Hello, and welcome to the n-lorem podcast series that focuses exclusively on the needs of Nana rare patients and their families. I'm Stan Crooke, I'm the founder and chairman and CEO of M n-lorem. Foundation. Today, we're privileged to have two
very special guests. Dr. Neil Schneider, who is the Clare cow, Associate Professor of Neurology at Columbia, School of Medicine, and Sonia camphor, who is a partner at vectus consultants and, and her her most important role, I suspect, she would say is, she's also the mother of a wonderful 16 year old daughter named Anna. Welcome to both of you. Great to have you. So Neil, I know that that you did your undergraduate degree at Harvard, and then an MD, PhD at Columbia. And then I think, spent some
time at the NIH and then came back home to New York. So I guess you're a New York boy, returned home. I am, I am a chosen New Yorker the best kind. If you're a real New Yorker, it's tough to take you out of the out of the city, right? Well, it's good to have you and and so I know all that Neil, but tell me how you got interested in motor disorders and in particular, ALS, and in those kinds of diseases, which are so devastating to so so many people?
Yeah, you know, my interest in ALS was a little indirect I, I did, as you said, an MD PhD, and I was I did my graduate training in basic neuroscience, molecular neurobiology. And after my residency, I returned to to basic neuroscience. And I was working with Tom Jessel, who's a developmental neurobiologist, and working in the motor system, trying to understand how motor neurons are born and established their identity, the specific
identity, but I was an HR ologists. And I wanted to integrate my science, my research with with my clinical activities, and so I walked across the street, I was at Columbia, then again, and I met up with with bud Roland, who was a great figure in neurology, and was an ALS specialist, and I began to see ALS patients at Budds knee, and, you know, I, if you, you know, understand anything about ALS, you, you understand that this huge need this great need of a population
that is desperate for answers. And, you know, in the time until those answers come, you know, clinicians, like me, need to take care of these patients, and these families need to help walk them through the disease, you know, to try to do everything possible, without real treatment and cure to, to lessen the burden on the on the patient and on their families, and to maximize the the length and the quality of their life. And it
becomes a mission. And, you know, not one that's easy, often but one to which you know, people like me become committed pretty quickly, and ALS becomes the enemy. Yep. It's pretty easy to understand how you become committed to that. And all you have to do is meet one patient. And it's pretty obvious. You know, I don't know about you, but I've been amazed at how much has been learned about the neurological central neurological system over the
last 2030 years. And, of course, motor neurons are such fascinating cells because they can have these long projections called axons that are, you know, meter long and longer. It's hard to imagine a single cell with that kind of projection. Yeah. Absolutely. And, you know, the motor neurons they're in they themselves are remarkable units, but they sit, you know, in this complex network of neurons and non neuronal cells, and they
function in this, you know, such a complicated system. And what we've learned, I think, over the last generation is that The dysfunction that leads to ALS is it's not just the dysfunction of the of the motor neuron, it's the entire system, that many elements of that system that are involved contributing to the
dysfunction and ultimately the demise of the motor neuron. And as we begin to think about how to treat this, how to how to prevent and treat ALS, we really have to think about all of the elements that are contributing to this disorder. Yeah, and if you just think about what we're learning in the, in the few patients that we've now been treated, been able to treat with us ALS, which we'll come to in a little bit, it's pretty remarkable. And your wife, Leah, is is curator at
MoMA. Is that right? Or a curator at MoMA? She's a curator, and she runs the research programs at the museum. Yeah, that's pretty cool. So you, you get into the you get to see the exhibits before they before they show up to the rest of us. Well, hers anyway, I get spoiled to get to see them before the crowds come. So it's quite a privilege. I'm going to hit you up. But next time, I'm in New York. You're welcome. And Sonia, I know that your husband is who a?
I pronounced that. Right. Very good. That's the that's the sum total of German I speak it. But anyway. Anyway. And I know he is head of an association of wine growers, I suppose is what you and your partner read vectus as a business consultant. And so is you are you still able to, to conduct your business activities with all the issues that ANA is having? No, I gave up my job. Yeah, for the time being, because it's, well, there's so much to do around Anna. And it's Yeah, and
I feel that I have to be there for her. And but it's not only a burden, it's also very rewarding to care for her and to see how, thanks to thanks to Neil and his colleagues, how she's developing and this sort of escaping this really terrible disease. Yeah.
