[music playing]

Oby: From the campus of Harvard Medical School, this is Think Research, a podcast devoted to the stories behind clinical research. I'm Oby.

Brendan: And I'm Brendan. And we're your hosts. Think Research is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center--

Oby: --and by NCATS, the National Center for Advancing Translational Sciences.

[music playing]

Brendan: In the realm of neurological movement disorders, many are familiar with Parkinson's and Huntington's diseases. When symptoms present, we see tremors and bodily stiffness that all appear to be the same. However, these two diseases, along with varying degrees of dystonia, differ in ways that are crucial to developing new treatments and slowing the progression. In both diagnostics and searching for new treatments, Dr. Samuel Frank is utilizing biomarker discovery to improve overall quality of life, and one day stop the progression of disease.

Samuel Franck is the director of the Huntington's Disease Society of America Center of Excellence and an associate professor of neurology at Beth Israel Deaconess Medical Center. Dr. Frank, Thank you for joining us. And welcome to Think Research.

Samuel Frank: Thank you for having me. It's a pleasure to be here.

Brendan: You're a neurologist that studies movement disorders, specifically Huntington's disease, Parkinson's disease, and dystonia. Could you tell us a little bit about these conditions? And let's start with Huntington's disease.

Samuel Frank: Sure. Huntington's disease is a disorder that is purely inherited. It's a genetic disorder. And it typically impacts people in their 30s and 40s, but it's a wide range.

And it causes, what I like to say, the three M's-- issues with Movement, Mood, and Memory. And so the movement side is something called chorea, which is extra involuntary, flowing type of movements. But it can cause other movements, as well.

It can cause some memory issues. And these are-- lots of different ways that it can impact memory, but it's not the outside part of the brain or the cortex like Alzheimer's, but more the deeper part. So people can pick words they were supposed to remember from a list, but they can't necessarily generate the list themselves. And then mood issues such as impulse control and depression, anxiety, that can be part of it as well. So even though I'm a movement disorder neurologist, a lot of the movement is what's most obvious and outside, but there's a lot more to all of the diseases that I deal with.

Brendan: And Parkinson's disease is-- I think people are familiar with Parkinson's because of Michael J. Fox, but there's more to it than the tremors and movement issues. Could you talk a little bit more about that?

Samuel Frank: Yeah, absolutely. And you're right that it's a bit more mainstream since there are only about 30,000 people that have Huntington's, but well over a million that have Parkinson's disease, so people are more aware of it. And the most recognizable feature is tremor, and more specifically a resting tremor, usually starts on one side of the body. But that can also go along with slowness and stiffness. And that's how we diagnose it, is with the motor side of Parkinson's disease.

However, just like all the other diseases that I deal with, there are many other features that go beyond tremor and movement in terms of how we diagnose this and what we look for. So for example, the majority of people with Parkinson's have sleeping issues, whether it's their sleep cycle being-- falling asleep earlier and waking up earlier or acting out their dreams, which is in about a third of patients. They can have skin issues, constipation, bladder issues, eye issues. The list really is quite long in terms of the non-movement side of what people have. And it's the entire picture that we put together that makes it Parkinson's disease and how we diagnose it rather than just a tremor.

Brendan: OK. So could you talk a little bit more about that-- you put all these things together, and then you diagnose it as Parkinson's. There's this third disease called dystonia-- and I don't know, maybe I'm not categorizing it correctly as a disease. But could you talk a little bit about how the diagnosis works? And maybe we could talk about a little bit of the treatment, too.

Samuel Frank: Sure. So all of these diseases, it's really in the eye of the beholder. And there are specific criteria that are set up that you can look up that are published. But really, it takes a neurologist to observe these findings and to pull them out sometimes in order to put the picture together and diagnose each of these disorders.

Dystonia can be a disease by itself, but it can also be a part of the other diseases. So for example, when I am running our neurotoxin injection clinic, I have patients all day long that have dystonia. Some of them also have Parkinson's disease, that have dystonia in the eyes or neck or feet. And dystonia is really just characterized by excessive involuntary muscle contraction that causes abnormal posturing, can result in tremors, as well. And so they're not necessarily-- dystonia can be a part of either Parkinson's or Huntington's or it can be its own disorder, as well.

