Each year an estimated 239,000 women die of cervical cancer. Over 99% of these deaths result from genital infection with human papillomavirus (HPV). As a result there is a pressing need to develop a therapeutic vaccine to resolve cancerous lesions caused by this disease. The broad goal of this proposal is to develop a device which will resolve pre-cancerous and cancerous cervical lesions caused by HPV. One objective of this work is to fabricate DNA vaccine delivery devices to be administered topically in the female genital tract. Furthermore, in vitro and in vivo preclinical studies will be performed to assess the efficacy of this device in administering an effective vaccine. To this end the following specific aims have been proposed: (1) characterize molecular and immunological events of intravaginal vaccination by controlled release of DNA; (2) investigate the influence of dosage, duration, and transfection agents from DNA delivery devices on immunological events; and (3) investigate the efficacy of tumor resolution by intravaginal DNA delivery. A device will be investigated which releases DNA in a controlled fashion. Specifically, plasmid DNA will be incorporated into a matrix comprised of a biocompatible material fabricated in the shape of a disk. This plasmid DNA will encode an oncogene of HPV which will act as a therapeutic vaccine to stimulate immune relevant responses. Pre-clinical experiments will be implemented in a model mouse, where the device will be inserted in the vagina. Persistence of DNA and mRNA expression in the genital tract will be evaluated by real-time PCR to assess the release from the device. Additionally, both humoral and cellular immune responses to the therapy will be assessed. Once these events have been characterized the device will be further modified to explore the influence of dose, duration of release, and addition of transfection agents on duration and magnitude of immune response. Finally, the device that elicits a response that is largest in magnitude and duration will be explored for resolving HPV specific tumor in a mouse model. At the conclusion of these studies a better understanding of intravaginal DNA immunization will have been elucidated and processes will be made for developing a device to resolve HPV specific lesions. A non-invasive device to resolve cervical lesions has immediate benefit to women's health worldwide by providing a therapy that is not limited by skilled personal to administer. Additionally, this vaccination strategy could be applied to develop new therapies for other sexually transmitted diseases. ? ? ?
| Look, Michael; Bandyopadhyay, Arunima; Blum, Jeremy S et al. (2010) Application of nanotechnologies for improved immune response against infectious diseases in the developing world. Adv Drug Deliv Rev 62:378-93 |
