Aquaporin-1 gene therapy as a novel method to treat radiation-induced salivary gland damage: The case for adeno-associated virus vectors.

Head and neck cancer imposes a substantial disease burden, with approximately 65,000 new cases annually in the United States and 500,000 cases worldwide. Radiation therapy remains a primary treatment modality for many patients with head and neck cancer. Despite advances aimed at limiting exposure of normal tissues within the field of radiation, salivary gland injury is a common and often unavoidable consequence of treatment. Although the mechanisms underlying radiation-induced salivary gland dysfunction remain incompletely understood, the resulting reduction in salivary flow is clinically evident and can cause substantial morbidity, including increased risk of oral infections, oral mucositis, dysphagia, and difficulty eating and speaking. Current therapeutic options are largely palliative, and durable, effective, and patient-acceptable treatments remain limited. Gene therapy offers a potential strategy for sustained functional improvement in irradiated salivary glands. The purpose of this work is to review the historical development of modified viral vectors for delivery of aquaporin-1, a water channel, to the salivary glands. We first summarize early studies using adenoviral vectors for gene delivery, which provided the basis for a Phase I clinical trial of adenoviral aquaporin-1 transfer for radiation-induced salivary gland dysfunction. We then describe the justification for our subsequent clinical trial using modified adeno-associated virus vectors for aquaporin-1 gene transfer. Finally, we outline the design of this trial, including subject recruitment, study procedures, and outcome measures.