Yeah, that's one of the features of disease of all sorts, but especially these extraordinarily severe and rare diseases is that they affect not just the person, they affect the family, and, and they're extraordinarily destructive, and they families either come together, or they split apart, it seems. And I'm pleased to see that your your family together. And for us, this meant, first of all, not being together for
Christmas and 2020. So I spent Christmas, and the New Year's Eve with Anna in New York, and her sister and my husband, they stayed in Germany, also because of this Corona situation, and really had a hard time. And we really had to find ways to still have a sort of normal family life. Yeah. So how old is on a sister? And a sister is 16. And Anna is 17. Now, yeah. On a sister is perfectly healthy, and everything's all
right with her. Yeah. And that adds a burden to a young person that is, is a challenge for most young people to contend with and the attention on the other child and all of the things that come into play. I'm sure your family's had to contend with a lot of that sort of thing, too. Yeah, sure. Well, why don't you Why don't you? Why don't we move to the star of the of the podcast and that's Anna. Why don't you just tell us about Anna before and then after she became you know, sick? Yeah.
Well, Anna was born in 2004 and Hamburg, and at the beginning she she was perfectly healthy, healthy child. It was only at the age of three, that some people in the kindergarten noticed that she was trembling from time. ample time, which was a bit strange, and we went to a neurologist for children, but he reassured us. There's nothing wrong with her. It's good for her to do lots of sports, but well, we don't have to worry. And we didn't worry. And she developed well, like a healthy
child. And she became very athletic. And she, she did well, at school, everything was was nice. We were just a normal family and at the age of 15, started, that she was sort of having problems with her breathing. She was short of breath when she ran up the stairs at home. And it was the first science and then it moved on to her having problems speaking. And then she lost a lot of weight. She had problems
eating. And well, it developed really horrible till the point that she really needed support for her ventilation that she got a gastro tube, because she was not able to swallow anymore. And we had horrible times. And what was also horrible was that we saw her suffering, getting weaker and weaker, and no one had any idea. We went to see lots and lots and lots of doctors. No one had any idea what this could be. Yeah. No one thought about ALS. Because ALS is not a disease of a 716 1516
year old person. Yeah. And it was then in well, almost after a year that one specialist in Munich, Professor Marilla Felber, who had seen a lot of very rare diseases in children, neurological diseases, especially, who was the first to mention ALS, that could be a very rare form, as and then we, well, we did genetic testings, and then the outcome was, yeah, it has ALS. We were well, completely shocked. Yeah, that was, it was short of breath initially. I imagine you got
referred to some specialists of some sort. What sort of specialist was was was that person? Yeah, the first person was a specialist on lungs and breathing. And they said, Okay, there's something some kind of obstacle, but we don't know what we don't see anything. Yeah. And then we had MRTS of her brain to the one neurologist told us, maybe there's a psychological problem. Yeah, maybe she has some well, like teenager problem that is showing in such rare
form. But when we went to see a lots and lots of specialists, yeah. But as I said, No one thought about ALS, except for this professor Muller favor in Munich. It is a tragically a very, very common story for these, what we call Nana rare diseases because physicians recognize patterns.
And if you've never seen that pattern, it's it's it's hard to recognize and your journey was, you know, typical in in the process, but maybe a little better than many that we've dealt with in that you got an answer, you know, in a year or so. When it seems like the average time to diagnosis for most of our patients somewhere around if they live five to eight years. So what you what you go through so that we're I understand how debilitating all that process is and regret that
you had to do it, but at least you did get to an answer. So Neal, why don't we Why don't you walk us through what's wrong with Anna. So Ana, has a very rare nano rare case of ALS, as um And Sonia suggested ALS is not a disease of 15 and 16 year old people it's a it's an old person's disease so to hear in your 40s 50s 60s not old anymore for me now, no no for me, either, but it is for honor for sure. And, and so
