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Miniature Brain Model Aims to Reduce Cost, Accelerate Drug Discovery for Alzheimer Disease

Yanhong Shi, PhD, director, stem cell biology research, City of Hope National Medical Center, discussed the potential of a new brain organoid model, which was developed to study sporadic Alzheimer disease.

With Alzheimer disease (AD) affecting nearly 6 million people in the US, experts continue to seek better routes for diagnosis and treatment, while simultaneously working to identify a cure.1 A new miniature brain model, developed by City of Hope National Medical Center, may offer a route for improvement, as investigators will now be able to study the mechanistic causes of Alzheimer disease, test disease-modifying drugs, and shift away from the use of animal models in preclinical research. 

Yanhong Shi, PhD, Herbert Horvitz Professor in Neuroscience, and director, division of stem cell biology research, Department of Developmental and Stem Cell Biology, Beckman Research Institute, City of Hope, sat down with NeurologyLive to discuss the brain organoid model, which was developed using human induced pluripotent stem cell (hiPSC) technology. The model may be of particular use preceding human clinical trials, during a preclinical study, as a human cellular platform that can test for both efficacy and safety, thereby reducing associated costs and potentially improving success rates. Shi discussed implications for the model, as well as its anticipated use in drug development for sporadic AD, the most common form of the disease.2

NeurologyLive: What is the miniature brain model, and why was it developed?

Yanhong Shi, PhD: Alzheimer disease is a disease that is affecting a lot of individuals, and there is no cure so far. The drug development of AD has been a big failure so far except the most recent approval of Aduhelm [aducanumab; Biogen], and its accelerated approval pathway. We believe the possible reason for the high failure rate includes incomplete understanding of AD, especially the sporadic form of the disease, which the majority of AD patients have, and also because of the use of animal species for preclinical study. 

To address these concerns, we decided to develop a human cellular platform, in which we use the human induced pluripotent stem cells (hiPSC) to develop an organoid model for sporadic AD. We believe that using this model, we will be able to review pathological mechanisms underlying AD that were not possible to uncover using the previous animal models, or familial AD models. Also, this model will give us a powerful tool to test drugs for AD prior to them proceeding to preclinical trials. 

How will the model be used in clinical trials? What will researchers be looking to observe?

Because the development of new drugs is enormously costly, mostly because of failure in drug development and particularly because of failure in late-stage clinical trials, we believe our model will be able to change the scenario because it can be used to test to the efficacy of potential disease-modifying drugs for AD in a human cellular platform before proceeding to patients. 

We can look at multiple AD key features in our model, including synaptic density, neural network activity, in addition to reduced Aβ and phospho-tau, that many people have been looking at. Another aspect is that a failure in drug development in part is due to unexpected side effects. The hiPSC-derived brain organoid model can also allow us to predict the likelihood of candidate drugs to cause neurotoxicity. In addition, the same hiPSC can be used to generate other cell types, such as cardiomyocytes to predict cardiotoxicity as well. 

We believe our model can provide a human cellular platform to evaluate both efficacy and potential toxicity. We can consider that a 0.5x clinical trial, preceding the phase 1 trial, so that we can test both efficacy and safety in human cells without going to patients. That would reduce the cost substantially and increase the success rate when it actually goes to the phase 1, 2, 3 trials.

What is the potential impact of the mini brain model if it were to be successful?

We believe the hiPSC-derived brain organoid model provides a powerful way to study sporadic disease, the vast majority form of AD. It can be used to model both genetic and environmental risk factors. In addition, in combination of with single-cell RNA sequencing, it can be used to reveal mechanistic basis underlying Alzheimer pathology. As I alluded to earlier, this module can also be used for AD drug development; it can be used to test the efficacy and safety of potential disease-modifying AD drugs before proceeding to actual clinical trials, so it can increase success rate and reduce cost.

What do clinicians need to know about this model?

I think the biggest advantage of our model is that is a human cellular model, and it mimics the human brain’s cellular contacts and structure as well…What we need to keep in mind is that it is an intellectual model. So therefore, it can't really directly assess cognition, although we do have [indicators] such as synapse and neural network activity, which has been shown to be a very good indication of cognitive function. Another thing is that our model doesn’t have a blood-brain barrier (BBB) at the present time, so to address this concern, we creatively used a method to expose our human brain working model to human serum to mimic the consequence of serum exposure resulted from BBB leaking. Therefore, it allowed us to see the age-related to BBB leakage induce the pathological features. But still, it is an investigational model, so in the end, the findings we can obtain from this model still need to be validated in a real clinical trial so that it can accelerate the drug discovery, increase the success rate, [and] reduce the cost again.

What specific benefits might the miniature brain model offer for drug development within the AD space?

With our model, we were able to recalculate multiple AD pathological features, including elevated Aß aggregation, increased phospho-tau level, and reduce the synaptic and the neural network activity. We believe it provides a powerful model to test the disease-modifying drugs for AD, and even related dementia. And it's timesaving, because we can test those drugs in the dish very quickly, winning days and weeks, instead of months, and it’s much more cost effective also. I think, to me, the human origin of it, the ability to model sporadic AD, and the cost- and the time-effective way to test the drugs are the major advantages of our model.

Are there any other key points you feel are important to mention?

The hiPSC-induced the brain organoid model provides a powerful tool for us to uncover pathological mechanisms underlying AD and to test drugs for AD and other human diseases, as well, in the future. Also, the combination of the hiPSC-derived organoid model with aging-induced aspects such as the age-associated BBB leaking or cellular stress and so on, I think that can provide us ways to unpack or to uncover both genetic risk factors, environmental risk factors, and the combination of them to the contribution to AD risk and risk to other dementias. So, in summary, I think those hiPSC-derived organoid model is a powerful platform for both mechanistic study and therapeutic development.

Transcript edited for clarity.

1. Alzheimer’s Disease Facts and Figures. Alzheimer’s Association. March 1, 2021. Accessed August 18, 2021. https://www.alz.org/alzheimers-dementia/facts-figures
2. City of Hope researchers develop miniature brain models to study the causes of Alzheimer’s disease and to test drugs in development. News release. City of Hope. August 2, 2021. Accessed August 17, 2021. https://story.cision.com/r/35x3Bk