Modulation of Adeno-Associated Virus (AAV) Replication by Host Cell Transcriptional Repressors: Pharmacologic and RNA Interference to Improve AAV Vector Delivery during Gene Therapy

PI: Prof. Jayandharan G. Rao

In recent years, gene therapy for human diseases such as hemophilia and hereditary blindness using adeno associated virus (AAV) vectors has shown great promise. Nonetheless, relatively large dose of vectors are used in clinical trials to achieve a therapeutic outcome. This large dose also triggers an immune response that clears the virus from the host, resulting in only a transient improvement in the patient's disease phenotype. Thus for this mode of therapy to be long lasting, it is important that the host immune response is resolved or minimized. We have shown previously that host-cellular proteins linked to unfolded protein response pathway play a major role in initiating immune response against AAV vectors. The current project attempts to extend these findings by further study of microRNA regulators involved in this pathway. This information will be useful in developing designer AAV vectors that will incorporate specific microRNA elements so as to overcome barriers imposed by host immunity. This project is supported by a Senior Innovative Young Biotechnologist (IYBA) award to Dr. Jayandharan Rao.