Human Parathyroid Hormone Is Secreted Primarily into the Bloodstream After Rat Parotid Gland Gene Transfer
- 1 January 2011
- journal article
- research article
- Published by Mary Ann Liebert Inc in Human Gene Therapy
- Vol. 22 (1), 84-92
- https://doi.org/10.1089/hum.2010.097
Abstract
Hypoparathyroidism is a hormone deficiency syndrome that leads to low blood calcium levels and for which current replacement therapy is inadequate. Gene transfer to salivary glands leads to safe and abundant secretion of therapeutic protein into either saliva or the bloodstream. We previously reported the successful transduction of rat submandibular glands with an adenoviral vector encoding human parathyroid hormone (Ad.hPTH), but unfortunately most of the hPTH was secreted into saliva. Because submandibular and parotid glands are morphologically and functionally different, we hypothesized that hPTH sorting might be different in parotid glands. After 2 days, the pattern of hPTH secretion from transduced parotid glands of intact rats was reversed from that of transduced submandibular glands, that is, most transgenic hPTH was detected in serum (5 × 1010 viral particles per gland; the saliva-to-serum ratio of total hPTH secreted was 0.04). Vector copies were localized to the targeted parotid glands, with none detected in liver or spleen. Ad.hPTH next was administered to parotid glands of parathyroidectomized rats. Two days after delivery no hPTH was detectable in saliva, but high levels were found in serum, leading to normalization of serum calcium and a significant increase in the urinary phosphorus-to-creatinine ratio. This study demonstrates for the first time differential sorting of transgenic hPTH between submandibular and parotid glands, suggesting that hPTH may be a valuable model protein for understanding the molecular basis of transgenic secretory protein sorting in these exocrine glands. We also show the clinical potential of salivary gland hPTH gene therapy for patients with hypoparathyroidism.Keywords
This publication has 60 references indexed in Scilit:
- Salivary epithelial cells: An unassuming target site for gene therapeuticsThe International Journal of Biochemistry & Cell Biology, 2010
- Transient detection of E1-containing adenovirus in saliva after the delivery of a first-generation adenoviral vector to human parotid glandThe Journal of Gene Medicine, 2009
- Expression of plasmid DNA in the salivary gland epithelium: novel approaches to study dynamic cellular processes in live animalsAmerican Journal of Physiology-Cell Physiology, 2009
- In vivo veritas: the power of in situ manipulation of cells in a living animal. Focus on “Expression of plasmid DNA in the salivary gland epithelium: novel approaches to study dynamic cellular processes in live animals”American Journal of Physiology-Cell Physiology, 2009
- Oral Gene Therapy for Hypoparathyroidism: A Rat ModelHuman Gene Therapy, 2009
- Differential Sorting of Human Parathyroid Hormone After Transduction of Mouse and Rat Salivary GlandsHuman Gene Therapy, 2008
- Effects of OnceVersusTwice-Daily Parathyroid Hormone 1–34 Therapy in Children with HypoparathyroidismJournal of Clinical Endocrinology & Metabolism, 2008
- HypoparathyroidismNew England Journal of Medicine, 2008
- Diagnosis and management of hypocalcaemiaBMJ, 2008
- Polarized Secretion of Transgene Products from Salivary Glands in VivoHuman Gene Therapy, 1999