Neurons derived from human induced pluripotent stem cells have a unique biomarker signature that may more accurately reflect drug responses in human patients than currently-used drug development approaches, according to researchers.
Although many drug candidates have been developed for Alzheimer's disease (AD), none have succeeded due to lack of efficacy or safety concerns, Shuana H. Yuan, MD, of the Department of Neurosciences at the University of California San Diego (UCSD), and colleagues explained in JAMA Neurology.
These drug development failures may be attributable to overexpression of wild-type or mutant proteins that occur in the transformed cell lines and animal models, they hypothesized.
To test this theory, Yuan and colleagues analyzed γ-secretase inhibitor and γ-secretase modulator (GSM) responses in purified neurons derived from human induced pluripotent stem cells from patients carrying three different presenilin 1 (PS1) mutations (A246E, H163R, and M146L) and those from controls without dementia.
The stem cells were derived from adult human skin biopsies from volunteers at the Alzheimer Disease Research Center at the UCSD. The researchers then treated cell cultures with either γ-secretase inhibitor or GSM, and compared total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 between the vehicle- vs the drug-treated cultures using enzyme-linked immunosorbent assay (ELISA).
Mutant PS1 neurons had elevated Aβ42:Aβ40 ratios (P<0.05) at the basal state compared with control neurons from those without dementia, the researchers found.
Treatment with a steroidal anti-inflammatory drug-like GSM revealed a new biomarker signature that differed from all previous cell types and animals tested. The signature was the same in both the neurons with dementia mutations and those from controls, and it consisted of a reduction in Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels.
The study results suggest that biomarker signatures obtained from transformed cellular models are "misleading," and that "human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment."
Although considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins.
It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells.