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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 are 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.

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Brendan: In a recent episode with researcher Lotfi Merabet, we learned of several innovative tools and imaging techniques being developed to help identify a fatal genetic disorder in young boys called cerebral adrenoleukodystrophy. With funding from a Harvard Catalyst Pilot Grant, Dr. Merabet joined forces with Dr. Florian Eichler to improve current cognitive detection tools.

On this episode of Think Research, we speak with Dr. Eichler about his work studying gene therapy and early detection of cerebral ALD. Dr. Florian Eichler is an associate professor of neurology at Harvard Medical School and director of the Leukodystrophy Clinic at Massachusetts General Hospital.

Dr. Eichler, thank you for joining us, and welcome to Think Research.

Florian Eichler: Nice to be here. Thanks for having me.

Brendan: You're part of a team that received a Vision Pilot Grant from Harvard Catalyst. And you have been working with Lotfi Merabet on that grant looking at diagnostics for ALD or adrenoleukodystrophy. Can you describe what ALD is and who it affects?

Florian Eichler: Sure. I explained adrenoleukodystrophy is a single-gene disorder that affects boys, predominantly, between the ages of four and 10 with its most devastating manifestation, which is that of childhood cerebral ALD. Childhood cerebral ALD is a progressive demyelinating disease of the brain. And boys are initially born normally, develop early milestones, and then between the ages of four and 10, they develop some attention problems, maybe some personality changes. And then they rapidly progress to losing the ability to walk and talk and are often either in a vegetative state or dead within one to two years.

So childhood cerebral form of ALD is a truly devastating genetic disorder that strikes boys really in the prime of their life.

Brendan: And the goal of your Pilot Grant-- the goal of this Pilot Grant is to improve early detection. And you talked about the disease affecting mainly-- is it exclusively boys?

Florian Eichler: Yes, it's an X-linked disorder. And with boys only having one X chromosome, they cannot compensate for the second X for the mutant gene. And so at the time they're born, they already have very distinct fatty acid abnormality that you can pick up on newborn screening. This is a very long chain fatty acid that can be detected at newborn screening. But that doesn't tell you whether and when these boys will be affected with the brain disorder.

And in order to know that, we have to do serial brain MRIs every six months to a year. And once we see on imaging the lesion progressing, often that lesion moves very fast. And the kinds of tools that Dr. Merabet is developing is helping us find the earliest signs and symptoms as this white matter of the brain is being affected.

Brendan: Mm-hmm. So you said that detecting the change from X-linked ALD to cerebral ALD is what's crucial. The research that you're focused on-- that you're working on is detecting these changes earlier to be able to intervene.

So could you tell us a little bit more about the current state of treatment and what the problem is with only being able to do brain scans and only having that interval six months to a year?

Florian Eichler: Mm-hmm. And those are very good questions. Let me first say that the area of the brain white matter that is usually affected in these boys is the posterior, the back portion of the brain white matter. It is exactly that white matter that is connecting to the visual cortex, which is at the back of the brain. And for that reason, we think that these early personality changes, these early attention problems in boys, are actually cognitive, visual problems, that these are difficulties in processing visual information in the brain.

And our tools as neurologists are rather crude in finding or detecting this kind of cognitive visual impairment. But Dr. Merabet has tools that are far more sophisticated and granular and have the ability to really measure processing as opposed to us neurologists, who are often just looking at the attentional aspects and how quickly a patient is able to follow simple commands or do tasks. But we certainly don't have the kinds of tools that Dr. Merabet is developing and applying here.

So with the current treatment for this disorder as you had asked-- and sorry, I--

Brendan: Actually, before we get to that, I wanted to talk about when you first became interested in studying ALD. It's been a major focus of your work throughout your career. And your mentor was actually one of the pioneers in the treatment of this disease. So maybe before we get into some of the specifics about standard of care, could you just tell us about how you became interested in studying the disease in the first place?

Florian Eichler: --sure. Yes, no, I was very fortunate to have Hugo Moser at Johns Hopkins as a mentor for my career in neurogenetics. And Dr. Moser was really a pioneer in the field of leukodystrophies in large part because of his knowledge of not just neurology but also biochemistry. He was the one who discovered the abnormalities in fatty acids.

And this happened by an interesting serendipity. When in his lab overnight, one of the postdocs left the gas chromatograph on. And then the next morning they discovered a very long chain fatty acids on the gas chromatograph.

Long story short, Hugo was beyond being brilliant diagnostician, also someone who cared deeply about patients and patients' experiences and went on to not only discover this diagnostic assay but also attempt to lower very long chain fatty acids with a compound that was named Lorenzo's oil. And he did this in collaboration with a family that was fighting for the life of their child.

Turns out that Lorenzo's oil is able to lower very long chain fatty acids. But it does not actually change the course of the brain disease, sadly.

