Treating Alzheimer's Disease with PMO RNA Therapeutics - ABSTRACT Alzheimer's Disease (AD) is a devastatingly progressive, fatal neurodegenerative disease. With approximately 30 million patients affected worldwide, it is the most common form of dementia and is predicted to grow exponentially. The pathology of AD is driven by Amyloid Precursor Protein (APP) and its proteolytic processed products, primarily the Aβ42 peptide, leading to amyloid plaques, Tau- containing neurofibrillary tangles and neuron death. Although there are now multiple FDA approved drugs to treat AD, including monoclonal antibodies (mAbs) that target Aβ plagues, unfortunately none of these target the root cause of AD, namely APP. Consequently, there remains a great unmet medical need to develop AD therapies that selectively target APP driven pathogenesis to prevent cognitive dysfunction and neuron death. The field of RNA therapeutics has come of age in the clinics. There are currently 16 FDA approved RNA therapeutics, including 4x Phosphorodiamidate Morpholino Oligonucleotides (PMO-ASOs), 7x Phosphorothioate Anti-Sense Oligonucleotides (PS-ASOs) and 5x siRNAs, with >50 ongoing early and late stage clinical trials. Due to their Watson-Cricket base pairing mechanism of target engagement, RNA therapeutics have exquisite on-target selectivity for all mRNAs, including APP, with minimal off- target genetic effects. Impressively, a single RNA therapeutic dose can achieve a 3 to 6 month pharmacodynamic response in the clinics. However, endosomal escape remains the rate-limiting problem to solve with only ~1% of PS-ASOs and 0.3% of siRNAs escaping from endosomes. Due to the endosomal escape problem, PS-ASO and siRNA therapeutics require excessively high doses resulting in cytotoxicity and safety profile concerns. In contrast to siRNAs and PS-ASOs, non-protein binding PMO ASOs can be dosed 20-times higher than PS-ASOs with no safety signals arising. Moreover, have longest metabolic stability and duration of response. To selectively target APP, we will develop new technology to generate a highly efficacious APP PMO therapeutic that efficiently escape the endosome by conjugation to a universal endosomal escape domain (uEED). We will test and optimize hAPP PMO- uEEDs in a humanized APP mouse model of Alzheimer's Disease.
