Pain and the Brain: Using Patient-Derived Neurons for Preclinical Phenotypic Screening

Ann Nguyen:
Hello, and welcome to another podcast from Cambridge Healthtech Institute for the 14th Annual World Preclinical Congress in Boston, Massachusetts, taking place June 10-12, 2015. This is Ann Nguyen, Associate Conference Producer for the 3D Cellular Models conference.

Today we're speaking with Dr. Elizabeth Buttermore, Research Fellow with the F.M. Kirby Neurobiology Center at Boston Children's Hospital and with the Neurobiology Department at Harvard Medical School. She'll be giving a presentation during the session on Applying 3D Models for Oncology Research.

Liz, thanks so much for your time.

Liz Buttermore:
Thank you for having me.

Ann Nguyen:
You studied neurobiology at the University of North Carolina, but then shifted toward more translational research. Can you share why and what it's like working with induced neurons in phenotypic screens now at Harvard?

Liz Buttermore:
Yeah, I think that's a great question, and there's actually a lot of reasons why I decided to work on something more translational. One of the obvious reasons anybody works on something translational is that funding is easier and I eventually want to transition into a research position in industry, so I kind of wanted to get experience developing screens and doing work that would help me make that transition. Really more than that was a desire to be working on something that's more applicable to human health and to be working on something that's closer to helping someone at the bedside in the clinic. The main reason for wanting to do something translational is that research is really hard and there's a lot of ups and downs and it really helps you get through the down times. When things are failing, when you feel more connected to the research and that you're actually helping someone in the end.

In terms of working with the induced neurons in phenotypic screens, I think this is a really great way to be involved in something translational that really feels like it will transition into the clinic well. For example, a previous postdoc in our lab, Brian Wainger, who now has his own lab at MGH, he was able to characterize human iPSC-derived motor neurons from both healthy control and patients with ALS, and he found that the ALS patient-derived neurons are hyper-excitable as compared to the healthy control-derived neurons. He was actually able to use a potassium channel blocker that's already FDA approved for the treatment of epilepsy to decrease the hyper-excitability and increase survival in the ALS-derived neurons. He's actually now using this potassium channel blocker, which is called Retigabine, in a clinical study that he's leading. This, within three years’ time, has gone from discovery that he made in our lab to the development of a clinical study. I really like the way that research, while still basic research at an academic institution, can really translate into the clinic at a rapid pace.

Ann Nguyen:
How might human-derived neurons enhance preclinical phenotypic screening and how do 3D culture systems come into play here?

Liz Buttermore:
I think, especially in terms of the pain field, there's a lot of failure for new compounds that are being discovered in preclinical settings to have success once they reach the clinic. This is for several reasons. One of which is that right now people are using rodents as model systems for neuroscience, and while they're a great model system for some aspects of the nervous system, I think we're all pretty well aware that a lot of the cellular and molecular architecture of the mouse nervous system is actually quite different from the human nervous system. Mice are really missing key aspects that are necessary for proper function in humans. These studies could be missing something when they go from preclinical to clinical research.

Another system that's frequently used for preclinical screens are heterologous expression systems. Again, these are good for looking at specific binding kinetics of ligand receptor interactions or something like that, but it doesn't really get to downstream signaling mechanisms that might be in play in a neuron. We thought that maybe to improve the efficiency of things, compounds being discovered in preclinical trials, that it would work better if we were testing them on the target cells. If we could use human-derived neurons in a preclinical screen, then these hits would be acting directly on the target cell with the downstream signaling intact.

One of the other benefits to a phenotypic screen is that it can really be unbiased. A lot of the heterologous screens that are done and other screens that are being done in pharma are for preselected targets, where a specific outcome to manipulating that target is expected. That can be based on other preliminary findings in rodents or heterologous systems, but again, may not be confirmed in human cells. By doing an unbiased phenotypic screen, we can maybe identify novel targets that could be responsible for these phenotypes that were not previously examined. Again, maybe this will lead to more success when moving into the clinic.

Ann Nguyen:
You'll be discussing “Modeling Pain and Peripheral Neuropathy Using Fibroblast-Derived Nociceptor Neurons” on June 12. What's the main idea you'd like to share with the pharma-oriented audience?

Liz Buttermore:
The thing I'd really like to highlight, especially for a pharma-oriented audience, is just the potential that this research holds, at a time when it seems like a lot of people are backing out of neuroscience research. I really hope to make an example for in the field of pain and peripheral neuropathy to show that we hope to 5, 10, 15 years down the line be able to take a skin biopsy from a patient with a particular sensory neuron disorder and then test an array of drugs on their derived neurons. Then based on the reaction of that patient’s neurons, we may be able to select the drugs that will work best for that patient. In the same light, drugs that are going to be used for maybe other non-neuronal treatments could be tested on a patient’s derived neurons kind of as a safety screen. For example, if you think about chemotherapy patients, we could test certain drugs, chemotherapeutic agents, on their induced neurons and see if they develop neuropathy, and maybe not use that particular chemotherapeutic agent for that particular patient. I really just hope to highlight what I think is the potential for these kind of model systems, for both the use in basic research but also in translating into the clinic in the future.

Ann Nguyen:
Sounds really exciting, and you'll get a chance to dig more deeply into the data this summer. For now Liz, thanks so much for sharing some of your experiences and observations with us.

Liz Buttermore:
Thank you.

Ann Nguyen:
That was Elizabeth Buttermore of Boston Children's Hospital and Harvard Medical School. She'll be speaking at the 3D Cellular Models conference during the World Preclinical Congress, taking place June 10-12 in Boston. To learn more from her in person, visit www.worldpharmacongress.com for registration details, and enter the keycode "Podcast". I'm Ann Nguyen. Thank you for listening.