ABSTRACT Most head-and-neck cancer patients receiving radiotherapy treatment develop life-long adverse effects. Side effects presented as hyposalivation and chronic xerostomia result from radiation damage to nearby salivary glands. Limited palliative options are currently available for these patients, reinforcing the need for regenerative therapies. Our regenerative efforts, using non-viral gene therapy to overexpress water channel Aquaporin-1 (AQP1) in radiation-surviving salivary gland epithelial cells, showed restorative results by increasing salivary flow into the oral cavity. However, as both viral and non-viral vectors are restricted by the ability to provide long-term expression, a next generation of AQP1 therapy that results in sustained gene expression awaits. Our preliminary data demonstrates that methylation of the endogenous AQP1 promoter in epithelial cells is an important mediator of gene expression. In addition, the methylation status alters after exposure to radiation. Based on these findings, we hypothesize that epigenetic altering of the AQP1 promoter in radiation-surviving epithelial cells facilitates a change towards sustained endogenous AQP1 expression. To test this hypothesis, we adapted a new CRISPR method and aim to (1) demonstrate the negative correlation between the level of methylation and AQP1 expression, and (2) develop in vitro and in vivo methods to optimally alter the methylation level of the AQP1 promoter in irradiated epithelial cells. These studies bring in vivo epigenetic editing to a reality as a means of modulating endogenous gene expression and sustained water movement in damaged salivary glands. As a result, this continuous production of salivary flow can resolve xerostomia in radiated head-and-neck cancer patients in a long-term setting.