The president of the ANA offered his perspective on these novel genetic therapies, as well as other a few other areas of interest.
David Holtzman, MD
A number of hot topics, including the advancement of gene therapies, grabbed the attention of attendees at the 143rd annual meeting of the American Neurological Association (ANA) in Atlanta, Georgia. In the midst of this excitement, David Holtzman, MD, a professor and the chair of neurology at Washington University in St. Louis in Missouri, as well as the president of the ANA, sat down with NeurologyLive at ANA 2018, the association’s 143rd annual meeting, to offer his perspective on these novel therapies, as well as other a few other areas of interest.
Although Holtzman’s research focus is rooted in treating Alzheimer disease and related dementias, as a meeting attendee, he set his sights on exploring the loads of research being done in other neurological and neurodegenerative conditions. Additionally, he shared his insight into the current state of care in dementia with Lewy bodies, the main facet of his research.
Much discussion in the field of neurology, as well as in medicine as a whole, surrounds the introduction of gene therapy for the treatment conditions that would otherwise essentially be regarded as death sentences. Holtzman discussed some of the most prominent data shared at the meeting and what sort of impact these therapies could make—and are making—on these debilitating diseases.
We know about a variety of neurodegenerative disorders, the most common being Alzheimer disease, but dementia with Lewy bodies is the second most common cause of neurodegenerative disease that we know of in man. Unfortunately, unlike Alzheimer disease, where a lot of insights have been gained, not only about the mechanisms that underlie the disease but also the ability to monitor it in living people through a variety of biomarkers, we haven’t made as much progress in that area—in dementia with Lewy bodies.
We do know a fair amount about the pathology that occurs and some about the clinical manifestations, but in an individual who presents with the typical, or classic, symptoms of dementia with Lewy bodies—which is often parkinsonism, change in cognitive abilities, visuospatial dysfunction, etc—we can’t confirm 100% that the pathology of that disease is occurring, because we don’t have the ability to detect α-synuclein accumulation in a living person. I think a lot of the plenary session was really about what we do know about the clinical manifestations: that sometimes it’s forward to make a diagnosis and sometimes it’s clearly not. That was beautifully illustrated by Susan Schneider Williams’ story about her former husband, Robin Williams. That’s why I was highlighting the fact that we really do need markers for the disease so that we can detect it early.
Some of the really promising things in the session were that we think that, as with a lot of neurodegenerative disorders, there’s a phenomenology where the protein that builds up in 1 part of the brain spreads from area to area along different pathways. If it starts in 1 area—in this case, with dementia with Lewy bodies, where it appears to probably start in the brainstem—it then moves along set pathways. Those have been really defined by work like that of Virginia Lee, MD, and others that show this phenomenon. It really means that, if we could identify this earlier, we might be able to have therapeutic approaches that block that spread. Some of those treatments are actually being developed now and in clinical trials, even in humans, where people are using—companies are using—antibodies to α-synuclein to try to block the spread from 1 cell to another. That didn’t come up in the session, but that is ongoing now. Maybe there are other ways to basically suppress the buildup of α-synuclein in the brain.
This inability to know when everything is going on, especially with these dementias…we have an idea that this is happening for decades prior, but the ability to pinpoint where we are, in terms of research of identifying a biomarker like that—that could help. With α-synuclein accumulation, people have been looking in the spinal fluid to see if you can measure synuclein, and that is measurable. On average—and studies have been published—it is a little lower in the cerebrospinal fluid of people who have Parkinson disease and dementia with Lewy bodies. But the amount of overlap between the groups and controls is pretty substantial, so it is hard to use it as a definite biomarker.
Perhaps the reason it goes down is that as the protein accumulates inside cells, it probably gets sequestered, so it does not come out of the cell as much. It is kind of like what happens with amyloid in amyloid-ß and Alzheimer disease. When it builds up, the main constituent of those plaques is a form of the amyloid peptide called a ß-42. That’s free-floating around in our blood, in our cerebrospinal fluid, and when it aggregates, it gets sequestered into the plaques. In Alzheimer disease, it goes down substantially, and you can pretty much tell who has amyloid in the brain or not from just a cerebrospinal fluid test. Now blood tests are being developed. But unfortunately—we’re not sure why—this biochemical change isn’t as robust with these synucleinopathies.
