Optimization of a clinical stage nanoparticle drug delivery platform

DESCRIPTION provided by applicant Hepatocellular carcinoma HCC is the third most common cause of cancer related deaths worldwide with the incidence increasing significantly in the West The prognosis for HCC is poor and the limited success of the standard of care drug sorafenib along with recent Phase III failures of other treatments underscores the need for novel HCC therapeutics Intrahepatic cholangiocarcinoma IHCC the second most frequent primary liver tumor is also associated with poor prognosis Colorectal cancer CRC is the fourth most common cause of cancer deaths throughout the world Despite the recent advances in treatment strategies post operative prognosis of CRC patients with liver lymph node or distant organ metastasis remains poor underscoring the need for novel therapeutics The Wnt signaling pathway is commonly activated in all three of these diseases and this is thought to be a causal event in their tumorigenesis In this application we continue the development of a lipid nanoparticle LNP platform using an RNAi based payload that targets a key component of the Wnt signaling pathway beta catenin CTNNB Beta catenin which is well validated as an oncology target with high clinical mutation occurrence and experimental evidence is considered undruggable via conventional approaches However by enabling pharmacological intervention at the mRNA level as opposed to the protein level our RNAi approach inhibits synthesis of beta catenin protein and causes tumor growth inhibition in preclinical models Building upon the successful development of our LNP encapsulated Dicer Substrate siRNA siRNA targeting the MYC oncogene we sought to improve LNP formulations and demonstrate effectiveness with a second payload delivering CTNNB to tumors Our in house experience with developing and cGMP manufacturing LNP formulated therapeutics as well as the similarities to approved liposomal oncology products led us to generate and characterize LNPs with unique chemical compositions carrying novel CTNNB DsiRNA payloads Here we demonstrate dramatic improvement in efficacy and other properties of tumor centric LNPs Through this work a formulated LNP CTNNB DsiRNA candidate that is suitable for preclinical development and IND submission has been identified In this application we seek to perform IND enabling studies process development and GMP manufacture of this candidate as well as perform translational research to guide the clinical research strategy The ultimate goal is to develop a Lipid Nanoparticle formulation that can be used to deliver a broad range of siRNA payloads with a tolerability profile to enable treatment of patients with a spectrum of disease states and prior therapeutic histories PUBLIC HEALTH RELEVANCE We will continue the preclinical development of lipid nanoparticle delivery platform demonstrating efficacy with a DsiRNA that targets the Wnt signaling pathway in tumors