Hydroxychloroquine enhances the endocrine secretion of adenovirus-directedgrowth hormone from rat submandibular glands in vivo

Use of gene transfer technology for treating single protein deficiency diso rders requires delivery of therapeutic levels of the transgene product. We have suggested that salivary glands may provide a potentially valuable targ et site for certain systemic applications of gene therapeutics (He et al., Gene Ther. 1998; 5:537-541). However, the ability of salivary glands to del iver therapeutic proteins to either the upper gastrointestinal tract via sa liva or to the bloodstream, as required, must be carefully evaluated. In th e anterior pituitary gland, human growth hormone (hGH) is secreted into the bloodstream via the regulated secretory pathway. However, when expressed f rom an adenoviral vector delivered to salivary glands, most hGH follows the regulated, tissue-specific, exocrine secretory pathway into saliva, where it is not therapeutically useful. We tested the hypothesis that the commonl y used, FDA-approved drug hydroxychloroquine (HCQ) can divert adenovirus-di rected hGH from this regulated secretory pathway in rat submandibular gland s and enhance delivery into the bloodstream. In untreated rats, there was s imilar to 20-fold more vector-directed hGH in saliva than in serum. Adminis tration of HCQ led to a shift of hGH secretion into the bloodstream. When d elivered at doses of 1 or 10 mg/kg body weight, via intraperitoneal injecti on plus intraductal infusion, the saliva: serum hGH ratio was similar to2:1 . Such HCQ delivery did not significantly alter the total amount of hGH mea sured, but increased the serum level of hGH 5- to 6-fold. Also, HCQ had no significant effects on serum chemistries or hematological parameters. We co nclude that HCQ is able to significantly enhance hGH secretion from salivar y glands into the bloodstream and may be useful to facilitate clinical appl ications of gene therapeutics via salivary glands.