April 30, 2021

Treating rare diseases with oligonucleotide technology

By Conor McKechnie and Dodi Axelson

Treating rare diseases with oligonucleotide technology

Remember our first episode on oligonucleotides, telling the story of Roy living with spinal muscular atrophy (SMA)? We were so amazed by this technology, we promised to follow up at a later date — and today is the day! Listen to find out how Roy is doing today, and hear from Harvard medical doctor and researcher, Tim Yu and Nikki Reyes-McIntosh, mother of Miles who also lives with SMA and is treated by oligos.


DODI: Conor, it's been one whole year since we tried to make sense of antisense oligo therapy.

CONOR: Right. And we heard that heartwarming story about Roy who had spinal muscular atrophy and the oligos that work like sort of a molecular patch to make the gene function correctly.

DODI: Exactly, and you'll be glad to know that Roy is doing fine. We heard from his family that Roy has stayed clear of COVID, he is progressing well and communicating with sign language.

CONOR: Oh, that's just lovely to hear. That's fantastic.

DODI: So since that last episode, we have been promising, and we have been wanting to take another look at, oligos taking a step forward, if you will.

CONOR: Okay, how so?

DODI: Long term clinical trials and looking at living with rare diseases.

CONOR: Alright, I guess that's what matters on today's episode.

DODI: So on your marks, get set, o-li-go!

CONOR: Okay, we can't do these every episode, but okay. So who are we starting with today?

DODI: Allow me to introduce you to Nikki.

NIKKI: So my name is Nikki McIntosh. I am a mother of Miles, who is an 8 year old boy. Miles has SMA type 2, and was diagnosed with SMA when he was about 18 months old.

CONOR: 18 months, that’s really young.

DODI: I know. And right after the diagnosis, Nikki started researching into what this was all about, because there was no one to help her through this.

NIKKI: About six months after Miles was diagnosed was the first Cure SMA annual conference. They have a conference each year, which gathers researchers, patients, their families and doctors all at the same time. So we attended the conference. And I think that's when our eyes were open to research, that research was going on or for spinal muscular atrophy. And we attended some of the research breakout sessions. After that, we started following it on our own. So we first became aware through the foundation and that conference, and then after that, we started following the progress of the trial specifically looking at https://clinicaltrials.gov/ website, finding out who the contacts were, reaching out to the contacts insistently.

CONOR: And so from all this detective work, she comes across a clinical trial at UCLA?

NIKKI: Miles was actually the first one dosed at UCLA. And so, you know, we've, we've gotten to know the doctors there. And because we've been for five years, we've been seeing them and they've been following us.

CONOR: The drug that Miles took, Spinraza, was injected into his spinal fluid. And you might remember from our first episode on oligos, that drug went on to be FDA approved in 2016. And so they've been participating in that trial ever since? Well, so five years five?

DODI: And plus, absolutely. He's 8 years old now.

CONOR: Wow, that is long term, that must be a harrowing journey. You know, what's that, like?

NIKKI: Journey is definitely a good way to put it, it really has been quite a journey.

DODI: And one of the most interesting parts of an otherwise tough emotional period for Nikki and the whole family has been diving headfirst into the science behind it all. In fact, they've made friends with the scientists and researchers and now Nikki says their relationship has progressed into something else.

NIKKI: Like partners, to be honest, I feel like we're all on this journey together, of starting off, not knowing how this was going to unfold, but obviously hoping for the best and all doing our part to try and move it forward. So it's felt like a real partnership with the doctors and the researchers to all do our part to see where we could take this. We feel really, really, really blessed and really honored to have been a part of it. We know there's a lot of children that could not participate. Perhaps they weren't healthy enough to participate. And so we just are so happy that our son was able to and that now all children, you know, are receiving this FDA approved drugs. It's been a part of our journey that I'll always, always look back on and just feel like we're so grateful to all the players in this.

CONOR: So Nikki and her family are kind of like one of these historic patient families that you hear about sometimes.

DODI: One of those firsts, one of those look back and how did it all begin?

