Skip to main content
SpringerLink
Log in

Salivary Gland Gene Therapy in Experimental and Clinical Trials

  • Chapter
  • First Online:
Salivary Gland Development and Regeneration

Abstract

Salivary gland gene therapy presents an opportunity to reprogram the organ on the molecular level and achieve unprecedented therapeutic advancements. This chapter will review the basic biology of gene transfer, with emphasis on those vector systems that have performed well in the salivary gland in animal models. Various therapeutic applications of salivary gland gene therapy will be discussed, including radiation-induced xerostomia and Sjögren’s syndrome. The concept of salivary glands as endogenous bioreactors for systemic gene therapeutics in monogenetic and acquired diseases will also be reviewed.

A brief history of the field, with regard to animal models, clinical translational studies, and ultimately a successful phase I/II clinical trial, will be presented. The merits and limitations of the several animal models of salivary gland gene therapy will be reviewed. The chapter concludes with a discussion of human salivary gland gene therapy clinical trials, completed and ongoing, and will point out congruence and discord between preclinical animal studies and clinical trials. Salivary gland gene therapy is now established as safe and therapeutically effective in humans, and the near future of this field will be focused on making this technology practical for outpatient use and broadly disseminating it into the practice of oral and dental medicine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Perez P, Rowzee AM, Zheng C, Adriaansen J, Baum BJ. Salivary epithelial cells: An unassuming target site for gene therapeutics. Int J Biochem Cell Biol. 2010;42:773–7.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mastrangeli A, O'Connell B, Aladib W, Fox PC, Baum BJ, Crystal RG. Direct in vivo adenovirus-mediated gene transfer to salivary glands. Am J Phys. 1994;266:G1146–55.

    Google Scholar 

  3. Leon J, Park A. Time. 1999;153:68–70, 73.

    Google Scholar 

  4. Shai E, Falk H, Honigman A, Panet A, Palmon A. Gene transfer mediated by different viral vectors following direct cannulation of mouse submandibular salivary glands. Eur J Oral Sci. 2002;110:254–60.

    Article  PubMed  Google Scholar 

  5. Katano H, Kok MR, Cotrim AP, Yamano S, Schmidt M, Afione S, Baum BJ, Chiorini JA. Enhanced transduction of mouse salivary glands with aav5-based vectors. Gene Ther. 2006;13:594–601.

    Article  PubMed  Google Scholar 

  6. Arany S, Benoit DS, Dewhurst S, Ovitt CE. Nanoparticle-mediated gene silencing confers radioprotection to salivary glands in vivo. Mol Ther. 2013;21:1182–94.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Passineau MJ, Zourelias L, Machen L, Edwards PC, Benza RL. Ultrasound-assisted non-viral gene transfer to the salivary glands. Gene Ther. 2010;17:1318–24.

    Article  PubMed  Google Scholar 

  8. Geguchadze R, Wang Z, Zourelias L, Perez-Riveros P, Edwards PC, Machen L, Passineau MJ. Proteomic profiling of salivary gland after nonviral gene transfer mediated by conventional plasmids and minicircles. Mol Ther Methods Clin Dev. 2014;1:14007.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245:1066–73.

    Article  PubMed  Google Scholar 

  10. Voutetakis A, Kok MR, Zheng C, Bossis I, Wang J, Cotrim AP, Marracino N, Goldsmith CM, Chiorini JA, Loh YP, Nieman LK, Baum BJ. Reengineered salivary glands are stable endogenous bioreactors for systemic gene therapeutics. Proc Natl Acad Sci U S A. 2004;101:3053–8.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Voutetakis A, Bossis I, Kok MR, Zhang W, Wang J, Cotrim AP, Zheng C, Chiorini JA, Nieman LK, Baum BJ. Salivary glands as a potential gene transfer target for gene therapeutics of some monogenetic endocrine disorders. J Endocrinol. 2005;185:363–72.

    Article  PubMed  Google Scholar 

  12. Racz GZ, Zheng C, Goldsmith CM, Baum BJ, Cawley NX. Toward gene therapy for growth hormone deficiency via salivary gland expression of growth hormone. Oral Dis. 2015;21:149–55.

