Studies on RNAi Based Delivery in Vivo

描述（由申请人提供）：基于RNAi的治疗方法为无数疾病提供了巨大的希望。Kay实验室已经成功地使用了基于AAV载体的方法来表达来自肝脏的shrna。我们已经证实，这种载体可以安全、持续地减少HBV转基因小鼠的HBV复制2 - 3倍。尽管如此，我们已经确定一些shrna的过表达会导致肝衰竭导致死亡。肝衰竭与内源性microRNA加工途径的干扰有关，并且至少部分阻断在Exportin-5水平。Rossi实验室已经开发了替代shRNA表达策略，其中一些绕过了Exportin-5途径。这两个实验室共同提供了一种协同方法，因此在拟议的联盟中，他们将共同努力，进一步揭示基于shRNA的毒性所涉及的机制，并为基于shRNA的体内治疗开发新的表达范式。

DESCRIPTION (provided by applicant): RNAi based therapeutics offers great promise for a myriad of diseases. The Kay laboratory has successfully used an AAV vector-based approach to express shRNAs from liver. We have established that such vectors can safely and persistently reduce Hepatitis B viral (HBV) replication by 2 to 3 logs in HBV transgenic mice. Nonetheless, we have established that over expression of some shRNAs can result in fatality due to liver failure. Liver failure was associated with interference in the endogenous microRNA processing pathway and at least part of the block was at the level of Exportin-5. The Rossi laboratory has developed alternative shRNA expression strategies some of which bypass the Exportin-5 pathway. The two labs together offer a synergistic approach such that in the proposed consortium, they will work together to further unravel the mechanisms involved in shRNA based toxicities as well as develop new expression paradigms for in vivo shRNA based therapeutics.