Human-on-a-Chip system models Alzheimer’s
Publication validates potential of drug discovery platform to study early stages of disease pathology
ORLANDO, Fla.—Hesperos Inc. reported recently that it had published a peer-reviewed article describing how its Human-on-a-Chip system can be used as a drug discovery platform to identify therapeutic interventions targeting the preclinical stages of Alzheimer’s disease (AD) and mild cognitive impairment (MCI).
The article, entitled “A human induced pluripotent stem cell-derived cortical neuron human-on-a-chip system to study Aβ42 and tau-induced pathophysiological effects on long-term potentiation,” was published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions. The work was conducted in collaboration with the University of Central Florida and with Dr. David G. Morgan, professor of Translational Neuroscience at Michigan State University and an expert in AD pathology.
Many potential therapeutics for Alzheimer’s have been abandoned or failed during clinical trials. Preclinical animal studies are often unable to capture the full spectrum of the human disease phenotype, including differences in drug metabolism and excretion. Human models, especially those that accurately recapitulate the functional impairments during the preclinical phases of AD and MCI, are needed for accurate research.
“Hesperos offers a breakthrough technology that provides a human cell-based assay based on cognitive function metrics to evaluate drugs designed to restore cognition at early stages of the Alzheimer’s continuum,” stated Morgan. “This system can serve as a novel drug discovery platform to identify compounds that rescue or alleviate the initial neuronal deficits caused by Aβ1-42 and/or tau oligomers, which is a main focus of clinical trials.”
According to Dr. James Hickman, chief scientist of Hesperos, and Dr. Michael L. Shuler, the company’s CEO, “Human-On-a-Chip systems have all the organs connected by microchannels that allows recirculating blood mimic to go through each chamber, which allows the cells to interact with each other as they do in the body. The medium does not contain animal serum, which is unique to the platform, and fluid can be recirculated continuously.”
“The other unique feature is they contain functional systems that can reproduce clinical parameters—such as cardiac electrical conduction, neuron electrical conduction, and cardiac and skeletal force transduction—without relying upon cell death as an indicator of cell health,” they continue. “This is much closer to what a doctor evaluates when examining a patient, or for information needed during a clinical trial.”
Hickman and Shuler state that “it is the first time a functional assay is available to provide information at the preclinical stage of AD that has a direct correlation to cognitive parameters that will be measured during a clinical trial at the pre-MCI stage of the disease.”
Hesperos’ in-vitro human induced pluripotent stem cell (iPSC)-derived cortical neuron human-on-a-chip system is meant for the evaluation of neuron morphology and function after exposure to toxic Aβ and tau oligomers, as well as brain extracts from AD transgenic mouse models. Hesperos received a Phase 1 Small Business Innovation Research grant in 2018 from the National Institute on Aging to help create a new multi-organ human-on-a-chip model for testing AD drugs. Research under this grant included a study to assess therapeutic interventions based on functional changes in neurons instead of neuronal death.
“Researchers are now focusing on biomarker development and therapeutic intervention before symptoms arise in AD and MCI. By studying functional disruption without extensive cell loss, we now have a screening methodology for drugs that could potentially evaluate therapeutic efficacy even before the neurodegeneration in MCI and AD occurs,” explained Hickman, who is also a professor at the University of Central Florida.
“The primary cognitive functional metric was long term potentiation (LTP), which has been shown to be a correlate of learning and memory in humans. Other neuronal parameters are also measured to determine overall culture health after exposure to the Alzheimer’s disease-causing αβ and Tau oligomers,” say Hickman and Shuler, who also note that “these studies are indicating the systems can accurately predict the effect of current AD therapeutics.”
Compared to controls, treatment with toxic Aβ and tau oligomers or brain extracts on the iPSC cortical neurons significantly impaired information processing, as demonstrated by reduction in high-frequency stimulation-induced LTP, a process thought to underlie memory formation and learning. Oligomer and brain extract exposure led to dysfunction in iPSC cortical neuron electrophysiological activity, including decreases in ion current and action potential firing.
“The primary value of this study is the cognitive function mimic without cell death. This is important because it has been shown that after reaching clinical stage of AD up to 50%-60% of neurons have died and even during the precursor stage […] that there is significant cell death. It is also now accepted in the field that drug development should focus on the pre-MCI stage—except that until now there were no good assays or animal models for this stage of the disease,” Hickman and Shuler point out. “This paper highlights a new assay for reproducible deficits in neural information processing without cell death, which we believe correlates with the pre-MCI stage of the disease.”
While exposure to the toxic oligomers and brain extracts caused morphological defects in the iPSC cortical neurons, there was no significant loss in cell viability.
“[For] the next stages of the project we are to continue drug testing to validate the system,” add Hickman and Shuler. “We are also integrating the LTP model with other organ systems or barrier tissues on the same platform to evaluate drug delivery options—we are adding a GI tract and a blood-brain barrier so we can understand the difference between oral or intravenous administration of a drug, and the system is in development at this time. Also, by adding a liver we will not only understand the effects of the parent drug, but any metabolites that are generated.”