And we diagnose all of these based on the clinical criteria that are laid out in guidelines and observation. In fact, James Parkinson, in his original essay in 1817, described a series of patients, but none of them were his, they were all out in the public, and what he observed in terms of their posture and their tremors and their shaking. And he would go and talk to them and get more information, such as related to their constipation and sleep.

But this was all something that he could observe from the outside. And that's how the diagnosis was made. And that's how we still do it today.

I wish we had a better way of diagnosing. And we are getting there. Recently, for example, there was a skin biopsy test that helps us to differentiate Parkinson's from other disorders, and there's been an imaging modality called DaTscan that helps us to differentiate Parkinson's from other disorders. But you have to suspect it to even get to those tests. We're by no means at a stage where we can just draw blood and do routine annual screening in everyone over 50 or 60 for something like Parkinson's.

Brendan: So you talked a little bit about the issues with diagnosing these diseases. And are there conditions that resemble these diseases that are often mistaken for them? And how do you-- I guess what's the gold standard or the most common way to diagnose any of these diseases?

Samuel Frank: It depends on which of the diseases that we're talking about. Huntington's disease, the gold standard, because it is purely genetic and we've known the gene since 1993, then to diagnose the disease itself still is based on symptoms. To confirm it, we can send off a gene test.

And we can also do predictive testing. Predictive testing should be done very cautiously and by people who know what they're doing because it can have major implications for the person and their family depending on the circumstances. People may not be eligible for life insurance, for example, if they have their Huntington's disease test done before they get that in place. So those are the kinds of issues that we deal with every day as we're considering doing testing. So we still diagnose people based on their symptoms, but there is a gene test that we can send off that is relatively routine in terms of Huntington's disease.

In terms of Parkinson's disease, it's really we diagnose it based on the symptoms that people come in with and our exam. For the vast majority of people, there is no gene test, although it is genetic in 5% to 10% of cases. And we can do some other ancillary tests to help to confirm it.

There are some other diseases that look like Parkinson's. And we look at exam findings such as eye movements, The eye movements should be totally normal in Parkinson's disease, but if they are not normal in many ways, then we have a long list of diseases that have a whole alphabet as their name that are Parkinson lookalike disorders, so things like progressive supranuclear palsy and corticobasal or ganglionic degeneration. These are some of the more rare diseases that we think about and why we do some of the exam aspects on the neuro exam that we do, to help differentiate some of those disorders from Parkinson's disease.

And as I said, dystonia can be part of these diseases or it can be its own. And it's really just doing a careful exam in terms of posture and looking, are muscles different sizes on one side versus the other? What can be a trigger?

What can relax the muscles in terms of dystonia? So much of what we still rely on is having a database in our head of, what other diseases look like this and what are exam findings that either confirm the three diseases that we're talking about or exclude them? And that's based on some standard criteria that are out there and published.

Brendan: Great. And so besides your clinical work, you're also involved in research and in biomarker discovery and drug development. Could you talk a little bit about your biomarker discovery research and why that's so important in these diseases?

Samuel Frank: Absolutely. And I spend about half my time in the clinic and the other half doing human-based research or clinical research. And I see the frustration when patients come in and I'm the third, fourth, fifth opinion.

And it's really because the first few people didn't do a more complete exam or didn't send off exclusionary tests or didn't think about some of the other lookalikes or just didn't have the confidence to say, this is what the disease is. You have this. You don't have anything else. And it's not so easy sometimes in neurology.

And it's frustrating for providers as well as patients to say, oh-- you can check your thyroid and you know you have hypothyroidism or your thyroid is underactive and there's no question about it. We don't have that same type of test for Parkinson's disease or for the onset of symptoms in Huntington's disease or for dystonia. And so some of my biomarker discovery work is in the context of drug discovery.

So for example, there's a study that we're doing now for Parkinson's which is a monthly infusion of a drug. And we're doing other biomarker discovery-related work, whether it's imaging or skin biopsies, different levels in the spinal fluid or in the blood. So I'm the person at one end of the spectrum, that I'm very good at collecting samples from patients so that we can test it in the lab and see, what's a better way of diagnosing and tracking these diseases over time?

Brendan: So let's talk about some of the clinical research that you're involved in now. Could you just give us an idea of what types of research studies you're involved with? And you work with the Huntington Study Group on some and foundations and other entities on others, but can you just give us a brief overview of some of the trials you're working on now?

