5.3.2. Promising Preclinical Studies

Although there is currently only one FDA-approved radioprotective therapy, there are promising preclinical studies investigating potential radioprotective approaches (Figure 4). We recently reported that antagonism of the ATP-gated ionotropic P2X7 receptor (P2X7R) by i.p. injection of A-438079 in FVB mice provided significant radioprotection and maintained carbachol-induced saliva flow rates similar to non-irradiated mice [48]. P2X7R is highly expressed in mouse salivary glands, where its activation induces pro-inflammatory responses, including membrane blebbing, caspase activation, IL-1β release, recruitment of immune cells and NLRP3 inflammasome assembly [161,225,226]. We also have previously reported that A-438079 attenuates lymphocytic infiltration of SMGs and increases saliva secretion in a mouse model of the autoimmune disease Sjögren's syndrome [161,227]. Another promising pharmacological approach is the use of tyrosine kinase inhibitors (TKIs). Delivery of TKIs, dasatinib or imatinib, protect the mouse salivary gland from IR-induced damage and loss of function

without affecting xenograft tumor growth [78]. This response was due to reduced activation of PKCδ, an important regulator of apoptosis in salivary gland acinar cells [63,77,228–230].

Introduction of human neurotrophic factor neurturin (NRTN) using an adeno-associated virus serotype 2 (AAV2) vector prior to IR, but not post-IR, was radioprotective, preventing hyposalivation in both murine and porcine models [54]. NRTN is essential for proper innervation of the salivary glands, which is required for salivary secretory function. RNA sequencing analysis revealed a reduction in expression of fibrotic genes and both innate and humoral immune responses in mice and minipigs receiving AAV2-NRTN [54]. While additional studies are warranted to further investigate immune responses and the duration of improvement of saliva secretion in the IR-treated porcine model, these exciting findings in the highly translational Yucatan minipig model [57,231] are promising for future clinical trials.