NIKKI: That feels funny to hear. But it's been such a big group effort and you know, the SMA community as a whole, they've held us up and in other ways and so I feel like we're all doing our part in ways that we can.

DODI: So three treatments a year and it's been hard for Nicki to see exactly when she sees a difference in Miles.

NIKKI: Sometimes it feels like it's right after he'll try something new that he wasn't able to do before. Sometimes it's more, later. And, you know, we're getting close to the next dose. And I'm feeling as if, perhaps we wouldn't see that that time because, you know, we're overdue for another dose, but there's still things happening, and he has not yet reached a plateau. In fact, we've worked with the same amazing physical therapist since the beginning. And you know, the goal always in the past for, I think SMA children, was to try and maintain or preserve their strength for as long as possible. And now we're just in unchartered territory. And now that we have new goals, we're making strengthening goals, we're making goals to actually do bits of strengthening exercises. These are things that you wouldn't do in the past, because he has not plateaued and we just keep moving forward in a positive direction. So we don't know where it will take us. But it's been amazing to watch, and for Miles, just gaining functional mobility, functional strength, allowing him to do more things just in his life is, is amazing. And I think the best part of it is that he never stops trying, which I'm really proud of him for. He just tries new things, and sometimes is able to accomplish them. It's, it's pretty exciting.

CONOR: And then the medicine being so tightly regulated, and this being an experimental therapy, and then you've got no idea exactly how or whether it's going to work. I mean, what would it be like to live like that for so long.

NIKKI: At the beginning, it definitely felt like a risk. But for us, the risk outweighed, you know, the negatives, because we knew, if we didn't do something, we knew what that life looked like, you know, we knew the statistics and the facts about SMA and how it would unfold if there wasn't an intervention. So it was a risk to be involved. But it felt like, perhaps there was potential for a different outcome.

DODI: What a ride, right? To live with the realities of a rare disease. But Nikki says it's the hope and the possibilities that keep her going.

CONOR: So what then, are our hopes for Miles?

NIKKI: It chokes me up to actually talk about it, my hope, for Miles. At the beginning, it was just health, good health. And now, I guess I get choked up, because I get to think of things beyond that. I get to think of typical things for him, for his life, to go on. And, sorry, it really chokes me up, to go out and be able to have a full life, and to go to college and to have a girlfriend, and maybe someday have a family and to go on and do great things. And I hope he really just takes this journey with him, I think he will just because I see such strength and determination with him to go on and just, you know, live a purposeful life and do something with purpose in his life, because it's really his life has just been such a gift. The way this has unfolded, it's so much different than what we were told at the beginning, what's going to happen with him. And so I'm hoping for great things.

DODI: Now let's head over and get an example of one of those scientists that Nikki sought out, learned from and developed a partnership with.

GUEST 2: Should I turn off my camera as well, you this is just going to be an audio recording. Is that correct?

CONOR: So who's this?

TIM YU: Well, my name is Tim Yu. I'm a neurologist and a geneticist, I have the pleasure of working at Boston Children's Hospital, and Harvard Medical School. I have the fortune of running a laboratory that investigates the causes, as well as tries to design treatments for diseases that affect children, and in particular, neurologic diseases that affect children.

CONOR: And how did Tim's work begin?

DODI: It all came from trying to understand how children's brains develop.

TIM YU: How different children's brains might develop in different ways. And some might develop in a way that led them to have cognitive challenges and autism spectrum diagnosis and so forth. And now it's really expanded to tackle problems faced by children with those types of conditions, as well as many other rare genetic conditions that might not only affect how the brain develops, but also affects how the brain functions and finding ways to understand that and then, when possible, correct. That is what drives us.

DODI: I wanted to know what was it like for someone like Tim, to focus on such a tragic thing as rare diseases within children who have conditions like SMA?