    Article  PubMed  Google Scholar 

  13. Passineau MJ, Fahrenholz T, Machen L, Zourelias L, Nega K, Paul R, MacDougall MJ, Mamaeva O, Steet R, Barnes J, Kingston HM, Benza RL. Alpha-galactosidase a expressed in the salivary glands partially corrects organ biochemical deficits in the fabry mouse through endocrine trafficking. Hum Gene Ther. 2011;22:293–301.

    Article  PubMed  Google Scholar 

  14. Voutetakis A, Cotrim AP, Rowzee A, Zheng C, Rathod T, Yanik T, Loh YP, Baum BJ, Cawley NX. Systemic delivery of bioactive glucagon-like peptide 1 after adenoviral-mediated gene transfer in the murine salivary gland. Endocrinology. 2010;151:4566–72.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Voutetakis A, Zheng C, Wang J, Goldsmith CM, Afione S, Chiorini JA, Wenk ML, Vallant M, Irwin RD, Baum BJ. Gender differences in serotype 2 adeno-associated virus biodistribution after administration to rodent salivary glands. Hum Gene Ther. 2007;18:1109–18.

    Article  PubMed  Google Scholar 

  16. Yan X, Voutetakis A, Zheng C, Hai B, Zhang C, Baum BJ, Wang S. Sorting of transgenic secretory proteins in miniature pig parotid glands following adenoviral-mediated gene transfer. J Gene Med. 2007;9:779–87.

    Article  PubMed  Google Scholar 

  17. Samuni Y, Cawley NX, Zheng C, Cotrim AP, Loh YP, Baum BJ. Sorting behavior of a transgenic erythropoietin-growth hormone fusion protein in murine salivary glands. Hum Gene Ther. 2008;19:279–86.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Samuni Y, Zheng C, Cawley NX, Cotrim AP, Loh YP, Baum BJ. Sorting of growth hormone-erythropoietin fusion proteins in rat salivary glands. Biochem Biophys Res Commun. 2008;373:136–9.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Voutetakis A, Zheng C, Metzger M, Cotrim AP, Donahue RE, Dunbar CE, Baum BJ. Sorting of transgenic secretory proteins in rhesus macaque parotid glands after adenovirus-mediated gene transfer. Hum Gene Ther. 2008;19:1401–5.

    Article  PubMed  PubMed Central  Google Scholar 

  20. La Sala MS, Hurtado MD, Brown AR, Bohorquez DV, Liddle RA, Herzog H, Zolotukhin S, Dotson CD. Modulation of taste responsiveness by the satiation hormone peptide yy. FASEB J. 2013;27:5022–33.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Acosta A, Hurtado MD, Gorbatyuk O, La Sala M, Duncan D, Aslanidi G, Campbell-Thompson M, Zhang L, Herzog H, Voutetakis A, Baum BJ, Zolotukhin S. Salivary pyy: a putative bypass to satiety. PLoS ONE. 2011;6:e26137.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Delporte C, Hoque AT, Kulakusky JA, Braddon VR, Goldsmith CM, Wellner RB, Baum BJ. Relationship between adenovirus-mediated aquaporin 1 expression and fluid movement across epithelial cells. Biochem Biophys Res Commun. 1998;246:584–8.

    Article  PubMed  Google Scholar 

  23. Delporte C, O'Connell BC, He X, Lancaster HE, O'Connell AC, Agre P, Baum BJ. Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cdna to irradiated rat salivary glands. Proc Natl Acad Sci U S A. 1997;94:3268–73.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shan Z, Li J, Zheng C, Liu X, Fan Z, Zhang C, Goldsmith CM, Wellner RB, Baum BJ, Wang S. Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cdna to irradiated miniature pig parotid glands. Mol Ther. 2005;11:444–51.

    Article  PubMed  Google Scholar 

  25. Braddon VR, Chiorini JA, Wang S, Kotin RM, Baum BJ. Adeno-associated virus-mediated transfer of a functional water channel into salivary epithelial cells in vitro and in vivo. Hum Gene Ther. 1998;9:2777–85.

