Utilizing endocrine secretory pathways in salivary glands for systemic gene therapeutics

Abstract

Mammalian salivary glands are commonly used models of exocrine secretion. However, there is substantial experimental evidence showing the physiological existence of endocrine secretory pathways in these tissues. The use of gene transfer technology in vivo has allowed the unambiguous demonstration of these endocrine pathways. We and others have exploited such findings and evaluated salivary glands as possible target tissues for systemic applications of gene therapeutics. Salivary glands present numerous advantages for this purpose, including being well encapsulated, which limits extra-glandular vector dissemination, and having the luminal membranes of almost all parenchymal cells accessible via intraoral delivery of vectors through the main excretory ducts. Existing studies suggest that clinical benefits will result from salivary gland targeted systemic gene therapeutics.

Protective MCMV immunity by vaccination of the salivary glandviaWharton's duct: replication‐deficient recombinant adenovirus expressing individual MCMV genes elicits protection similar to that of MCMV

“…Understanding the immunobiology of the salivary glands is also of particular interest at this time because of rapidly developing progress in gene therapy and tissue engineering as it relates to the salivary glands. The ability to “reengineer” the salivary glands via gene transfer in vivo with the resultant in situ restoration of fluid secretion (35, 36) and to utilize salivary endocrine secretory pathways for systemic gene therapeutics (37–39) provides additional reasons for gaining a better understanding of how salivary gland immunity interacts with the expression of transferred genes, especially because the transferred genes are frequently expressed utilizing recombinant viral vectors. In this regard, Zheng et al .…”

Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders

“…Efficient production and secretion of transgene-encoded proteins can occur with vector doses 10 to 100 times lower than required at many commonly used tissue target sites (e.g. muscle, liver, lung: Snyder et al 1997, Almazan et al 2000, Bohl et al 2000, Chao et al 2001, Auricchio et al 2002, Samakoglu et al 2002, Johnston et al 2003, Voutetakis et al 2004a,b, Zufferey & Aebischer 2004. The use of lower vector doses likely reduces the potential danger of a viral vectorrelated adverse event.…”

“…use of the gene as a drug : Crystal 1995, Voutetakis et al 2004a,b, Zufferey & Aebischer 2004. The classic physiological role of SGs is to produce an exocrine secretion, saliva.…”

Partial Redirection of Transgenic Human Growth Hormone Secretion from Rat Salivary Glands

“…Typically, such gene transfer is directed at a cell type that is not the normal physiological site of production of the therapeutic protein. For example, erythropoietin, which is normally produced in the kidney, has been targeted in gene transfer studies to numerous other tissues, including muscle, lung, and salivary glands (Voutetakis et al, 2003). To optimize the potential of gene therapeutics in any target cell type, it is essential to understand both the secretory pathways operative in that target cell, as well as the secretory pathway normally followed by the transgene product in its physiological site of production.…”