Brendan: Hmm. OK, so tell us a little bit more about that. You mentioned that the long chain of fatty acids are part of this demyelination process, and that's what-- correct me if I'm wrong-- but the long chain fatty acids are part of the demyelination process, which strips, basically, the coating of the nerves and disrupts the ability of the brain to send signals to the body. Am I getting that right?

Florian Eichler: Yeah, it's a complicated process.

Brendan: Yeah, I'm sure.

Florian Eichler: You're right. The very long chain fatty acids are a critical component of the disease. And if you have the gene defect, you have elevations and very long chain fatty acids at birth. And that is what has become this really valuable plasma assay to know whether somebody has the gene defect or not. You can at birth now measure very long chain fatty acids in blood of newborns. And you know whether they have the gene defect.

Unfortunately, it does not predict if you will have brain disease or not. And it turns out that lowering very long chain fatty acids as well does not prevent having brain disease. We have learned a few things about when and why brain disease takes place because of the only modality that has been able to halt progression of brain disease. And that is a bone marrow transplantation.

So it turns out that these bone marrow cells are vital cells that come up from bone marrow to blood and from blood to brain and then act as cells that can rescue the demyelination as these cells become microglia. And these microglia salvage the lesion and halt progression.

But it comes at a big cost. The boys that undergo bone marrow transplantation, they have to go through immune suppression. They get chemotherapy to make space in the bone marrow. But often the cells that they receive are cells from donors. And the body has reactions to those donor cells. They have graft versus host disease and engraftment problems that ensue. So it is a very difficult course to go through a conventional bone marrow transplantation.

And so Hugo Moser at Hopkins was hoping to find a better tolerated treatment in this Lorenzo's oil. But unfortunately, this did not work in stopping progression of brain disease.

At the time when I was with Dr. Moser and he was contemplating gene therapy, I was able to hear about work that a French group was doing where they were pursuing a new modality of gene therapy based on the bone marrow transplantation that had been done for a decade or two. And the simple ingenious step that they undertook was to not take donor cells from someone else but to take the donor cells from the boys themselves.

And these cells could then be taken from bone marrow harvested from the peripheral blood, transpected in a dish with a lentiviral vector that now delivered a healthy copy of the gene. These cells were then delivered back to the boys after a little bit of a mild ablation, meaning a little bit of chemotherapy that was making room in the bone marrow. And then the boys received the cells and were followed by MRI.

And the great thing about this is that we didn't see any engraftment problems. We didn't see any graft versus host disease. And if we did this early enough, we could really keep these boys in an asymptomatic state. And many of these boys now are returning back to me, reporting back from soccer camp, and leading fulfilled lives. That has made my clinic and my work really meaningful.

Brendan: So that gene therapy that you're talking about, this is the standard of care now. And this is helping halt the progression of ALD and preventing boys from developing this cerebral ALD, from developing the brain disease that is really devastating. Could you just tell us a little bit about the prognosis for children these days compared to maybe when you started this work and before the advancement of gene therapy?

Florian Eichler: Sure. Yeah, I will preface this by saying that gene therapy is not yet the standard of care. I think it is one of two modalities that can halt progressive cerebral ALD. The two being either conventional bone marrow transplant or ex vivo gene therapy. Both of them are based on a cell-based rescue that relies on good engraftment of the cells and early treatment of cerebral ALD.

So what our experience has been both with conventional bone marrow transplantation as well as with actually the protein therapy, if you treat these boys too late, meaning when the disease is already advancing rapidly and first symptoms have occurred, then often the disease does not respond. And the boys do not tolerate the treatment as well. So it has become really critical to detect these boys early, not only by newborn screening but also by very careful early detection of this conversion to cerebral ALD.

Speaking to my clinic when I first started this work 15 years ago, most of the boys at the time were detected in a symptomatic state, meaning after they had often had first symptoms and gone through a diagnostic odyssey. And by the time they came to my clinic, they were often wheelchair-bound and at death's door. So it was really a quite excruciating experience to meet these families and feel quite helpless.

But with time, as we have improved not only family screening but now also implemented newborn screening and come up with better and safer treatments through gene therapy, it's been a transformative experience. So the boys often come, are monitored very carefully, and then once they have early lesions that appear, we are able to treat them safely and effectively.

And they lead normal lives. And many of them go on to continue in school. And first boys are only six, seven years out. But I'm expecting great things from them.

Brendan: Well that's great. I mean yeah, it must be very gratifying to go from what you describe as an excruciating experience early on of seeing these families with children that we're not going to live very much longer after you met them to now being able to see patients flourishing and continuing to live their lives five, six, seven years out and continuing.

Florian Eichler: There's no question about it. One of the things my mentor taught me was that the patient's plight and the patient's suffering is central to our activities as doctors. And our failure as well as our success are contingent on that. And he told me as he had been taught, if something works, keep on doing it. And if something doesn't work, try something new. And that's exactly what I did.

