Using siRNAs against tau circular RNAs as a rational therapy for Alzheimer's disease

Summary:The formation of neurofibrillary tangles (NFT) formed by aggregation of the microtubule-associated protein tau (MAPT) is a hallmark of Alzheimer’s disease (AD) and the likely cause of neuronal death. Currently, there are no rational treatments available that directly target NFT formation and thus address the direct molecular cause for AD. Based on our academic research, we will develop an siRNA-based product that can be delivered nasally and prevents NFT formation in early stages of AD.In prior studies, we identified human-specific circular RNAs from the MAPT gene that are generated through backsplicing of exon 12 to either exon 7 or exon 10. These tau circRNAs are translated after epigenetic modifications that change adenosine residues to inosines (Aandgt;I editing). The translated proteins correspond to multimers of the microtubule-binding domain and promote NFT formation.Our company, CircCure, will develop siRNAs that selectively target tau circRNAs and thus prevent NFT formation; we will test this product in two specific aims: Aim #1: Define the optimal siRNA backbone sequence for the 12-andgt;7 and 12-andgt;10 tau circRNA by performing an oligo-walk to identify the backbone sequence with the highest efficacy toward tau circRNAs and lowest efficacy against linear RNAs. After undergoing standard chemical optimization, in Aim #2, we will test the siRNA efficacy (IC50) using intranasal and injection delivery in an in vivo model of human neuroblastoma cells grafted in mouse brains. This product is highly innovative, as it will directly address NFT formation targeting recently discovered circular RNAs.The final product of these Phase I studies will be an siRNA that can be delivered intranasally that reduces tau circRNAs and NFT formation in human cells embedded in a mouse brain. The product will thus directly target the cause of neuronal death in AD, which will provide supportive evidence for Phase II studies, where we will test pharmacology and safety to prepare for an investigational new drug (IND) application.Narrative: Currently, no rational treatment for Alzheimer’s disease is available. We will develop small RNAs that specifically target ‘pathological’ tau circular RNAs that promote neuronal death by causing protein aggregation and test them in human cell models and in human cells grafted in mouse brains.