Genzyme Corporation Ad2/CFTR-2 Gene Transfer Protocol: Single 
One Kendall Square, Cambridge, MA 02139 Aerosol Administration to the Lung of CF Patients 
Risks Associated with Administration of Ad2/CFTR-2 to the Pulmonary Airways 
The risks of administration of Ad2/CFTR-2 to the pulmonary airway itself are at present unknown. Inflammation in the 
lung has been observed in some animals exposed to doses greater than those proposed in the current study when 
considered per body weight. As discussed previously, at least 1 patient with CF experienced fever, dyspnea, and was 
noted to have a pulmonary infiltrate after exposure to adenovirus vector for CFTR by another researcher. This adverse 
experience involved a different investigator and a different adenovirus vector (adenovirus 5). An inflammatory response 
to Ad2/CFTR-2 in the lung or bronchial airway may produce an exacerbation of the patient’s symptoms of cystic fibrosis, 
including cough, dyspnea, fever, chest pain, or hemoptysis. It is possible that a subsequent increase in fibrotic change 
could result if significant inflammation were to occur. In the unlikely event that reproduction of the virus were to occur as 
a result of complementation or recombination then it is possible that a pneumonia could result. 
These risks will be minimized by beginning lung exposure with small doses of the vector which have been previously 
tested in the nose and sinus. Furthermore, the risk will be reduced by not administering aerosolized vector until after 3 
patients have received lobar administration of a comparable dose in the concurrent lobar protocol without adverse 
effect. If inflammation or cytopathic change were to develop it should be localized to the treated lobe preserving the 
majority of lung function. Only after 2 months of observation of the effect of the dose in a lobe of the lung will the same 
dose be administered via aerosol to the entire lung of other patients. Again risk is minimized, as the dose will be 
administered to a much greater number of cells and surface area in these subsequent patients such that the infectious 
dose per cell will be much less. A major feature that reduces risk in the study is the intercalated staggered dosing 
schedule using only half log increases in dose and verifying safety of one administered dose to one lobe in the lobar 
protocol prior to aerosolization of the next dose. Risk is minimized again by administration of only 1 dose of the virus to 
any patient and subsequent close monitoring of the patient. Restriction of the study population to patients with mild to 
moderate disease and optimization of lung function to within 10% of the patients' best function prior to treatment will 
further reduce risk. 
The administration of the virus to pulmonary airways is necessary for gene therapy for cystic fibrosis to be effective. 
Aerosolization offers the advantages of ease of administration without the risks and discomforts associated with 
bronchoscopic administration. Bronchoscopic administration requires pre-medication with sedative agents and 
application of a topical anesthetic. The procedure may produce fever, dyspnea, cough, transient hypoxemia and 
hemoptysis. Patients often experience anxiety, chest discomfort, severe coughing bouts during the procedure and a 
residual sore throat following the procedure - all factors which make repetitive dosing via bronchoscopy less practical 
and potentially less safe than aerosolized therapy. Although aerosolization exposes the entire lung to the risk of 
adverse events, prior experience with Ad2/CFTR-2 and the additional experience to be gained prior to commencement 
of this protocol (nasal administration, sinus administration, and lobar administration at higher doses than will be 
delivered via aerosol) should minimize the risk. 
Risks Associated with Procedures 
Bronchoscopy : As noted above bronchoscopy entails some risk including cough, hypoxemia, hemoptysis, dyspnea and 
fever associated with the actual instrumentation. To minimize discomfort the patient is sedated and local anesthesia is 
applied. The sedation may cause respiratory depression and allergic reactions may occur with local anesthesia. 
Pneumothorax is a rare but recognized complication of bronchoscopy. Topical anesthesia of the upper airway and 
sedation increase the risk of aspiration. 
Low voltage high resolution chest computed tomography . High resolution chest CT carries the risk of radiation 
exposure; we anticipate that a subject will have 3 chest low voltage HRCT scans during the course of the study. Using 
chosen “cuts” and low voltage, this procedure will expose the patient to less than 1 rad of radiation. The adverse effects 
of this amount of radiation are considered to be minimal, however the long term effects of such radiation are not known 
with certainty. 
Recombinant DNA Research, Volume 20 
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