Info

x 107 pfu/hamster

1.7 x

109 pfu/m2

Cotton rat

5 x

107 pfu/rat

1.9 x

109 pfu/m2

Rhesus monkey

2 x

107 pfu/monkey"

8.2 x

107 pfu/m2

Baboon

7 x

108 pfu/monkey

1.8 x

109 pfu/m2

Human

2 x

107 pfu/patient

1.2 x

107 pfu/m2f>

Note. Cotton rats, mice, and hamsters were administered increasing doses of adenoviral vectors encoding the human CFTR gene by intranasal instillation. Baboons, Rhesus monkeys, and humans were treated with adenoviral vectors encoding CFTR via bronchoscopic instillation into an isolated lobe of the lung. Animals were sacrificed 3 to 5 days after vector administration, and histologic sections of the lung were examined microscopically for evidence of inflammation [15]. The human data were obtained via chest radiograms and CT scans of a patient in a phase 1 clinical trial [13]. "NOAEL not available; lowest dose tested with minimum pathology Toxic dose in humans, 2 x 109 IU, or 1.2 x 109 IU/m2.

Note. Cotton rats, mice, and hamsters were administered increasing doses of adenoviral vectors encoding the human CFTR gene by intranasal instillation. Baboons, Rhesus monkeys, and humans were treated with adenoviral vectors encoding CFTR via bronchoscopic instillation into an isolated lobe of the lung. Animals were sacrificed 3 to 5 days after vector administration, and histologic sections of the lung were examined microscopically for evidence of inflammation [15]. The human data were obtained via chest radiograms and CT scans of a patient in a phase 1 clinical trial [13]. "NOAEL not available; lowest dose tested with minimum pathology Toxic dose in humans, 2 x 109 IU, or 1.2 x 109 IU/m2.

This finding allowed for a redesign of the clinical approach to gene therapy for cystic fibrosis, using smaller volumes for instillation of vector and a more targeted approach to deliver the adenovirus to the larger airway epithelial surfaces. To date, cystic fibrosis patients have been treated using two to three logs higher doses of adenovirus with this newer approach without the toxicities observed in the initial clinical trial [13].

In cases where gene transfer vectors may be in limited supply, or for vectors with inherently low toxicity, a maximum feasible dose may be administered as the highest level tested in the preclinical studies. In all studies, and especially when using animal models of the clinical indication, appropriate controls, such as naive or vehicle-treated animals should be included. This should allow determination of an adequate margin of safety for use of the vector in the clinical trial, as well as an acceptable dose-escalation scheme.

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