How an Ultra-Rare Disease Patient Foundation Advanced a Gene Therapy

Multiple sulfatase deficiency is a rare and progressive neurodegenerative disease. The patient advocacy organization United MSD Foundation has been able to advance a gene therapy into preclinical development for the ultra-rare condition through modest investment by pursuing a focused research strategy and leveraging partnerships. In May 2023, The Bespoke Gene Therapy Consortium, the National Institutes of Health-led public-private partnership selected the program for its clinical trial portfolio and will fund a phase 1/2 clinical trial for the therapy. We spoke to United MSD Foundation Executive Director Sarah Cortell Vandryspen, and UT Southwestern Gene Therapy Core Director Steven Gray, about United MSD Foundation’s research strategy, what enabled it to advance a gene therapy as fast as it did, and what other patient organizations can learn from its success.

Daniel Levine: Sarah, Steven, thanks for joining us.

Sarah Cortell Vandryspen: Happy to be here.

Steven Gray: Yeah, thank you.

Daniel Levine: We’re going to talk about the rare progressive neurodegenerative disease, multiple sulfatase deficiency, United MSD Foundation, and how through a relatively small investment, it’s been able to advance the gene therapy into preclinical development. Before we talk about this work though, let’s start with MSD, Sarah, for listeners not familiar with the condition, what is it?

Sarah Cortell Vandryspen: Yeah, multiple sulfatase deficiency, or MSD, is an ultra-rare autosomal recessive genetic disease that affects children. It’s a lysosomal storage disease, meaning the body does not break down and filter out the natural cellular waste that occurs in everyday cell functions. And this leads to the regression of every body system. So while it’s a neurological disease, it impacts nearly every bodily system there is. And additionally, MSD is a leukodystrophy, meaning that it significantly impacts the brain.

Daniel Levine: And how does it manifest itself and progress?

Sarah Cortell Vandryspen: So, our kids are typically without any symptoms at birth, but depending on their specific genetic variance, signs of MSD can begin either soon after children are born or later in the children’s life. MSD can vary in severity, with more severe cases presenting earlier in life and progressing more quickly. But we also have attenuated forms that present later in life and progress more slowly. So, we really have this spectrum, although traditionally, MSD has talked about three subtypes: neonatal, late infantile, and juvenile. And so what we see, the neonatal, which is the most severe form, is present sometimes in utero or at birth. And these kids worsen very quickly and often pass away within the first two years of their life. The late infantile form is the most common form of MSD. These children often begin life with normal cognitive and motor development, but begin to have delays in meeting milestones and begin to lose skills previously learned around 18 months of age. And this is normally when parents and then pediatricians start to pick up that there’s something wrong with these kids. And often at this point, there’s usually a diagnosis. And then the juvenile form of MSD is the rarest, at least that we know of at this point. And I could talk forever about newborn screening and our natural history study that we have ongoing. But with these kids, the juvenile form often develops much later. They don’t show signs or symptoms until middle to late childhood, and they lose skills much more slowly than children with other subtypes of MSD. But the clinical symptoms of MSD include global developmental delays, metabolic issues including growth delays, muscular skeletal problems, including short stature, low muscle tone, mobility issues, stiff joints. We see feeding difficulties and airway obstructions. Scaly skin is common among all our kids. for spatial features, loss of vision, that’s among other things. But those are some really common shared symptoms of MSD.

Daniel Levine: And how’s the condition generally treated today?

Sarah Cortell Vandryspen: Yeah, there’s no treatment or cure for MSD, so everything is focused on symptomatic management. In 2018, a team of international MSD experts published clinical care guidelines, and those guidelines help our families and their care providers provide the best care that we can as we continue to invest in research and push towards some kind of therapy.

Daniel Levine: How did you come to work with Steven?

Sarah Cortell Vandryspen: Yeah, so it was actually our organization’s founder, Amber Olsen, who was the one that tracked down Steven when he was at UNC Chapel Hill. So Steven, maybe it would be best for you to tell the story.

Steven Gray: Yeah, this was something where Amber Olsen had kind of been referred to the work that we were doing with other conditions, and she arranged a meeting with me when I was at UNC Chapel Hill, and I think my initial feedback to her was, we’ve got too much on our plate. We can’t help you with this, even though it looks like it might be a good candidate for gene therapy. But in the end, we did, or we did agree and commit to helping them with the vector design and making that and helping them move forward with other collaborators.

Daniel Levine: Well, Steven, you’ve been involved in the discovery of several gene therapies for rare neurological conditions. We’ve had you on the show previously to discuss your work to develop a gene therapy for spastic paraplegia 50, as well as several other gene therapies that had been in development with Taysha Gene Therapies, which is now focusing on an experimental gene therapy for Rett syndrome, which you discovered as a researcher. What do you need to go from a disease to a gene therapy candidate?

Steven Gray: Yeah, I think it really starts with understanding the existing technology and how it can be applied. And so we go through a little bit of an algorithm, I guess you could call it that, to look at a disease and think, is there the possibility that we could intervene and change the course of the disease? And that, just in terms of how the disease progresses, a lot of it gets into technical details. Like how big is the gene? Will it fit in the vector? Do we have good animal models that we can test the therapy in? And also, are we concerned that overexpression of the gene might be toxic, which can complicate the development a lot. So it’s a number of factors that kind of come together. And then a lot of it has to do with, is there a good partner in the patient advocacy realm, which in this case, Amber Olsen was a good partner, and the United MSD Foundation was a good partner.

