Beta-Amyloid Oligomer Specific Treatments for Alzheimer’s Disease

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Background

Amyloid- beta (Aß) has been the prime target for more than 20 different clinical therapeutic approaches in Alzheimer’s Disease (AD) and mostly failed because of a lack of robust efficacy or side effects, as observed for all beta and gamma-secretase inhibitors. Earlier beginning of amyloid-related treatments in populations at risk for AD and improved patient selection in MCI may not be sufficient to compensate for lack of clinical efficacy and cognitive side effects of secretase inhibitors in sporadic AD patients. Aß exists in three basic isoforms, which are classified as native Aß monomers, Aß oligomers and Aß fibrils. Increasing evidence for an important physiological role for native Aß monomers in synaptic processes and partly plaque dissolution associated side effects are teaching us to develop misfolded Abeta oligomer specific AD treatments, that at least do not compromise Aß monomer homeostasis anymore, like the first promising Aß oligomer binding antibodies, Aducanumab and BAN2401.First Aß oligomer specific treatments have been characterized preclinically. But for most compounds there are no compelling data for selectivity and specificity of the drugs, in particular under in vivo experimental conditions.
Major questions that should be addressed in this Research Topic: What are the key criteria for an optimal Aß oligomer binding or interfering drug? What are the key disease-relevant features for Aß oligomeric species. Is it size, n-number or epitope conservation and how can we best categorize those? By what methods should we characterize the isoform selectivity and the coverage of the majority of in vivo AD relevant oligomers species? Can we calculate the minimal drug load sufficient to fully neutralize Aß oligomer formation under sporadic AD conditions? What is the minimal oligomer affinity and brain penetration needed to be efficacious? Is cell penetration a critical factor? Is selectivity versus plaque-associated oligomers favorable or will it cause unwanted side effects, like ARIA? How can we profile biomarkers under preclinical and clinical conditions to establish an early clinical readout for meaningful Aß oligomer target engagement in the absence of plaques? Can we define pharmacokinetic requirements for highly oligomer selective Aß immunotherapies by setting up an Aß model?
Most of the experts know that the in vivo characterization of Aß oligomers is technically extremely challenging. Thus the goal is to get to a better understanding and make some steps towards the standardization of meaningful methods in the Aß oligomer field under AD- or AD-like in vivo conditions: •       Mild and transient Aß oligomer animal models;•       Comparative characterization of various existing Aß oligomer targeting compounds by meaningful methods;•       Aß oligomer binding characteristics of antibodies through immune precipitation methods for AD brain material;•       Target engagement of low molecular weight compounds;•       Practical Aß oligomer treatment responsive and sensitive biomarkers;•       Translational models suitable for early clinical development;•       Pharmacokinetic modeling.
Topic editor W. L. Klein is co-founder and stockholder of Acumen Pharmaceuticals, an Alzheimer’s biotech. Acumen has a therapeutic monoclonal antibody specific for amyloid-beta oligomers that is nearing clinical trials. He currently serves as a scientific advisor.Topic editor N. Cashman is Chief Scientific Officer and co-founder of ProMIS™ Neurosciences, Inc.The other Topic Editors declare no competing interests with regards to the Research Topic.

Keywords: Therapeutics, Diagnostics, Trials, Structure, Mechanism

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