Board of Supervisors of Louisiana State University and Agricultural and Mechanical College
发明人:
Michael Lan,Mary Breslin
申请号：
US15771110
公开号：
US20190247452A1
申请日:
2016.10.28
申请国别(地区):
US
年份:
2019
代理人:
摘要：
A conditionally replicating adenovirus were generated that can specifically replicate and express therapeutic genes in neuroendocrine tumors. The promoter-specific expression of the adenoviruses is regulated upstream by an INSM1 (insulinoma-associated-1) promoter that is silent in normal adult tissues but active in developing neuroendocrine cells and neuroendocrine tumors. By placing the INSM1-promoter with an insulator and two copies of neuronal restrictive silencer elements in an adenoviral vector, the construct can retain tumor specificity and drive expression of a mutated adenovirus E1A gene (424E1A) and the herpes simplex virus thymidine kinase gene. The INSM1-promoter-driven viruses could replicate specifically in the INSM1-positive cells and I NSM1-specific HSV-tk expression in combination with ganciclovir treatment displayed dose-dependent tumor cell-specific killing in insulinomas. When the INSM1-promoter driven HSV-tk was combined with 424E1A and INSM 1 p-HSV-tk viruses, the co-infected insulinoma expressed higher levels of HSV-tk and more efficient tumor suppression as compared to the INSM1 p-HSV-tk virus alone.
