SilencioMA: A single compound that targets both MAPT and APP as a potential disease modifying therapeutic for Alzheimer's Disease

Alzheimer's Disease (AD) is the most common age-related neurodegenerative disease and the leading cause of dementia worldwide. AD pathogenesis involves aggregation of amyloid-beta (A{beta}), produced from amyloidogenic proteolytic processing of Amyloid Precursor Protein (APP), and accumulation of misfolded, pathological tau (Microtubule Associated Protein Tau, MAPT). Current efforts focus on developing disease modifying therapeutics (DMTs) against single targets: A{beta} or tau. However, DMTs that concurrently target both tau and A{beta} are likely to have the greatest impact since they target both culprits of AD pathogenesis. Here we describe the development of SilencioMA, a single compound that targets both MAPT and APP messenger RNAs (mRNAs) based on silencing connected interfering oligonucleotides against MAPT and APP. Cerebrospinal fluid (CSF) administration of SilencioMA reduces A{beta} and tau and pathology after a single intracerebroventricular injection in 5XFAD/PS19 mice, an animal model of severe amyloidosis and tauopathy. SilencioMA does not rely on lipid nanoparticles or lipophilic conjugates for CSF administration. At the same time its modular design permits conjugation of ligands that facilitate transcytosis through the blood brain barrier, allowing systemic administration. Our findings provide proof-of-concept for a strategy that targets the dual A{beta} and tau pathologies of AD, and establishes a compelling foundation for further development of SilencioMA as a next-generation DMT for AD.