This proposal aims to advance a genetic medicine for Alzheimer’s disease using Switch Therapeutic’s novel and unique siRNA platform called Conditionally Activated siRNA (CASi). The CASi molecule is a three-stranded oligonucleotide that will be delivered to prodromal AD patients by intrathecal dosing. The CASi will target the APOE mRNA transcript. APOE4 is a toxic gain of function mutation and a genetic risk factor for AD. The Switch team has identified a potent (pM IC₅₀) CASi molecule that, when dosed in mice and non-human primates (NHPs), knocks down APOE. Prior work has identified this target to slow or reverse the progression of AD in mouse models of tauopathy.

This proposal to ADDF requests funding to further characterize the APOE CASi, SWT-12140, for more detailed profiling in NHP for PK/PD and safety studies.  Specifically, we are asking for support to cover the costs of a IND enabling GLP toxicology study in NHP.  Switch Therapeutics is currently running a NHP dose range finding study that will inform dosing for our NHP GLP toxicology study required for an IND submission.