway epithelial sheet? 
(5) Is there improvement in respiratory clinical parameters relevant to 
the disease process? 
(6) Does humoral immunity develop against the recombinant vector 
sufficient to prevent chronic administration in the future? 
5.2 Constraints in the Design of the Protocol 
There are a number of clinical and safety constraints that direct the design 
of the protocol. 
Anatomic Site of Administration of the Vector 
Constraints 
(1) The biologic abnormalities of CF are expressed in the nasal epithelium 
and in the airway epithelium. Safety considerations argue that the 
most conservative approach would be to first evaluate administration 
of the vector to the nasal epithelium. There have been prior human 
studies of the administration of live replication competent adenovirus 
to the nasal epithelium. If the vector causes acute toxicity to the 
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