Samuel Frank: Sure. And just in general, across all the disease, there's three main areas that I participate as a site investigator or other roles. One is observational studies. And so these are understanding disease better.

Sometimes it's in the context of developing a better biomarker, and how can we track these disease better with the natural history of some of the diseases, so observational. And observational does not mean non-invasive, especially if there's something like a radiotracer that's involved in imaging or lumbar punctures, things like that. So that's one bucket of research that I'm involved with.

The other is developing new symptomatic treatments. Because none of the treatments that are out there are perfect for the three diseases that I mainly deal with, the dystonia, Parkinson's, or Huntington's. So it's important to develop better symptomatic therapies for people who are experiencing the disease today and improve their functioning and quality of life.

Because even if we could stop the progression, they have the onset of the disease now. And so what can we do to address symptoms? We're not quite at the point of reversing the disease yet. I think we have to learn how to slow it down.

And that's the third bucket, is, how can we slow down the progression of these diseases? Dystonia is not progressive, but Parkinson's and Huntington's are both progressive, and inevitably change and get worse over time. And how can we change that sentence for it to not be inevitable? How can we slow down the progression or stop the progression of these diseases, is the third category of research that I participate in.

Brendan: OK. Great. And you're involved currently in several trials. And when the-- we spoke previously in July over the summer, and we were in the middle of the pandemic, and maybe coming out and starting to resume activities. Could you talk a little bit about how your research has been affected by the pandemic, maybe go back to March, when things started shutting down, and how that affected the trials that you were working on?

Samuel Frank: Well, I'd really rather not relive that.

Brendan: Yeah. I was going to say, I don't want you to spend too much time back there, but--

Samuel Frank: But I think that was an interesting era, and I hope we have a lot to learn from that. What we really did was we shut down all clinical research other than what was considered potentially life-saving. And observational studies are not in that category. And so anything that was an observational study, not interventional, was put on hold until the world opened up again.

And even the interventional trials, those that were symptomatic were important, I don't mean to diminish that they weren't, but they were not potentially life-saving. And so we were doing everything that we could at the time to prevent people from leaving their homes and coming to a place where we knew that the coronavirus impacted, such as hospitals. And so those trials, many of them were put on hold or abruptly ended unexpectedly.

I can tell you that I'm involved with about 11-- 12 trials, actually, right now. And there were two of them that we continued because they were potentially life-saving or disease-modifying and could have a significant impact if the drug-- if it did work, if we were to stop it. And so one of them was the monthly infusion into the vein for Parkinson's disease.

And it's not that we didn't change anything, because we certainly did. There were other aspects to monitoring the drug, so for example MRIs and different types of tests. And we pretty much put everything on hold other than safety evaluations that were important, and the drug delivery.

And that was the same idea with the Huntington's disease trial that was once every eight weeks, an infusion into the back. So I would say that if we could put things on hold, we did. And those studies that were potentially life-saving, we continued.

Brendan: And did you have to make modifications to those-- you talked about two studies that had to continue. What kind of changes did you have to make to those protocols?

Samuel Frank: Yeah. I wish that we did make changes at the time, but clinical research is very, very slow and doesn't work that fast. So the way that we dealt with it for the safety of everyone involved was really just consider the missed visits or missed assessments protocol violations, which nobody likes to have, but it also wasn't in the usual context, of course, in a pandemic.

So that's how we dealt with that. But I will tell you that moving forward, we have built in mechanisms to still assess safety and efficacy even if it doesn't happen in person. And we are working with making sure that these meet the regulatory goals, as well, so that the FDA can still put its stamp of approval, assuming that a drug is safe and it works.

Brendan: It sounds like you're building the airplane as you're flying.

Samuel Frank: Yes. Well, telehealth has been used in many states and for rural areas, actually, for a few decades. This is not a new concept. But I think more and more people have suddenly started using it and like not driving two or three hours and dealing with parking and all that. So I think that it forced us to take what was an unusual situation and made it usual.

I think that's the same thing in terms of clinical trials. There's no reason why someone needs to come to the hospital to have a safety assessment when we can do all of those same assessments remotely. And I should also say that remote clinical trials is not an idea-- one of the first completely remote clinical trials, from consent to drug delivery, safety monitoring, all that, that was done in 2011.

