siRNA-basierte Therapie von Tauopathien

• Applicant: Professor Dr. Günter Höglinger
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2008 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 66434555

The cellular accumulation and aggregation of the microtubule-associated protein tau is the defining hallmark of a group of neurodegenerative disorders, termed tauopathies. Alzheimer’s disease, Frontotemporal Dementia and Parkinsonism linked to Chromosome 17 (FTDP-17), Corticobasal Degeneration, Pick’s disease and Progressive Supranuclear Palsy are prominent examples for tauopathies. In Alzheimer’s disease, the degree of cognitive decline is correlated to the severity of the cerebral tau-pathology, suggesting that the cerebral taupathology is indeed responsible for the observed cognitive deficits. There are purely genetic forms of tauopathies caused by mutations in the tau-gene (FTDP-17). SantaCruz and coworkers (2005) have developed a transgenic mouse expressing a FTDP-17 mutant tau under control of an inducible expression system. When the expression of tau was shut down in these mice at a time, at which cognitive deficits were already present, these deficits were reversed and the progression of neuronal cell loss was halted. Thus, the question arises, how a controlled suppression of the expression of pathogenic tau-isoforms could be achieved for therapeutic purposes in human patients with tauopathies. RNA interference by small interfering RNAs (siRNAs) has been shown in recent years to be an efficient method for genesilencing. Therefore, we aim at developing a polyethylenimine-based delivery system to effectively deliver siRNAs targeting tau into the brain parenchyma. Using this technique, we aim to suppress the expression of the mutant tau protein in mouse models of FTDP-17 with the aim to stop the progression of neuronal cell loss and to revert the already established taupathology. This project will assess if the polyethyleneimine-based delivery of siRNA targeting mutant human tau in transgenic mice with either mild or moderate tau-pathology can achieve the following: 1) efficient suppression of the expression of the mutant tau protein; 2) suppression of the progression or even reversal of the already established tau-pathology; 3) suppression of the progression of neuronal cell death; 4) suppression of the progression or even reversal of already established behavioral deficits. Since the siRNA technique has a good perspective for a clinical application in human patients, a confirmation of our hypothesis would provide promising new therapeutic options for patients with tauopathies.

• DFG Programme: Research Grants