Several new and highly promising therapeutics for the management and possible prevention of Alzheimer’s disease were described at AAIC 2021. From the laboratory to early clinical trials, research is moving apace in search of targeted agents.
Targeted tau transport
Sarah L DeVos, Denali Therapeutics, San Francisco, CA, USA, presented early data on a tau protein targeted transport vehicle technology (TV). TVT is based on engineered fragment antigen binding (Fab) fragments that bind to specific natural transport receptors expressed in the blood brain barrier (BBB) thereby facilitating deliver of therapies directly to the brain.
In combination with a highly specific Tau-specific monoclonal antibody which binds human AD tau and prevents seeding in AD brain lysates, this antibody-TV therapy has been shown in vitro animal experiments using PS19 transgenic mice – mice that express a mutant tau protein – to be maintained at higher concentrations in the brain over 10 days than a the tau monoclonal antibody alone. It may be that therapy can be delivered to the brain via a peripheral route.
Antibody-TV therapy has been shown to be maintained at higher concentrations in the brain over 10 days than a the tau monoclonal antibody alone
Clearance of the pathological proteins that occur through neurodegeneration in AD was another possibility described by Angela Cacace, Arvinas, New Haven, CT, USA. She described heterobifunctional degrader molecules called proteolysis-targeting chimeras that hi-jack the inherent intracellular ubiquitin proteosome system (UPS) to bring about degradation of faulty tau proteins.
A Tau P3011-specific chimera molecule is under development and both in vitro and in vivo experiments suggest its being able to degrade tau P3011 insoluble aggregates. Ex vivo work also show a reduction in seeding potential.
A Tau P3011-specific chimera molecule is under development - in vitro and in vivo support its degradation of tau P3011 insoluble aggregates
Targeting toxic tau
O-GlcNAcase (OGA) inhibitors appear also to prevent tau’s aggregation into toxic assemblies. Dirk Beher, Asceneuron SA, Lausanne, Switerland, explained how removal of N-acetylglucosamine from tau allows it to hold on to certain sugars. This, in turn, blocks its aggregation into toxic assemblies.
In vivo, chronic treatment of transgenic mice suggests that not only does the therapy prevent tau pathology but also improves motor function. Initial pharmacokinetic studies suggest that the molecule is a long-acting OGA inhibitor in humans with the potential to target dysfunctional tau pathways. A clinical program to see if this is so is underway.
Pharmacokinetic studies suggest that OGA inhibitors have the potential to target dysfunctional tau pathways
Vaccination for prevention?
A placebo-controlled, randomized phase II clinical study to test the safety and efficacy of an active vaccine immunotherapy against pathological tau protein has recently been published.1 Petr Novak, Axon Neuroscience, Bratislava, Slovakia, reported the further findings of this vaccine study. First reports suggested that while the vaccine showed disease-modifying effects on AD patients, these, as yet, hadn’t translated into clinical outcome measures.
However, in a subgroup analysis of patients with a confirmed biomarker signature of AD, a treatment benefit was seen. There was a strong decline in core AD biomarkers confirming the effect on the neurodegenerative process in AD and a cognitive effect was noted. The importance of selecting the patients most likely to benefit is clear – as is the potential for the prevention of further disease through a subcutaneously injected vaccine.
A treatment benefit was seen in a subgroup analysis of patients with a confirmed biomarker signature of AD
AAIC : Alzheimer's Association International Conference
CA : California
USA : United States of America
Fab : fragment antigen binding
BBB : blood brain barrier
TVT : transport vehicule technology
AD : Alzheimer's Disease
CT : Connecticut
UPS : ubiquitin proteosome system
OGA : O-GlcNAcase
BE-NOTPR-0203, approval date : 10.2022