Gene Therapy for Radiation Induced Salivary Gland Hypofunction

Objectives: Therapy for head and neck cancer commonly includes ionizing radiation (IR). IR irreversibly damages the salivary glands causing decrements in quality-of-life and oral health. There are no therapies to correct this disorder or its sequelae. Previously, proof-of-concept studies have demonstrated the effectiveness of adenovirus vector gene transfer of human aquaporin-1 (hAQP1) to the parotid gland and correction of salivary hypofunction. To improve the stability of gene transfer, we developed an adeno-associated virus serotype-2 (AAV2) vector with low immunogenicity to achieve long-term salivary gland transduction. The primary objective of this study is to test the safety of AAV2hAQP1 in adult subjects with established IR-induced parotid gland hypofunction.
Methods:
A Phase I, open-label, dose-escalation study evaluating the safety of a single administration of AAV2-hAQP1 to one parotid gland in human subjects with IR-induced salivary hypofunction. Safety will be determined using conventional clinical and immunological parameters. The principle outcome measure for biological efficacy is parotid gland salivary output.
Results:
A previous study evaluated the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in eleven subjects. Subjective and objective responses were seen about 50% of those treated.
non-responders likely developed an immune response to this vector. The current protocol aims to test the efficacy of a more long-term adeno-associated virus type 2 (AAV2) based vector expression of the same transgene for the treatment of irradiation-induced parotid salivary hypofunction.
We have enrolled 20 patients and treated 9. The study is actively enrolling.
Conclusions: CONCLUSION.
AAV2-hAQP1 gene transfer is effective in models to correct IR-induced salivary hypofunction. With robust preclinical data, we have embarked on Phase I safety study to test AAV2-hAQP1 gene transfer to the human parotid gland. There have been no dose-limiting toxicities and the trial continues to accrue patients.