The misfolded proteins that make up the classic pathological hallmarks of Alzheimer’s disease—amyloid beta in plaques and tau protein in tangles—are both active targets in the drug development pipeline. In Alzheimer’s disease, amyloid beta begins to accumulate in the brain years before cognition changes, whereas tau tangle pathology emerges and propagates across the brain with timing that correlates closely with neurodegeneration and the development of cognitive symptoms. While the field is making progress in understanding how pathological amyloid beta and tau impact the functions of different brain cells, what ultimately causes the loss of normal cognition is still unclear. What is clear is that declining cognitive abilities are closely associated with both the loss of synapses (the connections between neurons) and the spread of tau tangles out of the hippocampus, suggesting a link between tau and synaptic loss.
Several therapies designed to reduce tau in the brain are now making their way through the clinical trial pipeline. Most of these target all forms of tau for removal or suppression rather than only those associated with disease. Since tau plays multiple roles in maintaining neuronal structure and function, including communication across synapses, there is a reasonable concern that the long-term reduction of all tau proteins could have negative consequences. Existing therapeutic candidates do not effectively remove all forms of tau despite targeting them, which may improve their safety profile. However, they fundamentally still target both healthy and pathological tau. The Verstreken lab is pursuing a more focused approach to redress the negative consequences of tau pathology.
Recognizing the central role synaptic connections play in cognition, the Verstreken lab is investigating ways to prevent pathological tau from disrupting synaptic function by targeting a protein with which it interacts at the synapse. Dr. Verstreken’s team previously found that, under pathological conditions, tau relocates within neurons from the axon to the axon terminal (the sending side) of the synapse, where it binds to a protein called synaptogyrin-3 (Syngr-3). When the Verstreken lab genetically deleted Syngr-3 from mice also engineered to develop pathological tau, the mice did not experience the otherwise expected adverse effects of toxic tau on synaptic communication and memory, suggesting that the availability of Syngr-3 as a binding partner is a prerequisite to tau’s negative impact on synaptic function.
Deletion of a target gene from neuronal DNA is not a currently viable therapeutic option, but scientists have developed drugs that instead prevent cells from making proteins from a target gene. Antisense oligonucleotide (ASO) drugs are short single strands of nucleotide molecules that bind complementarily to the messenger RNA (mRNA) from a target gene, precluding translation of the targeted mRNA. The Verstreken lab decided to develop an ASO to block the production of Syngr-3 as a treatment for preventing tau-induced cognitive decline. In their last funding cycle, the team successfully developed and validated several potent ASOs targeting Syngr-3. They also reported that a single injection of their lead candidate ASO rescued synaptic function deficits and preserved synapses in tau model mice (PS19).
For the current proposal, the Verstreken team proposed three initial aims. In the first aim, having demonstrated that their ASO engaged its target and protected synaptic function in tau model mice, and in recognition that clinical benefit is the ultimate goal, they are assessing whether lowering Syngr-3 with a potent ASO prevents or reverses cognitive decline in these mice. They are injecting the ASOs into mice at two ages (before or after the onset of cognitive issues) and measuring the effects on learning and memory in a standard lab test (Morris Water Maze). The work of the first aim is in mice, so in the second aim, they are looking for proof that lowering Syngr-3 is also protective in human cells by testing the effect of Syngr-3 ASOs on synaptic activity in human neuronal cultures exposed to toxic tau. In the third aim, they are seeking non-invasive biomarkers for their ASO, a vital consideration for future clinical trials. In lab conditions, scientists can examine the brains of treated mice, but to determine whether a drug is engaging its target and having the desired effects during a clinical trial, scientists need biomarkers that can be collected safely and repeatedly. The Verstreken team is pursuing two parallel strategies: a sensitive assay to detect Syngr-3 amounts in cerebrospinal fluid (CSF), which will then be correlated with blood levels, and PET imaging for synapses using a partially validated tracer (SV2A-PET).
In the first year, Dr. Verstreken’s team confirmed key efficacy and safety milestones for their Syngr-3 targeting ASO as part of Aim 1. They saw a 50% reduction in Syngr-3 protein levels in mice 8 weeks following injection. They observed no changes in the general behavior of the mice up to 16 weeks following injection, indicating the treatment did not cause side effects. In Aim 2, they found that lowering Syngr-3 levels with their ASOs protected synaptic integrity and function in patient-derived neurons with tau pathology, further supporting this approach as an effective therapeutic avenue. The experiments for Aim 3 to develop biomarker assays for Syngr-3 are underway and will be verified as treatments in the mice are completed during the second year of funding.