So I feel very fortunate to have been part of this gene therapy effort. And this clearly required a multidisciplinary team of various different experts working together and not just academic experts but also industry and, first and foremost, patients and families that were willing to inform us on what was most meaningful to them and also willing to engage with the new experimental treatment. So we were very lucky to have had their trust in our work so that we could proceed.

Brendan: So I don't think you mentioned that-- maybe we didn't really touch on it too much. But it sounds like from what you're saying that you were part of the development of gene therapy. So maybe you could just briefly talk about that, like what role you played in developing this therapy.

Florian Eichler: Sure. Yeah, so when we first embarked on the attempt at using not only bone marrow transplantation but eventually ex vivo gene therapy for a brain disease, it was not something that most neurologists thought could work because the hematopoietic system, the blood system, was considered a separate system from that of the brain and nervous system. And there was a lot of skepticism that cells could travel from the bone marrow to the blood and from blood to brain.

And so in order for us to really make this happen, I had to have very good collaborators in the field of gene therapy and hematology and oncology. And David Williams at Boston Children's made a big contribution to the field of gene therapy through his knowledge of retroviruses and the antiviral gene therapy. And working across two disciplines from hematology to neurology really made this interdisciplinary treatment come about.

So my role was essentially defining the progression of the neurological disorder, defining the way the brain is affected, how the blood-brain barrier in this disease opens up and how quickly the lesion progresses, what kinds of outcomes, what kinds of neurological outcomes to measure. But it was really David Williams who provided the knowledge on vector design and how to develop here a drug product in collaboration with industry.

Brendan: Hm. And the inspiration for that, was it the fact that the bone marrow transplants were just so difficult on patients?

Florian Eichler: Well, I think the first inspiration for this was that we knew that bone marrow transplantation could work. And that in and of itself was a huge step forward although gene therapy is really a small, incremental step from a conventional bone marrow transplantation because we simply said, instead of taking cells from a donor who is not the boy himself, let us take autologous cells, cells from the boys themselves.

But the approach of ex vivo gene therapy and conventional bone marrow transplantation were the same, which is that bone marrow cells appear to have the ability to halt progression of this disease. And presumably, this is by virtue of the fact that these bone marrow cells can become microglia-like cells. And the microglia in the brain are a really critical part of the brain network and are really the first responders to any injury in the brain.

And years ago, after I worked with Dr. Moser, I was able to show that it is these brain microglia in cerebral ALD that are the first cells to die in an autopsy tissue of boys with cerebral ALD. And this was, for me, a real eye-opener because I compared this with other demyelinating diseases such as multiple sclerosis, and it was distinctly different.

There was a zone of microglia cell death that surrounded every demyelinating lesion in boys who had succumbed to ALD. And it was almost like these lesions were trying to tell me something. And the message was that this is the critical cell type that needs to be salvaged. And luckily for us, this can be salvaged through bone marrow cells that can develop from bone marrow cells to monocytes and from monocytes to microglia.

Brendan: Wow, that's very interesting. And around what year was this that you started this project?

Florian Eichler: 2007, 2008. It was first really an idea. And then in 2010, there were really collaborations coming about that were more concrete. And I think the Boston community was a perfect place to launch this because of the close proximity of not only different specialists in hematology, oncology, gene therapy, and neurology but also industry. So this really allowed us to move forward very quickly.

Brendan: And so now your-- this project that you're working on with Dr. Merabet is seeking to improve early detection. And you were trying to push forward into even better outcomes. And I was wondering, we just talked about some of the recent work, recent past. Where do you see the future of diagnosis and treatment for this disease?

Florian Eichler: So, I think right now we're largely acting on early lesion detection on MRI. The big conundrum we face is that we don't know what the neurological manifestation of that early lesion truly is. We think-- we speak of attention problems, personality changes. But it is a rather fuzzy beginning to a disease that is on imaging so well circumscribed.

And the work with Dr. Merabet is really helping us become much more accurate and rigorous in our clinical tools. So instead of just saying there are some attention problems or there are some personality changes, we want to be able to measure the kind of cognitive visual processing that is becoming impaired in boys with cerebral ALD.

And if we can measure this and measure it early, then I think we will be able to not just improve in terms of the timing of administering gene therapy but also understand how can we make this treatment even more effective? How can we preserve vital function for these boys who are at this age of their life and taking in the entire visual world trying to learn, to study, to read, to do many things that will put them in a position for them leading a fulfilled life.

Brendan: Well, Dr. Eichler, thank you very much for joining us. It was a pleasure to have this conversation with you.

Florian Eichler: Thank you, Brendan. Yes, it was a pleasure on my side as well.

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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 guest on this episode, visit our website, catalyst.harvard.edu/thinkresearch.

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