Abstract
The loss of salivary gland function caused by radiation therapy of the head and neck or autoimmune disease such as Sjögren’s syndrome is a serious condition that affects a patient’s quality of life. Due to the combined exocrine and endocrine functions of the salivary gland, gene transfer to the salivary glands holds the potential for developing therapies for disorders of the salivary gland and the expression of therapeutic proteins via the exocrine pathway to the mouth, upper gastrointestinal tract, or endocrine pathway, systemically, into the blood. Recent clinical success with viral vector–mediated gene transfer for the treatment of irradiation-induced damage to the salivary glands has highlighted the need for the development of novel vectors with acinar cell tropism able to result in stable long-term transduction. Previous studies with adeno-associated virus (AAV) focused on the submandibular gland and reported mostly ductal cell transduction. In this study, we have screened AAV vectors for acinar cell tropism in the parotid gland utilizing membrane-tomato floxed membrane-GFP transgenic mice to screen CRE recombinase encoding AAV vectors of different clades to rapidly identify capsid isolates able to transduce salivary gland acinar cells. We determined that AAVRh10 and a novel isolate found as a contaminant of a laboratory stock of simian adenovirus SV15, AAV44.9, are both able to transduce parotid and sublingual acinar cells. Persistence and localization of transduction of these AAVs were tested using vectors encoding firefly luciferase, which was detected 6 months after vector administration. Most luciferase expression was localized to the salivary gland compared to that of distal organs. Transduction resulted in robust secretion of recombinant protein in both blood and saliva. Transduction was species specific, with AAVRh10 having stronger transduction activity in rats compared with AAV44.9 or AAV2 but weaker in human primary salivary gland cells. This work demonstrates efficient transduction of parotid acinar cells by AAV that resulted in secretion of recombinant protein in both serum and saliva.
Highlights
Salivary glands serve the critical exocrine role of producing saliva in the oral cavity
Quantification of acinar cell transduction by AAVRh10 and AAV44.9 showed that 10%–15% of parotid and sublingual cells were GFP-positive compared to less than 1% with AAV2 (Table 1)
The development of salivary gland-targeted gene therapy could be useful for treating both diseases of the salivary gland and systemic diseases because of the natural exocrine and endocrine secretory activity of the gland
Summary
Salivary glands serve the critical exocrine role of producing saliva in the oral cavity. The average individual produces approximately a liter of saliva per day, which will contain almost a gram of proteins. This represents an enormous secretory ability given the relatively small size of the salivary gland compared with other secretory tissue such as the liver. Salivary glands have the capacity to secrete proteins in an endocrine manner that traffics to the blood. Because of the salivary gland’s unique location and activity as both an endocrine and exocrine organ, gene transfer to this organ possesses the potential to treat genetic or acquired disease conditions. Vectors can be delivered to the salivary gland by retroductal cannulation, allowing access to every cell within the gland
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