people, as you said, don't recognize the patterns. 1516 year olds don't don't have ALS, so it doesn't get into the into the differential. And to make it more complicated, I'm not has no family history of ALS. Honest mutation is what we call de novo, or spontaneous mutation. Neither ouvir or Sonia have this mutation. And so it's like other young people with with this mutation arose spontaneously, for reasons we don't entirely
understand, arose on its own in Ana's genome. And it laid dormant, not entirely dormant, she had symptoms, the tremors and maybe other issues that that Sonia describes, you know, suggested were suggestions on recognize that there was a problem, but it wasn't until she was 15 that this problem manifested itself as ALS as motor neurone disease. And this is a mutation that is one of if not the most aggressive causes
of ALS. I did it. I did relatively well, she had perhaps because she had respiratory and bulbar symptoms, she became aware of the problem a year before diagnosis. I think other young people with the same mutation, like like JC and her sister who had limb onset, they didn't figure this out until much later, they could compensate more for their problems in the way that you can compensate for breathing and
bulbar problems. And so I had a more of a pre diagnostic phase, which was lucky, I guess, I mean, not to say that she was lucky in any way here. But it gave time for her to go through a diagnostic process to get a genetic diagnosis. And she was lucky to again and that she had extraordinary parents who were going to leave no stone unturned for her. And out upon the you know, as soon as they have the genetic diagnosis, they began to reach out and made their way to me, I think in pretty rapid
order. And we had a duck point treated a number of patients with the ASO that we call Jason Heusen. That was a ASO developed by Jonas shared with us and made Iris made the pre MRO of course, but made the the the this therapeutic available to us in a way that allowed us to treat Ana with with an antisense molecule
and anti sense therapy. The goal of that therapy was to lower the levels of this toxic protein FOSS fu s in our system in her nervous system, and to sort of put the brakes on a process that had begun a year early. And her response has been, in my mind remarkable. people, young people with this mutation don't do well. They progressed very rapidly as Ana began to do and they usually reach some kind of a terminal point within a year most 18 months of disease onset. And we met on a in December of
2020. And were 18 months almost since the initiation of her her therapy. And if you were to look at her now I think you would you would say that she is doing well in a way that it's hard to explain based on the natural history of of that disease. So what So Ana has a form of ALS called Fusce ALS, and the mutation is in this first gene. And, and it's what's called a toxic gain of function mutation in that the protein just being made is itself toxic to neurons and causes them to deteriorate.
And at the time to the decision about the FOSS als effort, and I own us of course, I was chairman and CEO there and so I'm well aware of what was going on. And, and you mentioned bulbar symptoms, you might just just explain what what kind of symptoms while bars are. So I've just maybe, because I didn't say ALS is a disease that affects motor neurons, motor neurons are the neurons that
control muscular function. Those muscles include the muscles of our limbs, our arms and legs, also includes the bulbar muscles, those which control talking and chewing and swallowing. And ALS is ultimately a fatal disease because those motor neurons also control the muscles of respiration of breathing, the diaphragm and accessory muscles of breathing and all of those things are compromised when the neurons motor neurons degenerate, ALS, in most cases,
we there's no known underlying genetic cause. And, but in about 1510 to 15% of our patients, we know that there is a mutation, a genetic mutation that underlies the problem that causes the disease. There are dozens of ALS associated genes, FOSS is one of one of them, and a relatively rare cause of ALS represents
about maybe 4%, you know, of the genetic cases overall. And but in the pediatric cases, juvenile pediatric cases, like I'm as fus mutations are more highly representative, it's more common cause of this rare form of ALS is nano rare form of ALS. And, and so in this case, fuss is our targets, right? The ASO, the therapeutic is aiming at this one causal gene in this limited rare form of ALS.
