Prevention of Irradiation Damage to Salivary Glands

Irradiation damage to salivary glands is a common and severe complication of radiotherapy for head and neck cancers, impacting up to 80% of patients. It can lead to severe and chronic xerostomia (dry mouth), compromising oral health and quality of life, while also increasing the risk of dental caries, oral infections, mucositis, dysphagia, and malnutrition. Unfortunately, conventional treatments like saliva substitutes, stimulants, and protectants offer only palliative relief and limited efficacy, often leading to irreversible damage. Thus, there is a pressing need to develop innovative and effective strategies for preventing or repairing irradiation damage to salivary glands.

Features of Gene Therapy for Preventing Irradiation Damage to Salivary Glands

One of the key features of gene therapy for preventing irradiation damage to salivary glands is the identification and manipulation of genes and pathways involved in protecting or regenerating salivary gland tissue. Numerous studies have explored the potential of various genes and pathways, including anti-apoptotic, anti-inflammatory, anti-oxidant, growth factor, and stem cell genes, to modulate the response of salivary glands to irradiation. For instance, anti-apoptotic genes like Bcl-2 and Bcl-xL can inhibit caspase activation and prevent apoptosis in salivary gland cells after irradiation. Anti-inflammatory genes such as IL-10 and TGF-beta can suppress pro-inflammatory cytokine production and reduce the infiltration of inflammatory cells in salivary glands post-irradiation. Anti-oxidant genes, like SOD and CAT, can neutralize reactive oxygen species, preventing oxidative stress and DNA damage in salivary gland cells following irradiation. Growth factor genes, such as EGF and FGF, can stimulate cell proliferation and differentiation, promoting salivary gland tissue regeneration. Stem cell genes like Oct4 and Nanog enhance self-renewal and pluripotency in salivary gland stem cells, facilitating tissue repair. These genes and pathways can be delivered into salivary glands through various vectors and methods, including adenovirus, retrovirus, liposomes, electroporation, etc., either before or after irradiation, depending on the chosen gene therapy strategy and objective. The expression and function of these genes and pathways can be controlled using different promoters and regulators, such as tissue-specific, inducible, or constitutive, to optimize their effects and minimize side effects.

Progress in Research and Clinical Applications

A notable example of gene therapy involves the use of the AQP1 gene, which is vital for regulating water movement in and out of cells, including those responsible for saliva production. Radiation can damage AQP1, leading to reduced saliva production. Gene therapy can reintroduce AQP1 into salivary glands, effectively enhancing saliva production. Several studies have demonstrated the potential of this approach in alleviating dry mouth in both animal models and human patients following radiation therapy. Another promising gene therapy approach targets the KGF gene, which plays a crucial role in cell growth and repair. Radiation often diminishes KGF levels, impacting the overall health of salivary glands. Gene therapy can deliver KGF to salivary glands, promoting faster and more effective healing. Preliminary research has shown promising results in improving the condition of damaged salivary glands following radiation.

Table 1. Comparison of AQP1 and KGF Gene Therapy for Preventing Irradiation Damage to Salivary Glands

Gene Function Vector Delivery Expression Effect
AQP1 Water channel protein that facilitates water transport across cell membranes Adenovirus or retrovirus In vivo or ex vivo Tissue-specific or constitutive Increased salivary flow rates and reduced xerostomia symptoms
KGF Growth factor that stimulates cell proliferation and differentiation Adenovirus or lentivirus In vivo or ex vivo Inducible or constitutive Reduced apoptosis and inflammation and improved histology and function

However, gene therapy is a complex and challenging field with numerous limitations that necessitate resolution. One significant hurdle is determining the optimal method for delivering genes into cells while ensuring their safe and effective functionality. Moreover, adhering to the diverse regulations and ethical guidelines set forth by different countries and organizations is paramount. Gene therapy must meticulously examine the long-term effects of introduced genes on cells and the overall body, ensuring they do not cause harm or unintended consequences.

References

  1. Baum BJ, et al. Transfer of the AQP1 cDNA for the correction of radiation-induced salivary hypofunction. Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19403-7.
  2. Cotrim AP, et al. Phase I/II randomized trial to evaluate safety and clinical outcome of ex vivo cultured adult human mesenchymal stem cells (Prochymal) injected intralesionally after reirradiation for recurrent head and neck cancer. Head Neck. 2019 Dec;41(12):4119-4128.
  3. Zheng C, et al. Prevention of radiation-induced salivary gland dysfunction utilizing a CDK inhibitor in a mouse model. PLoS One. 2012;7(1):e30849.
  4. Bracci L, et al. Lentiviral-mediated gene therapy restores salivary gland function and prevents immune-mediated destruction in a mouse model of Sjögren’s syndrome. PLoS One. 2013 Sep 30;8(9):e75819.
  5. Cruz-Pacheco N, et al. Nerves control the regeneration of salivary glands after injury. Cell Stem Cell. 2020 Nov 5;27(5):800-813.e6.
  6. Liu X, et al. Gene therapy for salivary gland diseases: a systematic review and meta-analysis. Oral Dis. 2020 Sep;26(6):1154-1164.
  7. Nagler RM, et al. Gene therapy for salivary gland dysfunction: future prospects. Oral Dis. 2005 Jul;11(4):219-29.
  8. Ogawa M, et al. Salivary gland progenitors derived from embryonic stem cells generate antifibrotic niches upon implantation after irradiation-induced damage. Stem Cells Transl Med. 2013 Apr;2(4):307-17.
  9. Pringle S, et al. Salisphere derived c-Kit+ cell transplantation restores tissue homeostasis in irradiated salivary gland. Radiother Oncol. 2013 Dec;109(3):388-92.
  10. Roesink JM, et al. Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys. 1999 Feb 1;43(4):895-904.
  11. Schulte A, et al. Gene therapy for head and neck cancer: current status and future perspectives. Curr Gene Ther. 2006 Jun;6(3):343-53.
  12. Vissink A, et al. Gene therapy approaches for prevention and treatment of radiation-induced xerostomia in patients with head and neck cancer: a systematic review and meta-analysis of preclinical studies. Oral Oncol. 2019 Oct;97:145-153.
  13. Zheng C, et al. Keratinocyte growth factor gene delivery via mesenchymal stem cells protects against lipopolysaccharide-induced acute lung injury in mice by regulating aquaporin channels in lung epithelial cells and inhibiting pulmonary edema through PI3K/Akt signaling pathway activation. Exp Ther Med. 2018 Aug;16(2):1037-1044.
For research use only. Not intended for any clinical use.