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ACU193: An Immunotherapeutic Poised to Test the Amyloid β Oligomer Hypothesis of Alzheimer's Disease

期刊

FRONTIERS IN NEUROSCIENCE
卷 16, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2022.848215

关键词

Alzheimer's disease; immunotherapy; oligomer-selective; therapeutic antibody; A beta O = amyloid beta oligomer; synaptic plasticity

资金

  1. Acumen Pharmaceuticals

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Alzheimer's disease is a neurodegenerative disease with devastating impacts on patients and families, and current treatments have limited effectiveness. Research has shown a clear link between Alzheimer's disease and elevated levels of amyloid beta in the brain, prompting a search for targeted therapies.
Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects 50 million people worldwide, with 10 million new cases occurring each year. The emotional and economic impacts of AD on patients and families are devastating. Approved treatments confer modest improvement in symptoms, and recently one treatment obtained accelerated approval from the United States Food and Drug Administration (FDA) and may have modest disease modifying benefit. Research over the past three decades has established a clear causal linkage between AD and elevated brain levels of amyloid beta (A beta) peptide, and substantial evidence now implicates soluble, non-fibrillar A beta oligomers (A beta Os) as the molecular assemblies directly responsible for AD-associated memory and cognitive failure and accompanying progressive neurodegeneration. The widely recognized linkage of elevated A beta and AD spawned a comprehensive 20-year therapeutic campaign that focused primarily on two strategies - inhibition of the secretase enzymes responsible for A beta production and clearance of A beta peptide or amyloid plaques with A beta-directed immunotherapeutics. Unfortunately, all clinical trials of secretase inhibitors were unsuccessful. Of the completed phase 3 immunotherapy programs, bapineuzumab (targeting amyloid plaque) and solanezumab (targeting A beta monomers) were negative, and the crenezumab program (targeting A beta monomers and to a small extent oligomers) was stopped for futility. Aducanumab (targeting amyloid plaques), which recently received FDA accelerated approval, had one positive and one negative phase 3 trial. More than 25 negative randomized clinical trials (RCTs) have evaluated A beta-targeting therapeutics, yet none has directly evaluated whether selective blockage of disease-relevant A beta Os can stop or reverse AD-associated cognitive decline. Here, we briefly summarize studies that establish the AD therapeutic rationale to target A beta Os selectively, and we describe ACU193, the first A beta O-selective immunotherapeutic to enter human clinical trials and the first positioned to test the A beta O hypothesis of AD.

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