So it is one of the big advantages that we have as genetic therapy that the Netta rare patient brings to us as they almost all not all but almost all have a clearly defined mutation in a single gene that that is the cause and many of the times that we can correct that. And Neil, I know that this all began with two identical twins. And one of whom had developed CLS and, and died when she was 16, as I recall, and then the other despite being an identical twin didn't
manifest her problems until somewhat later. Can you can you just briefly tell us about that family? Right, so So JC Hampstead was my patient. And Jason Heusen is is named in her honor. You know, this is a remarkable family that's been horribly affected by this disease, Alex, who said was 1112 years old at onset. And she was kept alive on a ventilator for a number of years and ultimately came to come to her disease at age 17. On his age now, and JC her sister lived
without symptoms until she was 24 years old. And there why there was a 12 year difference, you know, identical twins with the same mutation de novo again, spontaneous mutation, why it took an additional 12 years for JC to become symptomatic is one of the great questions, big questions that we would love to understand. Because it speaks to the trigger events, right? It's not enough just to have the genetic mutation. There's a second event of some kind that triggers the onset of the
disease. Why, why did ama live for 15 years with this mutation and not have motor neurone disease? Right. Well, there's some second event, some second hit, if you will, that triggers the disease onset and we're very much would like to understand what this is. We also don't care in a sense So that whatever that event is we would like to intervene before that event
happens right in the future. What if we can identify these mutations early and reduce people's risk of onset using the same kind of technologies, the same antisense therapeutics that we're using in the symptomatic affected individuals? We think, you know, we could maybe influence that, that that that onset event. So JC was the first the therapeutic was developed
with her in mind. Her disease onset prompted our initial approach to Frank Bennett and I honest about this as a potential therapeutic strategy for our patient, the first FDA program, expanded access, investigational new drug protocol was written for JC and she was the first assuming all of the risks and and potential problems associated with a therapeutic that had never before been given to a human being. So Anna,
benefited from Jaycees. Courage and, and sacrifice and a number of small number of other patients who were treated with Jace a few soon before Anna, and what's been lovely, and Sonia has met Lori met or spoken to Lori, JC and Alex's mom. And there's a community, you know, of people that has gathered around this problem. Oh, I'm gonna turn you back on. I suspect that the day that that you were told you had ALS was the end of the world. In the way
you fell. And I'm sure that you heard there was no treatment. It was hopeless, right. Yeah. As from the doctors, we heard there's no cure. Yeah, you can do therapies just to? Well, to make it easier, maybe to to have a bit more time. But there's no cure, or you can't cure this disease. And yeah, it was my my father in law. And as granted, who was a physician, himself. He contacted a relative in New York, near New York. And yeah, this person he well used
his network to, to ask for anyone in the US. Who knows anything about this fast mutation. And so we got into contact with the niche Nida. And that was, for us. That was, well, the best, best best thing that could have happened to us. Yeah. Yeah. And you just described one of the really serious issues that we're trying to contend with, with, with anatomy or patients is there is no path. There is no way to navigate. You
were very fortunate. Sadly, most are not. And, and so as a community, we have to come together and find ways to build better navigation systems for people. And I think we're committed to working on that. But I want to now, so December, you spent Christmas in New York. Yeah, hardly a great way to spend Christmas if you're separated from your family and, and at that stage, how sick was on it. She could walk still could walk. And we walked from the hotel to
the first dose of JC fusion together. But she was not able to really speak anymore. She had a disgusting tube, so she was not able to eat anymore, to eat properly and anymore. And while she was quite weak, it was really exhausting for her the flight to New York and then the treatment itself was was exhausting and she needed time to relax afterwards. That was it. Well, her biggest problem was breathing and not being able
to eat or to speak or to swallow like this bulbar symptoms. Were quite elaborated already. If you had a feeding tube in and that was the only thing that was keeping her from just wasting away, and what is so she was treated. I'm sure you have hope, but not expectations. What what, what what did you watch out over the next little bit? I mean, over the last weeks, because we stayed in New York to the tail end of February, we noticed I noticed because I live
for Canada. That sort of stabilized. I mean, from May till December, yeah. You could really watch her. How do you say that veering off or getting weaker and weaker. And I had the impression with the first dose, the second dose two weeks later. She's still lost some ground, but it was much, much slower than before. And we could still do some sightseeing in New York, and she loved Central Park, and she could walk there and things
like that. So she so we really enjoyed our time in New York. We were missing of the family, but Well, we had to make the best of it. Yeah. Yeah. Oh, yeah. Right. So then she continued to get a little better. And eventually, she had another swallowing problem, I think. Right. So yeah, walk us through all that. Yeah. I mean, when we came back, she sort of slightly lost more function, the the ability to walk, she got weaker walking, it was more the distances became much shorter. And I remember in
June last time, we were in New York. She was not able to, to stand up and sit down on her own. But after June it got better than her ability to to get up and sit down came back in July. She was able to walk upstairs slowly. But she was able to do that again. Before in June, and May, my husband had to carry her upstairs. And it was there were signs of recovering. I mean, we had this hope. But this was really a little miracles were little miracles for us. And but then,
