AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands.
Previously (Shan et al, 2005), we reported that adenoviral vector-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to minipig parotid glands following irradiation (IR) transiently restored salivary flow to near normal levels. This study evaluated a serotype 2, adeno-associated viral (AAV2) vector for extended correction of IR (single dose; 20 Gy)-induced, parotid salivary hypofunction in minipigs. At 16 weeks following the IR parotid salivary flow decreased by 85-90%. AAV2hAQP1 administration at week 17 transduced only duct cells and resulted in a dose-dependent increase in salivary flow to approximately 35% of pre-IR levels (to approximately 1 ml per 10 min) after 8 weeks (peak response). Administration of a control AAV2 vector or saline was without effect. Little change was observed in clinical chemistry and hematology values after AAV2hAQP1 delivery. Vector-treated animals generated high anti-AAV2 neutralizing antibody titers by week 4 (approximately 1:1600) and significant elevations in salivary (approximately 15%), but not serum, granulocyte macrophage colony-stimulating factor levels. Following vector administration, salivary [Na(+)] was dramatically increased, from approximately 10 to approximately 55 mM (at 4 weeks) and finally to 39 mM (8 weeks). The findings demonstrate that localized delivery of AAV2hAQP1 to IR-damaged parotid glands leads to increased fluid secretion from surviving duct cells, and may be useful in providing extended relief of salivary hypofunction in previously irradiated patients.
Gao
R
R
Salivary Gland Disease Center and Molecular Laboratory for Gene Therapy, Capital Medical University School of Stomatology, Beijing, PR China.
Yan
X
X
Zheng
C
C
Goldsmith
C M
CM
Afione
S
S
Hai
B
B
Xu
J
J
Zhou
J
J
Zhang
C
C
Chiorini
J A
JA
Baum
B J
BJ
Wang
S
S
D000818:Animals; D051398:Aquaporin 1 / Q000008:administration & dosage / Q000235:genetics*; D018076:DNA, Complementary / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D010306:Parotid Gland / Q000737:chemistry / Q000378:metabolism* / Q000528:radiation effects*; D013552:Swine
C496020:AQP1 protein, human; D018076:DNA, Complementary; D051398:Aquaporin 1