Preclinical Analysis of Synaptogyrin-3 Oligonucleotides to Target Tauopathy

Alzheimer’s disease (AD) patients accumulate protein plaques and tangles in their brain; a major constituent is the protein tau. Dysfunction of tau causes ‘tau pathology’. This correlates well with the loss of contacts between nerve cells (synapses) as well as with the development of cognitive decline in AD and other neurodegenerative conditions. Experimental drugs are aiming to remove tau or tau-tangles, but most of these strategies indiscriminately target all tau protein, not only the tau at synapses, thus potentially causing adverse effects. Work from my group found that tau is associated with synaptogyrin-3, a protein uniquely present at synapses in disease. Removing synaptogyrin-3 from the mouse genome is benign but strongly prevents tau-induced synaptic and cognitive defects. We have now developed potent therapeutic tools that remove synaptogyrin-3 (antisense oligonucleotides, ASOs), and injecting these in mice prevents tau-induced loss of synapses. We will now assess if our ASOs also prevent the decline of cognitive function. Furthermore, we will assess if our ASOs are effective in protecting human-induced nerve cells against pathogenic tau using multielectrode array recordings, allowing us to determine the effectiveness of our ASO approach in a human context. Finally, before moving to patients, we will also develop two non- or minimally-invasive strategies that enable us to measure if our ASOs are active: (1) an approach to measure synaptogyrin-3 levels in spinal tap fluid or plasma and (2) a PET scan strategy to measure synaptic density. Together, these preclinical studies will lay the groundwork and prepare our ASO-based approach for first-in-human studies.