Organoids And Their Impact On Pre-Clinical Drug Discovery

June 7, 2019

June 7, 2019 | Pharmaceutical companies are looking for ways to save time and money in the drug discovery process. If there was a way to determine a therapy's impact in the pre-clinical process, researchers would have a better understanding of where to focus their efforts. This is where organoids come in, says Robert Vries.

Vries, CEO of Hubrecht Organoid Technology (HUB), says organoids—miniatures of in vivo tissues and organs—are perfect predictive tools in the clinic, where researchers can identify a patient's response to treatment before treating the patient directly.

Initially working in developmental biology and stem cell research in the Hans Clevers group, Sato, also a scientist in the group, developed the organoid technology.

"After the Clevers group discovered the adult stem cells of the human intestine, we wanted to do see whether we could isolate these stem cells and grow them in vitro. Until then the major problem of in vitro model systems was that it was impossible to grow primary cells from patients without genetic alterations," Vries told Bio-IT World. "So we wanted to see if we could , for the first time, grow the adult stem cell in vitro, which became the organoid technology."

On behalf of Bio-IT World, Mana Chandhok spoke with Vries about the benefits of organoids in pre-clinical drug discovery, the implementation process for new technology like organoids, and the trajectory of disease modeling and screening technologies.

Editor's Note: Mana Chandhok, a conference producer at Cambridge Healthtech Institute, is planning a track dedicated to 3D Cellular Models at the upcoming World Pharma Week event in Boston, June 17-20. Vries will be speaking on the program. Their conversation has been edited for length and clarity.

Bio-IT World: What are the benefits of using organoids in pre-clinical drug discovery?

Robert Vries: When you grow in vitro models, until now, you need to change the genetics of cells in order to grow them in vitro. And the alternative is to grow pieces of tissue or  isolated cells of organs in a dish. The problem is that they are basically slowly dying, and we cannot expand them for a very long time.

With our recent identification of adult stem cells, we can expand them in a way that they're genetically stable. That's the big change with organoids, where a specific mixture of growth factors is provided to the  stem cells. We started with the intestinal epithelial stem cells and subsequently developed organoids from  pancreas, liver, and basically all the epithelial organs. You give them the growth factor mix, and it basically allows you to expand them without having any genetic change. So the cells, they keep all the characteristics that they had when they came out of the body. The big advantage now is that we, on the one hand, can expand as you would do a traditional cell line. On the other hand, you don't have any alterations, and functionally, they are still like the patient. And this is where we started actually growing healthy cells when we first developed the technology, so just normal intestinal cells, or liver cells, etc. And then subsequently, we felt that now we can finally grow healthy cells, we can also grow disease cells, such as cancer, cystic fibrosis, and other diseases. What we have now is a system that basically has long-term expansion, without functional changes, so you can test the drugs in vitro  as if you are working with the patients themselves.

Another important point is that it's not something that is an infrequent event. You can basically do it with every patient, so the success rate of establishing an organoid culture cause is very high. Because we can take these samples directly out of a biopsy or resection and grow them in the lab, and at the same time see what will happen to the patient in the clinic. You can see what the responses of the patients to the treatments in the clinic is and compare it to the results of the same patient’s organoid in the lab. This way then allows us to actually confirm that we don't have something that theoretically is interesting or have a model that confirms the biology we consider important, but we can actually confirm that our in vitro model mimics the clinical response of the patient establishing he relevance of the in vitro model.  And in fact we are actually treating cystic fibrosis patients based on the organoid responses.

Is there one model that you've enjoyed working so far?

Cystic fibrosis was a very interesting model for us to begin with because it had this particular medical need. The problem is that the FDA, and also in Europe EMA, approved a new drug for maybe 25 different genetic mutations. There are, however, another 2,000 of these different mutations that are so rare, it's very difficult to do a statistically relevant clinical trials.

So in the Netherlands, very early on, we started generating organoids of patients that have mutations that are not EMA-approved. But when the organoids responded, insurance companies, hospitals, etc.,  allowed us to start treating these patients. So that was for us a very good example, first of all, of the clinical relevance of the organoids, and also of course, a great start because  these patients have a lethal disease and now have access to drugs that they otherwise would not have.

Drug discovery has a long and complicated validation process for new technology to ensure that human lives are not at danger. How does this impact the acceptance and implementation rate of new technology for you?

HUB is currently running clinical validation trials to determine the use of organoids as a predictive diagnostic to help direct patient treatment as in the case of CF. However, because the organoids were shown to mimic a clinical response of patient so well in disease like cancer, the model can already greatly improve pre-clinical drug development. Companies want to use it because it saves them time and money by knowing in a pre-clinical phase what the response to the compounds in the clinic will likely be.  

So for instance, for cystic fibrosis we have 600 models at the moment, and for colon cancer we have about 150, which serve as a pre-clinical patient population. Based on clinical or genetic criteria, we select specific organoid models and take them out of the freezer. We than test these organoids against the company’s drug, knowing that the results are relevant for the patient population to be treated later. For us, the scientific and medical acceptance by the community of the model is very important. At the next steps HUB is following up to obtain regulatory approval to implement he technology as a  predictive diagnostic tool.

What other disease modeling and screening technologies do you project will be game changers in the drug discovery realm?

This is maybe one of the most important questions. I think that organoids, and also technologies, for example IPS technologies developed by others, are now so advanced that they are really allowing us to generate model systems in our lab that are predictive for patients. The last 30 years has been focused on novel drug systems, and not so much on the model system, as most models are virtually the same as they were 30 years ago. There are technical differences, but no fundamental differences.

But now with organoids derived from adult stem cells or IPS these really new technologies, and we can do much, much more. This will fundamentally change pre-clinical drug development and make it much more efficient because we can now actually start using model systems that are like the patient.