Researchers have been on a fast-track to develop drugs to slow or prevent Alzheimer’s disease. And while many of the new compounds appear to work well in animal and cell models, they have all failed in human clinical trials.
In a new study, reported online in the journal Stem Cell Reports, researchers provide interesting clues on the failures.
In the article, experts suggest why non-steroidal anti-inflammatory drugs (NSAIDs) — which have successfully treated molecular signs of Alzheimer’s disease in cell and animal models — eventually failed in clinical studies.
They discovered that although the compounds worked in non-neuronal cells lines typically used in pharmaceutical drug screening, human neurons are resistant to this class of drugs.
“The results of our study are significant for future drug development approaches, because they imply that compound screening and validation studies might be much more reliable if they are conducted using the human cell type affected by the disease in question,” said Oliver Brüstle who senior-authored the study with colleague Philipp Koch, M.D.
Alzheimer’s disease is the most common cause of dementia among older people, yet there currently are no effective drugs to stop, slow or prevent disease progression.
Alzheimer’s is characterized by the accumulation of compounds called Aβ peptides in the brain, and this process is believed to cause progressive neurodegeneration and dementia.
Longer Aβ42 peptides tend to aggregate more than shorter Aβ40 peptides, and a high ratio of Aβ42 to Aβ40 is used as a biomarker of Alzheimer’s disease.
NSAIDs have been found to restrain Aß processing, resulting in decreased Aß42/40 ratios in several cell and animal models of the disease.
But for previously unknown reasons, these drugs failed to delay disease progression in phase 2 and phase 3 clinical trials.
Brüstle and Koch revisited this enigma and for the first time directly tested the effectiveness of NSAIDs in human neurons.
They used an induced stem cell approach, which involved taking skin cells from patients with Alzheimer’s disease, reprogramming these cells into embryonic-like stem cells, and then converting them into neurons.
These neurons showed high Aβ42/Aβ40 ratios, which failed to respond to therapeutically relevant concentrations of NSAIDs.
In contrast, commonly used non-neuronal cell lines typically employed in drug screening responded strongly, thereby wrongly suggesting efficacy of the drugs.
“The results highlight the importance of testing compounds directly in authentic human cells,” said Dr. Jerome Mertens, lead author of the study.
“Until recently, it was difficult to obtain native human neurons for drug testing in the field of neurodegenerative diseases.
With recent advances in stem-cell technology, it has become possible to generate virtually unlimited numbers of human neurons from individual patients,” Brüstle says.
“We hope that our findings will promote the use of stem cell-derived neurons for drug screening in the field of neurological disorders.”