Genzyme Corporation Ad2/CFTR-2 Gene Transfer Protocol: Single 
One Kendall Square, Cambridge, MA 02139 Aerosol Administration to the Lung of CF Patients 
In addition to Ad2/CFTR-2 administration to the nasal airway, another alternative to the lung for evaluation of the limited 
clinical efficacy of Ad2/CFTR-2 is the maxillary sinus, which provides a model system of substantial utility. The upper 
airways of the nose and sinuses are almost universally involved in CF. Chronic colonization of the paranasal sinuses 
with Pseudomonas and other organisms may contribute to CF lung disease. 
Use of the sinus epithelium provides several safety advantages: a) relatively small total amount of virus is applied to a 
limited area; b) accessibility and less invasive assessment; and c) less severe consequence if problems occur. Testing 
clinical efficacy limited to the maxillary sinus has the advantage that the tests to assess function (sinus CT and cell 
counts and inflammatory mediators in sinus washes) may be more sensitive and are less invasive than those required 
to test clinical efficacy in the lung. 
The clinical study utilizing Ad2/CFTR-2 (ORDA #9312-067) has been initiated by Drs. Michael Welsh of the University of 
Iowa and Bonnie Ramsey of the University of Washington. Part A of this study examines the effect of repeat 
administration of progressively increasing doses of Ad2/CFTR-2 to the nasal epithelium to determine if there is an 
adverse systemic, immune, inflammatory or respiratory response. Evidence of the biochemical efficacy after repeated 
administrations of Ad2/CFTR-2 is also being assessed. 
The safety and limited clinical efficacy of multiple progressively increasing doses of Ad2/CFTR-2 in correcting the upper 
airway epithelial disease observed in the maxillary sinus is being evaluated in Part B. Patients are closely monitored for 
evidence of an adverse systemic, immune, inflammatory or respiratory response. The effect of repeat administration on 
clinical efficacy limited to the sinus is being assessed using computed tomography scans as well as cellular and 
biochemical measures of efficacy. The data on clinical efficacy, though limited, will assess the balance between 
efficacy in correcting the biochemical defect and any potential adverse effects associated with vector administration. 
The study involving nasal and sinus application is a non-randomized, non-blinded evaluation of repeat administration of 
recombinant Ad2/CFTR-2. We plan to enroll up to ten clinically stable patients with cystic fibrosis of mild to moderate 
severity in each Part of the study (A and B). 
Each nasal/sinus study participant is undergoing 2 pretreatment evaluations on days -21 and -7 to ensure that they are 
clinically stable. In Part B, maxillary sinus patients are then treated for 7 days with antibiotics and sinus lavage prior to 
the initial administration of Ad2/CFTR-2. Each participant in Part A receives the same progressively increasing doses 
of Ad2/CFTR-2. Patients in Part A will receive up to 6 administrations of doses ranging from 2 x 10 7 to 1 x 10 10 IU. 
Patients in Part B will receive 1 dose of 5 x 10 8 IU followed by up to 6 doses of 2.5 x 10 9 IU. Nasal/sinus patients are 
being enrolled and receiving treatment in a staggered manner. 
In Part A of the nasal/sinus study Ad2/CFTR-2 is being administered to one nasal cavity and saline to the other. In Part 
B, one maxillary sinus is being treated with Ad2/CFTR-2 and the other with saline. In Part B, a blinded review of the CT 
scans of the maxillary sinuses will be performed, using the saline-treated contralateral maxillary sinus as a control. 
To date, Part A, of the nasal/sinus study has commenced. Two patients have received 4 administrations of Ad2/CFTR- 
2 (2 x 10 7 , 2 x 1 0 8 , 2 x 10 9 and 6.6 x 10 9 IU) and two additional patients have received a 2 x 10 7 IU dose to the nasal 
epithelium with no study drug-related adverse effects. Evidence of transient restoration of CFTR channel activity has 
also been obtained in the first 2 patients. We anticipate that Part B will begin soon. 
ORDA Protocol #9409-091: Safety of Single Administration to the Luna 
Our approved lobar protocol is scheduled to begin before this proposed aerosolized protocol. In the lobar protocol we 
intend to study 8 groups of 3 patients each at the same dose levels as the proposed aerosol protocol. 
Rationale for Design of Proposed Lower Airway Study 
The target tissue for effective CFTR gene transfer is the airway epithelium within the lung of CF patients. Our preclinical 
and clinical data suggest that adenovirus is an effective vector system for transfer of CFTR cDNA to correct the CF 
pulmonary defect in the target tissue and appears to be safe in animal models at doses believed to be relevant for 
human treatment on a weight basis. These data indicate that the use of adenovirus vectors as a treatment for CF lung 
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Recombinant DNA Research, Volume 20 
