Toxicity and Biodistribution of a First-Generation Recombinant Adenoviral Vector, Encoding Aquaporin-1, After Retroductal Delivery to a Single Rat Submandibular Gland

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Abstract
Before conducting a phase 1/2 clinical trial of a serotype 5 adenovirus encoding human aquaporin-1 (AdhAQP1) for the treatment of radiation-damaged salivary glands, we have conducted a detailed toxicity and biodistribution study in adult rats. AdhAQP1 (2 × 108–2 × 1011 particles) was delivered to a single submandibular gland by retroductal cannulation. Administration of this vector resulted in no animal mortality or morbidities, and no adverse signs of clinical toxicity. In addition, over the 92-day time course of the study, with both male and female rats, there were no consistent treatment-related changes in serum indicators of hepatic, renal, and cardiac functions. Importantly, we also observed no vector-associated effects on either water consumption by, or hematocrit levels in, study animals. However, three suggestive mild gender-related response differences were seen. Female, but not male, rats exhibited small reductions in food consumption (∼10–15%) and body weight gain (5–10%), and evidence of persistent inflammation, after vector treatment. These were vector, but not dose, related. Three days after delivery of 2 × 1011 particles of AdhAQP1, vector was detected primarily in the targeted gland; 9 of 10 samples from the targeted gland were positive, whereas only 5 of 90 nonoral samples were positive. There was no evidence of the generation of replication-competent adenovirus in saliva or blood samples. In aggregate, these findings show that localized delivery of AdhAQP1 to salivary glands appears to occur without significant toxicity.

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