Toxicity and biodistribution of a first-generation recombinant adenoviral vector, encoding aquaporin-1, after retroductal delivery to a single rat submandibular gland.
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 (2x108-2x1011 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 2x1011 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.
Zheng
Changyu
C
Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Goldsmith
Corinne M
CM
Mineshiba
Fumi
F
Chiorini
John A
JA
Kerr
Andrew
A
Wenk
Martin L
ML
Vallant
Molly
M
Irwin
Richard D
RD
Baum
Bruce J
BJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000097:blood; D051398:Aquaporin 1 / Q000096:biosynthesis / Q000235:genetics*; D004333:Drug Administration Routes; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000633:toxicity; D008297:Male; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013363:Submandibular Gland / Q000187:drug effects*; D014018:Tissue Distribution; D019076:Transgenes
D000906:Antibodies; C496022:Aqp1 protein, rat; D011994:Recombinant Proteins; D051398:Aquaporin 1