M.J. Welsh and A.E. Smith, RAC Application 
Ad2-ORF6/PGK-CFTR 
Item 5 - Clinical Protocol 
Maxillary Sinus Mucosa Biopsy. 
Purpose : To determine if there was: a) biochemical efficacy (by RT-PCR, by in situ hybridization, and 
by immunocytochemistry); b) clinical efficacy (by histologic evaluation of the mucosa and submucosa for 
inflammation characteristic of CF); and c) another inflammatory or immune response induced by virus 
application (by histologic evaluation and immunocytochemistry of inflammatory cells). There is no 
definitive way to distinguish between an inflammatory response resulting from CF and chronic infection, 
and an inflammatory response secondary to an immune response to the vector. However, we may fmd a 
histologically different picture in the two situations. For example, if in the treated mucosa there is a 
predominance of mononuclear cells and lymphocytes and the presence of CD4 or CD8 positive cells that 
is different from that in the control mucosa, then we would conclude that vector administration produced 
inflammation. 
Methods : The patient will be sedated with intravenous midaxolam and meperidine, titrated to padent 
response. The patient will be continuously monitored with EKG, pulse oximetry and intermittent 
automatic blood pressure assessment. The upper gingivo-buccal sulcus will be infiltrated with 4 ml of 
1% xylocaine with 1/100,000 epinephrine, with injection of the underlying periosteum. After 10 min a 
2.5 cm sublabial incision is made and a subperiostial flap elevated to expose the canine fossa. Once the 
canine fossa is identified a medium cutting burr will initially be used to drill away the cortical bone over a 
5 mm area. A diamond burr will then be used to remove the remaining bone and expose the underlying 
maxillary sinus mucosa over the same 5 mm diameter area. The mucosa will be sharply excised to obtain 
a biopsy specimen. The interior of the sinus will be inspected and photographed endoscopically, and Vt 
measured. Hemostasis will be monitored and observed until the patient is fully awake. 
Interpretation and Advantages. 
These studies should provide data about the potential for clinical efficacy of adenovirus-directed transfer 
of CFTR in treating CF airway disease. This part of the study has several advantages. 
a) The quality of the control (the opposite maxillary sinus) is excellent Virus will be administered to 
one of two maxillary sinuses: otherwise both sinuses will be treated identically. All other systemic 
factors, such as administration of antibiotics for pulmonary exacerbations, will be identical for both 
maxillary sinuses and should have little appreciable effect on the course of sinus disease. 
b) Adenovirus has the potential to cause an inflammatory/immune response on its own. Because this 
study will measure clinical efficacy, which is the net beneficial effect of expressing CFTR and the 
potential adverse effects associated with administration of vector, our results should give an indication 
of the net balance between the benefits and the risks. 
c) If vector administration does not prove clinically efficacious, we will be able to determine whether the 
lack of clinical efficacy resulted from a failure to express CFTR. 
d) We should be able to assess clinical efficacy in a relatively short period of time without entailing the 
risks and potential complications of repeated bronchoscopy. 
e) Studies of the maxillary sinus epithelium should provide us with an assessment of safety and clinical 
efficacy while minimizing risk to participants. 
The results of these studies are critical to: the design of future studies in larger numbers of patients; the 
design of future studies directed at delivering the gene to the pulmonary airways and treatment of lung 
disease; and the design and development of future vectors to treat CF. 
Potential Risks Associated with the Virus. 
The potential risks associated with the virus are described in detail in Part A. 
Potential Risks Associated with the Study Procedures. 
The potential risks associated study procedures common to Parts A and B are described in Part A. The 
following are the potential risks associated with study procedures that are specific to Part B. 
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Recombinant DNA Research, Volume 18 