    Article  PubMed  Google Scholar 

  26. Gao R, Yan X, Zheng C, Goldsmith CM, Afione S, Hai B, Xu J, Zhou J, Zhang C, Chiorini JA, Baum BJ, Wang S. Aav2-mediated transfer of the human aquaporin-1 cdna restores fluid secretion from irradiated miniature pig parotid glands. Gene Ther. 2011;18:38–42.

    Article  PubMed  Google Scholar 

  27. Wang Z, Zourelias L, Wu C, Edwards PC, Trombetta M, Passineau MJ. Ultrasound-assisted nonviral gene transfer of aqp1 to the irradiated minipig parotid gland restores fluid secretion. Gene Ther. 2015;22:739–49.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Baum BJ, Alevizos I, Zheng C, Cotrim AP, Liu S, McCullagh L, Goldsmith CM, Burbelo PD, Citrin DE, Mitchell JB, Nottingham LK, Rudy SF, Van Waes C, Whatley MA, Brahim JS, Chiorini JA, Danielides S, Turner RJ, Patronas NJ, Chen CC, Nikolov NP, Illei GG. Early responses to adenoviral-mediated transfer of the aquaporin-1 cdna for radiation-induced salivary hypofunction. Proc Natl Acad Sci U S A. 2012;109:19403–7.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Palaniyandi S, Odaka Y, Green W, Abreo F, Caldito G, De Benedetti A, Sunavala-Dossabhoy G. Adenoviral delivery of tousled kinase for the protection of salivary glands against ionizing radiation damage. Gene Ther. 2011;18:275–82.

    Article  PubMed  Google Scholar 

  30. Timiri Shanmugam PS, Dayton RD, Palaniyandi S, Abreo F, Caldito G, Klein RL, Sunavala-Dossabhoy G. Recombinant aav9-tlk1b administration ameliorates fractionated radiation-induced xerostomia. Hum Gene Ther. 2013;24:604–12.

    Article  PubMed  Google Scholar 

  31. Zheng C, Cotrim AP, Sunshine AN, Sugito T, Liu L, Sowers A, Mitchell JB, Baum BJ. Prevention of radiation-induced oral mucositis after adenoviral vector-mediated transfer of the keratinocyte growth factor cdna to mouse submandibular glands. Clin Cancer Res. 2009;15:4641–8.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zheng C, Cotrim AP, Rowzee A, Swaim W, Sowers A, Mitchell JB, Baum BJ. Prevention of radiation-induced salivary hypofunction following hkgf gene delivery to murine submandibular glands. Clin Cancer Res. 2011;17:2842–51.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Guo L, Gao R, Xu J, Jin L, Cotrim AP, Yan X, Zheng C, Goldsmith CM, Shan Z, Hai B, Zhou J, Zhang C, Baum BJ, Wang S. Adltr2ef1alpha-fgf2-mediated prevention of fractionated irradiation-induced salivary hypofunction in swine. Gene Ther. 2014;21:866–73.

    Article  PubMed  Google Scholar 

  34. Cotrim AP, Sowers A, Mitchell JB, Baum BJ. Prevention of irradiation-induced salivary hypofunction by microvessel protection in mouse salivary glands. Mol Ther. 2007;15:2101–6.

    Article  PubMed  Google Scholar 

  35. Lee HJ, Lee YJ, Kwon HC, Bae S, Kim SH, Min JJ, Cho CK, Lee YS. Radioprotective effect of heat shock protein 25 on submandibular glands of rats. Am J Pathol. 2006;169:1601–11.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Park YS, Gauna AE, Cha S. Mouse models of primary sjogren’s syndrome. Curr Pharm Des. 2015;21:2350–64.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17a in induction of sjogren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010;12:R220.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Vosters JL, Landek-Salgado MA, Yin H, Swaim WD, Kimura H, Tak PP, Caturegli P, Chiorini JA. Interleukin-12 induces salivary gland dysfunction in transgenic mice, providing a new model of sjogren’s syndrome. Arthritis Rheum. 2009;60:3633–41.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Vosters JL, Yin H, Roescher N, Kok MR, Tak PP, Chiorini JA. Local expression of tumor necrosis factor-receptor 1:Immunoglobulin g can induce salivary gland dysfunction in a murine model of sjogren’s syndrome. Arthritis Res Ther. 2009;11:R189.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Nguyen CQ, Yin H, Lee BH, Chiorini JA, Peck AB. Il17: potential therapeutic target in sjogren’s syndrome using adenovirus-mediated gene transfer. Lab Investig. 2011;91:54–62.

