Small molecule autophagy modulators for tauopathies

Rationale:

The accumulation of tau is a feature of many neurodegenerative disorders, including Alzheimer’s disease and frontotemporal dementias. We aim to identify drugable targets and pathways that enhance tau clearance, particularly through autophagy. This is a rational mechanism for treating tauopathies, as the prevailing evidence suggests that these conditions are caused by toxic properties of tau and moderate lowering of tau is well tolerated. Furthermore, there is the possibility that compounds that act on the key tau clearance pathways (autophagy or the ubiquitin-proteasome system) may have protective effects in a wide range of neurodegenerative diseases.

Drug Discovery Program Status:

We have taken two approaches. First, we have screened FDA-approved compounds to identify autophagy-inducing drugs and novel signaling pathways that can activate autophagy. One of these drugs, felodipine, activates clearance of autophagic substrates in mouse brains at plasma concentrations similar to those seen in humans taking this drug for hypertension. We are planning dose-finding and safety studies with felodipine in human neurodegeneration in the near future.

Our second approach has been to use genetic screening with siRNAs and CRISPR/Cas9 and chemical screening with probes to identify drugable targets that enhance autophagy and tau clearance.

Executive Summary:

The accumulation of tau is a feature of many neurodegenerative disorders, including Alzheimer’s disease and frontotemporal dementias. We aim to identify drugable targets and pathways that enhance tau clearance, particularly through autophagy. This is a rational mechanism for treating tauopathies, as the prevailing evidence suggests that these conditions are caused by toxic properties of tau and moderate lowering of tau is well tolerated.