TIM YU: You know, that's a great question. And I sometimes think back to a conversation that I had when I was actually a teenager. It turns out that my mother is a pediatrician herself. She's a pediatric hematologist-oncologist - which means that she takes care of children who have blood disorders and cancers. And I remember visiting her clinic one day, and seeing her waiting room full of young kids, younger than me at that time. Many of them in hospital gowns, many of them with IV poles, and perhaps they were from chemotherapy that they were getting. And I remember asking my mom, isn't this really sad to be working with kids who had these terrible diseases? Why do you do this? And she said that she began working in this field, because when she started 90% of the children that she worked with would pass away from their cancers. But by her mid-career, only half of them were passing away. She understood that, to an outside observer, seeing so many kids suffer, and half of them passed away from the conditions seems incredibly sad and a great loss. But from her standpoint, there was so much work to be done, and the improvements that she could see over the span of her own professional career motivated her to want to work in that space. I think that a similar story fits with rare genetic disease today. I think there are many folks who are drawn to this space, because on one hand, it is so terrible to see so many kids suffering and so few treatments. But it's our hope that we want to be able to turn that around and change that. That drives us to work in the space.

DODI: Should we just take a moment and hear it for science moms?

CONOR: Yeah, that's absolutely yes, that's a hashtag, we should make it. Maybe it is one, maybe, yeah. So why does Tim think that oligo therapies, for example, are a good option for people like Nikki?

TIM YU: Here's one way to think of it. In the past, we've devoted huge amounts of effort to sequencing the human genome, in order to set out a roadmap for disease. And the sequencing of the human genome was completed in 2002-2003. And what that allowed us to do is to take diseases that we were trying to study and to pinpoint the genes that were responsible for them. And then to use that knowledge to build a model of the disease from a cell, or perhaps a mouse or some other animal model organism that we could use to study the disease better. However, when it came to actually trying to fix that disease, we were still using the relatively older methods of developing small molecule synthetics, to use to treat these, for instance, diseased mice or other mouse models - to find the treatment. What we've all been waiting for, is the opportunity to use the knowledge that came from the sequencing of the human genome, to not just build a better model, but to build a better drug. That idea, I think, was apparent to folks 30 years ago, but it's only begun to come into fruition in the last five years. Where the tools for deciphering the genome have now gotten to the point where we can actually modify how the genome works. And this is the new wave that we're seeing right now.

DODI: I told Tim about Nikki and about Roy from our previous episode on oligos. And how exciting it is to hear about progress in these kids after treatment they've been going through and Tim agreed, of course, 100%

TIM YU: It is really, truly exciting. And I think that I'm in the health industry, I'm a scientist and a professional neurologist. And I think that excitement that you just referenced, we all feel that same excitement, too. When those first results began being presented in professional conferences, and then coming out and in print, we were thrilled. And what we were seeing, what we're thrilled about was the fulfillment of this promise, the first blood so to speak, demonstrating that this promise that we have all invested, in many cases, many of our careers, banking on this coming around the corner, we were seeing this first success roll out into clinic and help our patients, and we really couldn't be more thrilled.

CONOR: So super exciting. I agree. Can it get more exciting?

TIM YU: We're in the very early stages of seeing these gene therapies and oligonucleotide therapies roll out. And already the successes that we've seen underscore how important and game changing this is going to be to our field. We ourselves have been in the lucky position to closely follow in the footsteps of Spinraza™ to design an oligonucleotide therapy for a young girl that had a fatal neurodegenerative condition called Batten disease. And in that project, our laboratory following similar footsteps to scientists that had developed Spinraza, we identified the genetic mutation in a young 6 year old who's losing her ability to speak, her ability to walk and having progressively worse seizures - we were able to isolate her particular gene mutation that diagnosed her with something called CLN7 Batten disease. And we were able to use oligonucleotide, antisense oligonucleotides to custom make a drug for her and treat her with it with significant improvement in her quality of life. I think that the fact that we've gone from a first example, with SMA to correct an underlying gene defect, for a condition that affects 10s of 1000s of patients. And then, with just a few years turnaround, be able to use that technology to develop a therapy for a young child with the disorder who had a particular mutation that's actually only found in her. So we've gone from a drug for 10s of 1000s to a drug for 1. I think that just shows how much potential this field has. And as we get better and better with these tools, I think we're going to be seeing this type of technology rollout for a whole span of diseases, ranging into those diseases that were always considered too rare for drug companies to go after them in a sustainable way. And that concept gives a lot of hope to a lot of families that are coming into our clinics, who up to this point had been patiently waiting their turn.

