The advent of intensity-modulated radiotherapy (IMRT), wherein radiation beams are shaped to avoid vulnerable organs, such as the salivary gland, has been a great advance in reducing radiation-induced xerostomia, lowering the incidence from ~90% to ~40%. While amifostine could also be used as a radioprotectant to lower radiation-induced damage to salivary glands, it causes frequent and severe systemic side effects such as nausea and vomiting, which often leads to discontinuation of the treatment. Other treatments, such as saliva substitutes and saliva stimulants (e.g., pilocarpine and cevimeline) can provide temporary relief, but their effectiveness is limited to patients that have significant amounts of functional saliva secreting cells remaining post-irradiation. This leaves a pressing unmet need for a new therapy.

Aquaporin-1 (AQP1) gene therapy has been explored as an alternative treatment for these patients. An initial adenoviral delivery of AQP1 gene to the salivary gland has demonstrated successful outcomes to increase saliva production after irradiation in Phase I/II clinical trials; however, a highly inflammatory host response to this therapy was observed. Ultrasound-Assisted non-viral Gene Transfer (UAGT) of AQP1, in development by the team of Drs. Isabelle Lombaert (University of Michigan) and Michael Passineau (Allegheny Health Network) aims to deliver a solution to this problem.

UAGT is a technique that delivers a non-viral plasmid to cells through transient sonoporation and permeabilization of the cell membrane, thereby avoiding activation of the patient’s immune response.

Gene therapy, while promising, has a complex set of regulatory requirements to ensure safety. As the only gene therapy program in the MPWRM Resource Center (RC) portfolio, the RC Regulatory Core has been an integral part of this project since its matriculation in the program. The team has spent multiple sessions with the Regulatory Core to chart the preclinical translational development requirements to enable an FDA IND submission to gain approval to initiate the first-inhuman clinical trial. An initial GLP study to demonstrate the safety of UAGT without a vector was completed. In addition to the Regulatory Core, the Quality Assurance Core also supported this GLP study by completing an in-person pre-qualification visit of the GLP facility, preparing the study protocol in collaboration with the team, and reviewing and finalizing the study reports. With added pharmacology/toxicology regulatory expertise through the RC Core, the team has planned a streamlined regulatory approach to an IND filing in 2024.

The Resource Center’s Market Assessment and Commercialization Cores have been an integral part of this team to chart a road map towards the commercialization AQP1 UAGT. The team identified and interviewed a variety of clinical specialists, ranging from otolaryngologists to oncologists to oral maxillofacial surgeons, to understand the clinical management of radiation-induced xerostomia in head and neck cancer patients. Subsequently, the team investigated the medical reimbursement landscape to gain an understanding of potential reimbursement strategies. In addition, Dr. Lombaert has leveraged translational training resources at her home institution for the advancement of this project. Furthermore, with collective support from the home institution and RC experts, Dr. Lombaert has applied to and was successfully awarded the Frankel Innovation Initiative to support future GLP work. With the integrated support from the RC and the home institution, this project is poised to make great strides in the uncharted territory of gene therapy for radiationinduced xerostomia. With learnings from this indication, it is likely that the UAGT can be applied with other non-viral genes, serving as a platform technology that can be explored for various indications.