Targeting PDE4 in Sjögren's Syndrome Xerostomia - Project Summary/Abstract Saliva is indispensable for oral health, and by extension for the overall health of the organism, as demonstrated by the major harms suffered by patients with salivary gland hypo/dysfunction which include xerostomia, the feeling of dry mouth, as well as loss of taste, oral infections, or difficulty chewing, digesting, and swallowing food leading to malnutrition. There is a critical need for novel effective therapeutics as current mainstay treatments (eg saliva substitutes or muscarinic agonists) provide only short-term relief and/or are effective in only a portion of the patient population. We have found that the inhibition of Type 4 cAMP-phosphodiesterases (PDE4s) induces salivation in healthy mice by itself, can further potentiate both the parasympathetic- (eg muscarinic) as well as the sympathetic (eg β-adrenergic) stimulation of salivary secretions, and protects from hyposalivation induced by acute, lipopolysaccharide-induced hyperinflammation. We thus propose the overall hypothesis that targeting PDE4s may represent a promising novel therapeutic approach that may alleviate both the causes (eg inflammation) and the symptoms (eg xerostomia) of salivary gland hypo/dysfunction in several independent ways, including: 1. the potentiation of both parasympathetic- and sympathetic- stimulation of saliva secretion, 2. the production of saliva components vital for oral health, and 3. through anti-inflammatory effects that facilitate salivary gland protection/regeneration. Sjögren’s syndrome (SS) is an autoimmune disorder associated with severe xerostomia in humans, and we propose to evaluate the therapeutic potential of PDE4 inactivation in a model of SS-like disease in mice. The PDE4 family comprises four isoenzymes, PDE4A to D. Non-/PAN-selective PDE4 inhibitors have established therapeutic benefits, but adverse effects, including nausea, emesis, and diarrhea, have long limited the clinical utility of these drugs. As each PDE4 isoform serves unique and non- overlapping physiological roles, targeting individual PDE4 proteins can serve to dissect the therapeutically beneficial, from the side effects associated with current PAN-PDE4 inhibitors. Under this exploratory grant, we will use genetic models of subtype-selective PDE4 ablation in mice, as well as treatment with proprietary subtype- selective PDE4 inhibitors, to test the hypothesis that inactivation of PDE4B and/or PDE4D mediates the therapeutic benefits of PAN-PDE4 inhibitors in a model of Sjögren’s syndrome-like disease in mice. If outcomes are as expected, this proposal will confirm the therapeutic potential of targeting PDE4s as a novel therapeutic approach for Sjögren’s syndrome xerostomia, identify specific PDE4 subtypes and/or saliva components as targets for future drug development, and lay the foundation for subsequent studies aimed at delineating the cell types and molecular mechanisms whereby individual PDE4s exert their roles in the regulation of saliva secretion.
