Nanocomplexed siRNA based gene therapy in salivary gland diseases

Objective: Salivary gland damage, due to therapeutic radiation for patients with head and neck malignancies, or salivary gland diseases, such as Sjögren’s syndrome, leads to hyposalivation and concomitant xerostomia. The loss of salivary gland function is initiated by the expression of specific genes, which push the cells toward apoptosis, but the mechanism underlying activation of the signaling cascades and key regulators for apoptosis are not fully understood. A preventive approach would be the effective knock down of key mediators involved in the apoptotic pathways.

Method: In this study, we evaluated the efficacy of the selective knock down of pro-apoptotic genes in mouse salivary gland cells, both in vitro and in vivo. We used a unique nanoparticle-mediated delivery system to carry small interfering RNA molecules (siRNAs) into target salivary gland cells.

Result: The pH-responsive property of the siRNA/nanoparticle complexes ensured approximately 80% transfection efficiency in vitro, and promoted internalization into salivary gland cells, in vivo. Treatment of salivary gland cells with siRNAs targeting the pro-apoptotic genes Pkcδ, or Bax, resulted in more than 50% knock down in vitro, as well as in vivo. Moreover, silencing of these pro-apoptotic genes provided a radioprotective effect, as measured by the significant reduction of apoptosis, in vitro.

Conclusion: We propose that transient knock down of pro-apoptotic genes in salivary glands prior to radiation can prevent salivary gland damage after radiotherapy and may suppress cellular apoptosis in other salivary gland diseases, as well.