So this is not new, but I think that it needs to be embraced in a broader context. And our technology is such that we can build upon what's been done in the past and move forward and incorporate it into current and future trials. So I think what the pandemic showed us is that we need to have contingency plans not necessarily just for a pandemic, but for a 20-inch snowstorm that comes through or hurricane in some areas or heat that shuts down electricity in some parts of the country. So there are many circumstances where people can't leave their homes, can't get to study sites, and we need to be able to appropriately assess our research participants from a safety and efficacy perspective.

Brendan: Yeah. And I think if you can get-- maybe that would attract more participants if they didn't have to come into a hospital in Boston every month or something, too.

Samuel Frank: Oh, my gosh, the number of people that are so thankful that they don't have to drive in here just for clinical visits is huge. And I think the same attitude is true for clinical research visits.

Brendan: And so as you got started resuming study operations for some of the nonessential or non-life-essential research, what kind of changes have you made and implemented?

Samuel Frank: We have restarted everything, which is really nice. And we obviously have some paperwork to get caught up on, to say why we didn't do certain measures. But some of the visits that required an MRI, for example, we can do those MRIs now. So we're catching up. And I think at this point, we're all caught up.

And so how are we doing things differently from here forward? I would say that our interactions with patients-- our research participants are similar to our patients in clinic in that we wear the appropriate personal protective equipment, whether it's just mask and face shield or more than that. And so we obviously weren't doing that pre-pandemic.

And I think everyone is a little bit on pins and needles waiting to see, are we going to have to shut down again? Are we going to have to cancel visits for certain studies? And what can we do to get the appropriate assessments in, and drug exposure, for example, in an appropriate amount of time and over enough time to make a decision about what needs to happen if we were to have to shut things down again? So I think that we're planning for a rough road ahead. And I think that we're taking standard precautions today that we weren't doing prior.

Brendan: You're working on a couple of drug trials looking at treatments for Huntington's and Parkinson's. And you talked about trying to get things done and looking towards possible shutdown again. How are those trials going? And would you be able to finish those up before any potential shutdown? Or is that something you're-- I guess what's the outlook for these essential trials?

Samuel Frank: I think the outlook is actually quite good. Some of the trials are international. And so if the US component gets completely shut down, I think that there's still a strong arm in areas of the world that are not as impacted by coronavirus. And the research that was restarting, say, in July, we have another three months under our belt.

And I think everyone is optimistic that we're not going to go through the same shutdown because we're more prepared. We are all taking precautions. And I think that we live in a part of the world that is doing our part to prevent further spread. And our rates are pretty low.

So I think we're doing what the community should be doing. But we have to really take it one week at a time and see how things are going in terms of the pandemic. And I think the regulatory agencies that oversee a lot of drug development programs for the symptomatic or disease modification through the programs that are overseen by companies and hopefully being submitted to the FDA-- I hope that the data that we have will be enough.

Brendan: Yeah. I mean, I guess that's the fear, is that you do all this work, and it's not good enough, and then you have to scrap it and start over, right?

Samuel Frank: Yeah. I don't I don't think that anyone is going to make foundations or companies start over with the research. I think that if there is adequate data to support it, I think that we-- the FDA is going to have to take a look at that in terms of what we have.

Not sure that there's a whole lot more that we can do. And I think it just shows that everyone needs to make some adjustments to see what's going on. But it still needs to meet the minimum standards for safety and efficacy in order to move forward from an FDA perspective.

Brendan: Right. Yeah. It's a crazy time for every-- I mean, everybody's in the same boat, so there has to be a new baseline or new criteria or something.

Samuel Frank: Yeah. I think you're right. Everyone's in the same boat. And so even though I focus on one particular aspect of neurology, there are hundreds or thousands of trials that have been impacted and may be impacted in the future in a similar way. And so there has to be some policies and standard operating procedures that are similar across the board and give people some guidance in terms of how to move forward productively.

Brendan: Well, I wish you the best of luck and I appreciate you coming on. Thank you for joining us. It was great to have this conversation with you.

Samuel Frank: Thank you so much for having me. And thanks for your interest in this topic. It's really a passion of mine and an interest. And I also hope that we get to continue and follow through for the sake of our patients.

Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community.

Oby: To learn more about the guests on this episode, visit our website, Catalyst.Harvard.Edu/ThinkResearch.