What a lot of people are trying to do now is develop imaging agents in which you can take some sort of a small molecule, radiolabel it, and have it bind to the α-synuclein in the brain, and then image it with a PET [positron emission tomography] scan. That has not yet been definitively shown to work, but that’s what a lot of groups are trying to see if they can get to work.
This came up in a discussion—at least I certainly brought up, and actually, Dimitri Krainc, MD, PhD, brought it up in his talk. I really think that in the longer run, the way that we’re going make an impact on these diseases is to identify them before they are clinically manifest; in other words, before there are symptoms. In all these diseases, the disease is starting years before the symptoms.
If you think about the biggest impact we have made in heart disease or stroke, it is prevention. So, how do you do that? You screen people for blood pressure, you screen them for cholesterol. If those things are abnormal, you start treating people when they are fine, and you try to normalize those things. That has made a huge impact on the risk of stroke and heart attacks. These things have gone down a lot. But you can’t really do that unless you have indicators of the disease in normal people. To me, that’s going to be the biggest impact we can make on neurodegenerative disease, like dementia with Lewy bodies: early identification even before symptoms, so that some of the things being developed for therapy, which look really attractive, have a much better chance of working.
One reason I work a lot on understanding these biomarkers, is then when developing treatments, we are able to affect the biomarker even before there are symptoms. There are trials like this going on in Alzheimer disease, but I think that’s where these other disorders need to go—like ALS [amyotrophic lateral sclerosis], Huntington disease, dementia with Lewy bodies. They are all protein aggregation disorders, and they start before the symptoms.
Virginia Lee showed some really interesting data suggesting that these synuclein-spreading models look like a reasonably interesting model for dementia with Lewy bodies—at least in animals. It looked like α-synuclein could seed another important protein, tau. In humans who develop dementia with Lewy bodies, many develop not only α-synuclein buildup but also amyloid buildup and tau buildup, and if that can be modeled better in animals, we ought to be able to test the different therapies that are being developed all together instead of just 1 at a time—sort of a combination approach.
During Saturday evening’s pre-meeting symposium on viral gene therapy, I was really struck by the progress that’s been made. One, there is now an approved gene therapy treatment for a rare retinal disease that really looks like it has a major effect. It is now approved, and people can get that treatment. But perhaps [gene therapy will have an impact] in a bigger, much more robust disease in terms of numbers, like muscular dystrophy. Although it is not yet approved, there were really promising, very early data in humans showing that gene therapy for muscular dystrophy might be having an effect. That would be a game changer. That is such a terrible disease. Some of the other data on replacing the enzyme that makes dopamine, called AADC, already seemed to show benefit in a rare disease where there’s a deficiency of that enzyme in the brain. They put it back into the brain using gene therapy. That is also now going into trials in Parkinson disease, and so that’s really promising.
We have a treatment that was just approved about a year ago for a rare form of motor neuron disease, spinal muscular atrophy, which causes children who were going to die to live—now we have another gene therapy for that disorder that will probably get approved soon. And all these other disorders that, potentially, could respond to gene therapy make this look like it is really going to emerge as a major new mode of treatment for some diseases. That, to me, was really striking.
I don’t think so. Of course, whenever you develop any kind of a therapy now, at least in the United States and in Europe and most other countries, the regulations are really quite tight. Everything is very well regulated. You can’t just go in there without having done a lot of safety studies first in animals. Then, when you first go into humans, you start at very low doses, and if something comes up, you can usually detect it before there’s a major problem. As long as people are doing this under the guise of agencies like the FDA, they’re not going to just go in there and do something that’s not monitored appropriately. I think we’re OK, and most of the diseases that we’re starting a lot of these things in first are those where if you don’t do something, the person is going to die. In fact, many of these diseases where this is being tried first are worse than many forms of cancer in many ways. And in cancer, a lot of times you do try some treatments that can be harmful as well as beneficial, so I’m not so concerned as long as we follow the rules.
Transcripted edited for clarity .