Challenges and Future Directions of Blood-Brain Barrier Research

Kaitlin Searfoss:
Hi everyone. Welcome to this Podcast from Cambridge Health Tech Institute for the Blood-Brain Conference, which runs June 15th and 16th, 2016, as a part of the World Preclinical Congress. I'm Kaitlin Searfoss, conference producer. We have with us today one of our chairs. This is Dr. Robert D. Bell, Principle Scientist, Integrative Neuroscience at Pfizer. Dr. Bell, thank you for joining us.

Robert Bell:
It's great to be here. Thanks for having me.

Kaitlin Searfoss:
First question. What are the biggest challenges scientists are facing in terms of delivering drugs across the blood-brain barrier?

Robert Bell:
I think the biggest challenges really lie around delivering large molecules, such as biologics, that have been very successful for treating peripheral diseases, so these are things like antibody and protein therapeutics that just don't cross the blood-brain barrier. I think neurochemistry has gone a long ways in terms of being able to predict how small molecule drugs will be affectatious in crossing the blood-brain barrier.

There was actually a talk at the meeting given by another Pfizer colleague, Bo Feng, where she'll talk about how you can understand different efflux transporters, like PGP and BCRP are two that are well-known, and how we've become fairly efficient at understanding early on if a small molecule drug is going to have an liabilities in terms of not being able to get in to the brain.

The challenge is really when we start moving into protein therapeutics, things like antibodies and biologics. I think while the field has been working on this for quite a long time and has made significant progress, especially in the past years, in identifying that this is possible. You can take advantage, for instance, of different transport mechanisms that already exist in nature at the blood-brain barrier, and utilize those to deliver protein therapeutics into the brain.

The challenge with them, as we started to learn, though, is they're not necessarily specific, and hey may come with other types of liabilities, such as safety liabilities, for instance. That's something that, as a part of any therapeutic development process, you're always trying to weight the efficacies, so in this case, finding things that actually can cross the blood-brain barrier, and then looking at the safety window at the doses you need, and then thinking about things like feasibility. It is reasonable in terms of how much drug you would need to give to a patient? Is this something that would even clinically be feasible? I think these are all things that are emerging in the field, and look forward to seeing these challenges being faced.

Kaitlin Searfoss:
So you're also leading a round table discussion where you'll be talking about the future directions of the field. Can you give us a little bit of what you think that will be?

Robert Bell:
Well, I think there's a lot of advances that are happening in the field. I think some of the challenges are really to continue some of the excellent work that's already happened in the fields of drug delivery, and really understand the clinical utility of some of these approaches. What I mean by that is most of the work to date has been done in cells, as well as in small animals, and it's time to really understand the clinical translation of some of these approaches, because that's what we're ultimately trying to do is to combat diseases of the brain and people.

I think understanding, ultimately, the potential of some of the pathways that have already been identified, so one that comes to mind is from a group at Roshe from [inaudible 00:03:22] group, where they've identified a transferrin pathway that may be used for drug delivery. I think that the challenges in this space are identifying pathways at the blood-brain barrier that may be more specific to the brain, and what I mean by that, for instance, is that work using the transferrin receptor, which is involved in iron transport, has paved the way in understanding that we can actually get biologics into the brain, but the challenge is that because the transferrin pathway exists in multiple tissue types, multiple cell types, you're essentially also going to be delivering whatever your therapeutic is all over the body. In some cases, that may be okay, but in other cases, it may not. It's all going to depend on what your therapeutic payload is.

I think understanding other transport pathways that work as good, or maybe even better, than transferrin that could be more specific to the brain and not necessarily expressed in all peripheral cells, so that's one area I think folks are working diligently on. I think another aspect is that neurosurgeons and devices in terms of devices for drug delivery have really advanced, and so you're starting to see things for focal delivery, so if you only need to deliver a drug to a specific area in the brain. One disease that would come to mind here is glioblastoma, and so if you're able to surgically deliver things safely, I think that this is also something that we're starting to see more and more clinical application for, both neurosurgical delivery, as well as ultrasound-based transient opening in a focal area. There will be a couple talks, which I'll be excited to see, on the ultrasound-based methods for opening the blood-brain barrier just enough to deliver some drug in a reversible manner.

The other aspect I think advancing is around gene therapy, and especially thinking about monogenic disorders, where we know what genes to target and whether or not we can do that specifically to help in these oftentimes rare, but very debilitating and oftentimes fatal disorders. I think advancing what we understand in other targets at the blood-brain barrier that could be used for transporting drugs in, understanding those pathways is one area, the options of surgical delivery is another one, and then gene therapy. From my perspective, these are all three areas in the field that are quite exciting to see advance very rapidly.

Kaitlin Searfoss:
You mentioned a few groups that will be on the program. What are you most excited to see at the Blood-Brain Barrier Conference?

Robert Bell:
I think I'm biased, just because my lab is really focused on understanding how the blood-brain barrier and how the cerebral vasculature is impacted during disease processes of the brain. There will be an entire session dedicated to understanding what happens mechanistically to the blood-brain barrier during some of these disease, during neuron inflammatory problems, during viral infection, for instance, so I look forward to seeing some of the research coming out in that area.

As I mentioned, I'm also interesting to see the talks on ultrasound delivery, again, for focal use. This is already being implemented in the clinic, and so I think understanding the long-term aspects of doing this in patients is important. Then, there's another aspect that I sort of was looking, in terms of in-vitro methods for evaluating different mechanisms. It's been very difficult to use in-vitro cell-based methods for predicting transport of biologics, but it sounds like there'll be some talks on that, as well as one talk from Ludwig Collins, also from Roshe, talking about basically challenging the concept that there's low vesicular transport at the blood-brain barrier. It sounds like he'll have something interesting to talk about that essentially goes a little bit against the dogma that exists that there's very low transport potential, vesicular transport potential, at the blood-brain barrier.

Kaitlin Searfoss:
Thank you for your time and insights today, Dr. Bell

Robert Bell:
You're welcome. Thanks for having me.

Kaitlin Searfoss:
That was Dr. Robert D. Bell, Principle Scientist, Integrative Neuroscience at Pfizer.