    Article  PubMed  Google Scholar 

  41. Roescher N, Vosters JL, Yin H, Illei GG, Tak PP, Chiorini JA. Effect of soluble icam-1 on a sjogren’s syndrome-like phenotype in nod mice is disease stage dependent. PLoS ONE. 2011;6:e19962.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Lee BH, Carcamo WC, Chiorini JA, Peck AB, Nguyen CQ. Gene therapy using il-27 ameliorates sjogren’s syndrome-like autoimmune exocrinopathy. Arthritis Res Ther. 2012;14:R172.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Vosters JL, Roescher N, Illei GG, Chiorini JA, Tak PP. Taci-fc gene therapy improves autoimmune sialadenitis but not salivary gland function in non-obese diabetic mice. Oral Dis. 2012;18:365–74.

    Article  PubMed  Google Scholar 

  44. Wu C, Wang Z, Zourelias L, Thakker H, Passineau MJ. Il-17 sequestration via salivary gland gene therapy in a mouse model of sjogren’s syndrome suppresses disease-associated expression of the putative autoantigen klk1b22. Arthritis Res Ther. 2015;17:198.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ice JA, Li H, Adrianto I, Lin PC, Kelly JA, Montgomery CG, Lessard CJ, Moser KL. Genetics of sjogren’s syndrome in the genome-wide association era. J Autoimmun. 2012;39:57–63.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Burbelo PD, Ambatipudi K, Alevizos I. Genome-wide association studies in sjogren’s syndrome: What do the genes tell us about disease pathogenesis? Autoimmun Rev. 2014;13:756–61.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kaiser J. Gene therapy for blindness may fade with time. Science. 2015. http://www.sciencemag.org/news/2015/05/gene-therapy-blindness-may-fade-time

  48. Zheng C, Baum BJ, Liu X, Goldsmith CM, Perez P, Jang SI, Cotrim AP, McCullagh L, Ambudkar IS, Alevizos I. Persistence of haqp1 expression in human salivary gland cells following adhaqp1 transduction is associated with a lack of methylation of hcmv promoter. Gene Ther. 2015;22:758–66.

    Article  PubMed  Google Scholar 

  49. Voutetakis A, Zheng C, Cotrim AP, Mineshiba F, Afione S, Roescher N, Swaim WD, Metzger M, Eckhaus MA, Donahue RE, Dunbar CE, Chiorini JA, Baum BJ. Aav5-mediated gene transfer to the parotid glands of non-human primates. Gene Ther. 2010;17:50–60.

    Article  PubMed  Google Scholar 

  50. Li J, Zheng C, Zhang X, Liu X, Zhang C, Goldsmith CM, Baum BJ, Wang S. Developing a convenient large animal model for gene transfer to salivary glands in vivo. J Gene Med. 2004;6:55–63.

    Article  PubMed  Google Scholar 

  51. Li J, Shan Z, Ou G, Liu X, Zhang C, Baum BJ, Wang S. Structural and functional characteristics of irradiation damage to parotid glands in the miniature pig. Int J Radiat Oncol Biol Phys. 2005;62:1510–6.

    Article  PubMed  Google Scholar 

  52. Baum BJ. Radiation-induced salivary hypofunction may become a thing of the past. Oral Dis. 2016;22:81–4.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gene Therapy Program, Allegheny Health Network, Pittsburgh, PA, USA

    Michael Passineau

Authors
  1. Michael Passineau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Passineau .

Editor information

Editors and Affiliations

  1. Oral and Maxillofacial Diagnostic Sciences, University of Florida, Gainesville, Florida, USA

    Seunghee Cha

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Passineau, M. (2017). Salivary Gland Gene Therapy in Experimental and Clinical Trials. In: Cha, S. (eds) Salivary Gland Development and Regeneration. Springer, Cham. https://doi.org/10.1007/978-3-319-43513-8_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-43513-8_12

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-43511-4

  • Online ISBN: 978-3-319-43513-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation