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The status of drug discovery and development for Alzheimer's disease

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By Leonie Krijger

A review of the progress made in drug discovery and development for Alzheimer’s disease, focusing on promising candidates identified utilizing iPSC technology.

Alzheimer's disease is a type of dementia that progressively deteriorates memory, thinking and behavior. It’s the most common neurodegenerative disease, affecting more than 36 million people in the world1. Main hallmarks are the formation of amyloid-β (Aβ) plaques and the aggregation of pathologic Tau that eventually lead to neuronal cell death in the cortex and hippocampus2. Most cases of Alzheimer's disease are sporadic, but several gene mutations have also been associated with familial cases2.

Despite the vast number of therapies under development, all currently approved treatments improve cognitive and behavioral symptoms without altering the course of the disease. It has been reported that 99% of clinical trials fail to show any treatment efficacy3. Even the only exception reaching the market in 2020, Aducanumab, is facing fierce controversy about its efficacy, leading to market withdrawals4. However, efforts remain: there are currently 143 unique therapies for Alzheimer's disease being investigated in clinical trials, 85% of which are disease-modifying therapies5. To increase the chances of success, researchers are now investigating the role of non-neuronal cells in disease pathology and looking for alternative models to diversify the number of targets available.

Human iPSC-derived neurons from Alzheimer's disease patients recapitulate the key pathological hallmarks6,7 and can be co-cultured with iPSC-derived astrocytes or microglia to generate a more relevant environment7,8. To illustrate, a phenotypic screening of 1684 approved and preclinical drugs identified 96 compounds that were able to inhibit Tau accumulation in iPSC-derived neurons from Alzheimer's patients9. In line with previous findings10, cholesterol metabolism was found to be an stream regulator of Tau in the early stages of Alzheimer's disease and a new potential target for drug discovery. In the same study, an efficacy and toxicity screening was performed with iPSC-derived neurons and astrocytes, which identified a new druggable pathway to modulate cholesterol metabolism and Tau accumulation without affecting astrocyte homeostasis9.

Additionally, iPSC technology can improve patient stratification for clinical trials. A drug repurposing screening with 1258 compounds was performed on cortical neurons derived from Alzheimer's disease patients' iPSCs and showed three drugs to be effective in reducing Aβ plaques11. Before moving into clinical trials, iPSC technology was used to confirm the efficacy and select the most optimal population for the study. Among the 3 drugs, bromocriptine showed the strongest Aβ-reducing effect, being more effective for people with a particular form of familial Alzheimer's disease12.

Most reported iPSC-based screens for neurodegenerative diseases assess approved or experimental drugs rather than large compound libraries. This is partially due to the significant expertise and time required to effectively differentiate iPSCs and develop optimal assays with these models. Ncardia's 10+ years of experience in neural drug discovery facilitates the differentiation and assay development to make iPSC-derived models available for high-throughput screenings in the early stages of therapeutic development. Read our case study to explore how our iPSC platform could fit your Alzheimer's disease project.


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