Development of a vectorized RNA-based nanomedicine as novel therapy for Alzheimer’s Disease – siRNAlz

The siRNAlz project aims to develop a siRNA-based nanomedicine that can be used to regulate a specific genetic risk factor involved in the pathobiology of Alzheimer’s disease (AD). The achievement of effective RNA-based therapies for AD relies on the development of cutting-edge nanotechnologies with enhanced capacity to deliver biologics across the blood brain barrier (BBB) into the brain. We have patented (WO 2020144233 A1) a family of transferrin receptor (TfR) targeting nanobodies (nTfRs) with cross-species binding properties, that cross the BBB and that transport siRNAs into brain structures to down regulate remarkably the expression of specific target mRNAs. Therefore, the overall objective of this project is to further enhance the current brain penetrating features of our proprietary nTfRs through protein engineering designs that will take advantage of yet unexplored intracellular trafficking mechanisms. Firstly, siRNAs targeting a selected AD risk factor will be synthetized (Aim 1). The siRNAs will be functionalized with an innovative engineered protein construct designed to enhance its overall BBB transcytosis properties (Aim 2). The implementation of the siRNA with the protein engineered construct will be performed through a two-step chemical reaction (Aim 3). Finally, the obtained nanomedicine will be tested in vivo in wild type and AD mice models as proof of concept (Aim 4). Aim 5 is dedicated to project management and dissemination of results. This project will be accomplished through an interdisciplinary approach and will involve an intersectoral collaboration between academy (P1) and a biotech partner (P2). The development of this nanomedicine is expected to substantially foster the advancement of more effective and accessible RNA-based therapy for AD and more generally for neurodegenerative diseases.