DODI: And you know, before we release this episode, we had spoken to Nikki a year ago, and we just called her back just before this episode to check back in and see how things were going.

NIKKI: Hi, so nice to talk with you again!

DODI: And we want to find out a little bit more about next steps and research. We asked Nikki, what would she say to anybody who is researching or experiencing living with a rare disease?

NIKKI: I would say that when we as parents receive, you know that devastating diagnosis that kind of turns our world upside down, we definitely need all the education and expert advice we could get, all the knowledge, we also need a dose of hope. And that's what I hear so many rare disease parents talk about is that sometimes they walk away from appointments, and diagnoses, feeling like there is no hope. And they desperately need that to move forward. It's what helps them get up each day and go to the therapies and what helps them look into the research, what helps them learn the best care practices. And that's actually what moves the needle for all of us. Having the researchers push from their end, the doctors pushing from their end, parents pushing from their end, it's all of us, it's a collaborative effort of us all doing what we can with what we have in the space we're in to move the research forward for rare diseases. And so I would say that what I've learned is that this really is a collaborative effort. And that we all need that sense of hope, because that's what drives change. And so that's the big, the biggest thing I've taken away with us: a sense of courage, collaboration, and hope.

CONOR: And that's tough, right? courage and collaboration and hope, when it's not a disease that the whole of the healthcare community seems to be focused on.

DODI: Completely right. And with that mantra in mind, Nikki set up www.raremamas.com, which is going to be in our show notes. It's an online resource for families of children with rare diseases. And the idea is to empower these families to go from distress to prowess, as she says, it's super awesome.

NIKKI: Rare Mamas is, is really just my passion. It's really become my purpose from the pain, going through my experience with Miles, my journey with Miles. I just kept thinking about these other mothers out there going through, you know, a rare diagnosis for their child and those feelings of isolation and aloneness, that can creep in so quickly. And because so many rare diseases are small populations, and because so many of them don't have organizations and foundations, those families have to dig so much deeper and harder to find other support. And so, I wanted to have a place where moms could come and find that support.

DODI: And on raremamas.com there's everything that Nikki wishes she would have known when Miles was 18 months old and newly diagnosed.

NIKKI: It offers practical tips and tools for everyday living, there's a lot of encouragement. There's a lot of information about the mindset we need to have, as we're rare disease parents in order to fight this fight. It's just everything I feel like will help these moms on their path forward.

CONOR: And that is just great. And it's fantastic that is coming from somebody with the experience rather than just from the medical community, as it were. So what does she see in the immediate future?

DODI: She's hoping that as science progresses, that the recipe of courage, collaboration and hope continues to get used.

NIKKI: because I really do think that it's the best recipe for change.

CONOR: This has been, you know, a lovely continuation of the previous story, because it's an ignored area, oligos. And they're focused on rare diseases, and they don't get as much press as maybe they should, because it is very niche. Isn't it, Dodi?

DODI: Its niche. It's important. It's impactful. I'm not sure if I would say ignored but easily overlooked because we are still living with this pandemic. But there are still conditions that need the attention of the scientific, the research, the healthcare community.

CONOR: Core science must go on, despite the immediate focus of what we're dealing with today. Absolutely, exactly.

DODI: So thank you, Nikki, for your story. And thanks again to the family of Roy, for the story and for the update. And thank you listener for joining us for this episode of Discovery Matters.

CONOR:That’s right, recommend us to your friends, rate us wherever you get your podcasts and we'll see you next time.

DODI: Our executive producer is Andrea Kilin. Discovery Matters is produced in collaboration with SoundTelling. This episode was produced by Tanvir Mansur and Thomas Henley. Music by Thomas Henley.

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