unfortunately, in August, she got a lung infection. And that was really horrible because her airways were blocked one night. So she she had to be had to get reanimated. You say that reanimated that? She had to be put on a ventilatory support. Right? Yeah. I mean, she was, like, 30 minutes without own circulation. Yeah, she had to be into people brought back to life. And then it took the doctors two hours to really
stabilize her again. And yeah, and because of this infection, she was so weak that they put her in a in an artificial coma. And at the end of two weeks, the doctor said, we can't get her to
breathe on her own again, she needs tracheotomy. And while we had talked about that before, because what happened in between was that in July, we found the possibility with Professor veba in Saigon in Switzerland, that he could give the doses of JSON fusion to Anna in Switzerland because before in March, April, May June 2021. We are always travelled back for a week to New York back and forth to get JC fusion from Dr. Schneider and his team. But it got that was really exhausting for Anna. And
we didn't have any possibility to get that in Germany. Yeah, because there are a lot of regulations and very bureaucratic things again, this treatment in August, Stan, we well sort of had this crisis. She needed the Tokyo, Tokyo to me. And we had talked about that with Professor V by the beginning of August, just in case. And we were happy that we had done that. So we were able to, well, to be sure that Anna wants that, because she had told us, she is convinced is getting
better. And if a tracheotomy is necessary, she wants that to be done. So she had that. And in the beginning, she needed ventilation 24 hours a day. And, well, in September, we were really devastated. We thought maybe she couldn't move anymore because of this artificial coma and or the medication she had, she was completely paralyzed. She couldn't move her fingers. She couldn't move anything. Yeah, she couldn't talk to us. Well, it was really horrible to see, we really had to guess what
she was meaning when we're standing at her bed. But end of September, slowly, step by step, she got functions back she end of September, she was able to type on her iPhone. And then she she was able to move more and more than in October, she was able to get up, walk. And it became better, better and better. Yeah. And at this point, she's able to do nine hours a day without any ventilation, or new record from last week. She's
able to walk up to four or five kilometres. She is training to speak again, which is hard, because her tongue is still still paralyzed. We have a a team of people here. People coming every day to work with her therapists for breathing. And she's very ambitious. She's doing two hours of schoolwork every day today, so well, really have more than hope now that she can get back into a state where she's able to lead alive on your own. Yeah. That's wonderful story. And so she had a swallowing problem.
Got her her airway clogged and probably aspirated and had an aspiration pneumonia is what that's called. I'm sure at that stage near you. You felt that, that despite all the progress that she had made, that it would be unlikely that you'd see any more progress out of out of ANA. Yeah, the event that Sonia describes was very serious, it
was life threatening. And we were worried. Typically, with our patients, when something like that happens, it often is life ending on a has the advantage of being 17 years old and otherwise healthy and and strong and was able to fight her way back. But our point here is that yes, she recovered from the acute insult from the from the event that brought her into the
hospital. But her motor system was able to recover, right? I mean, typically you would expect that her disease will continue to progress through that period and that the disability associated with her hospitalization and illness would compound with the motor neuron disease and it would really just spiral downward but no she she was able to recover. And in fact, I think she is better now than she was before
the event in August. And so that that is just not what we would expect based on again, the natural course the natural history of the forms of ALS associated with this mutation is particular mutation, right, which is very stereotypical. Well, it's a wonderful story punctuated by tragic events and, and deep sadness and loss. And, you know, those are the stories
of our patients. And but it's a story of hope fulfilled and, and, and a family that can look forward to a future that is, we hope very different from the from the future that they had just a year or so ago. And I'm sure this Christmas was better than some other Christmases, and I'm hoping next Christmas will
be even better for the family. And I want to thank both of Neil and Sonia for this, but please, especially thank Ana for her for her courage and stamina and, and for staying in there and putting up the good fight that she's had. It's, it's wonderful sharing the story with you. And I'm sure you'll hear all kinds of appreciation from all our other listeners as well. Thanks so much. is convinced that one day she will give her own interview to you? Training for that?
Well get her going. I look forward to doing it. We need we need the star on this show one of these days. Okay. Okay. Thanks so much, everyone. Thank you. And n-lorem is a nonprofit committed to discovering and providing personalized experimental treatments for free for life to patients with genetic diseases that affect one to 30 patients worldwide, referred to by n-lorem as nano rare. Many of these patients progress and die without ever
achieving a diagnosis. This is where n-lorem comes in. They do the impossible by providing hope, and for those that they can help free lifetime treatment. For more information about n-lorem or today's episode, visit n n-lorem dot org. Any questions can be sent into podcast at and n-lorem dot org, search and n-lorem on Twitter, Instagram, YouTube, LinkedIn and Facebook to connect with us. Please rate and review
the podcast on Apple Spotify or wherever you listen. This truly helps us climb the charts and allows others to find the show. This podcast is hosted by Dr. Stan Crooke, our videographer is John Magnusson of Mighty One productions. Our producers are John Magnuson and Kira Dineen of DNA today. Thank you for listening