Daniel Levine: The experimental therapy is using an AAV9 vector, which you’ve used in other neurological diseases. What’s the advantage of using that same vector over and over?

Steven Gray: Yeah, and this is just to put things in context. When we first started looking at this, it wasn’t looking at a treatment for this disease in isolation. It was really following on a lot of work that we had done with AAV9 and others had done with AAV9, which really created a wealth of literature and a wealth of data on where does the virus go, what doses should we use, what’s the safety profile of the vector by itself? And so, in a sense, it provided a roadmap and a template for how we could use this same vector and apply it to this other disease, MSD. So that really saves you, I think it helps eliminate a lot of unknowns from day one and lets you focus on a known path. And then I think there’s certain aspects of this—preclinical studies along the way—that you can kind of abbreviate and rely on that wealth of past data from other applications.

Daniel Levine: I know you’ve worked with, I’m sorry, I’m going to start this over. How did your work with United MSD set the stage for pursuing a gene therapy? Were you involved in the effort to develop an animal model, registry, biobank, or natural history?

Steven Gray: Yeah, so I really didn’t have any involvement directly with the United MSD Foundation at the outset of this. They approached me really specifically around could the gene therapy technology that we’ve been working with for other diseases, could that apply to this and could we help them develop a treatment and take it forward? But once I took an interest in this and became involved with it, I realized there was really a huge wealth of resources the researchers and the advocacy groups had been building around this disease. So there was animal model. It wasn’t perfect, but it existed. There were patient samples and work that had been done on biomarkers. There was a natural history study that was ongoing in collaboration between CHOP and a group in Germany. So it was really, there were a lot of pieces in place that made it so that the work that we might be doing could proceed faster. And if we had something that looked like it could move towards a clinical trial, then that clinical trial would’ve a better chance of being successful.

Daniel Levine: CHOP is the Children’s Hospital of Philadelphia. I know you worked with researchers there to help advance the gene therapy from preclinical studies to the clinic. Did you provide any input on the design of the clinical trial?

Steven Gray: Yeah. This was because I had been involved with other related clinical trials where you have to deal with immunosuppression strategies and safety assessments and thinking about how to administer the drug and logistical details. So, it was really a very collaborative effort, I’d say, mostly stemming from Children’s Hospital of Philadelphia, their team, and their deep expertise in the clinical presentation of MSD, and also their experience with other gene therapy trials that they had been involved with. So it was really combining that knowledge and comparing notes and taking the best of both worlds to put together really the best approach that we could take forward into a clinical trial.

Daniel Levine: And do you think there’s anything you’ve done differently with all that experience combined than you would’ve done, say, if this was a fresh out-of-the-box approach?

Steven Gray: Well, certainly if we had been trying to run it on our own, then I think it would’ve been focused a lot more purely on safety with some basic efficacy outcome measures. But because of all of the natural history data/biomarker data that had been gathered beforehand then, it really poised this to set up as a clinical trial that would have the best chance of capturing safety data as well as relevant efficacy data. So I guess to put that more simply, we’re getting the most out of every patient from the first patient in terms of data to show that the treatment is both safe and effective.

Daniel Levine: The Bespoke Gene Therapy Consortium, the NIH led public-private partnership that seeks to take a platform approach to gene therapies did select this as one of eight programs it’s pursuing. What has that meant to advancing this to the clinic?

Steven Gray: Well, it really provided a very clear and solid path to taking it into the clinic and doing so in a way that had input from world experts, industry groups, academic groups, and there’s a history with MSD where there have been companies that took an interest in it and then lost interest and kind of going from an academic effort to an industry effort and back. And so it’s been a bumpy road in terms of trying to take these steps to move it into a clinical trial. But I think becoming part of this Bespoke Gene Therapy Consortium, I think in one important aspect for the patients is, it’s happening, it’s going to happen, and it’s as guaranteed as it could be to happen. And I think the other benefit is now the MSD can contribute back to the rare disease community at large by taking all of the learnings from this translational effort and making that publicly available to help everybody else move their programs forward.

Daniel Levine: Sarah, United MSD lists its research investments on its website. It lists a total of $1.2 million in project that it’s funding. I think it would surprise most people that a gene therapy could be ready to enter the clinic on what’s a relatively small investment. What’s it taken to get here, and how have you leveraged partnerships to do that?

Sarah Cortell Vandryspen: Early on in our history, and we only started in 2016, so I think keep that in mind, we funded a variety of projects, but pretty quickly we zeroed in on gene therapy as a potential treatment option as MSD is caused by a single gene mutation. So, the bulk of funding went into a mouse model and toxicology, but we also funded important preclinical work that would be critical to any IND application, such as a natural history study, our biobank that we run in partnership with Genetic Alliance, which we’re very proud to say it’s helped to identify two biomarkers. And we have a patient registry. The Bespoke Gene Therapy Consortium award is paying for manufacturing and the phase 1/2 clinical trial. And I agree with everything Dr. Gray said that this award and bringing gene therapy to clinic is hope for our community. And partnerships have been absolutely key in leveraging that million dollars in investment. Having amazing scientists like Dr. Gray obviously helps. He was able to advise us on what was essential to be done in the toxicology study. So we didn’t overspend. Jackson Labs has been a wonderful partner on our early mouse studies. I’ll say, and I can’t speak to other rare disease communities, but our MSD experts are extremely collaborative. Even on our gene therapy project, we will have three different institutions adding in data, just the initial ones, plus the public-private partnerships, so the various departments from the NIH plus the private industry partners that are adding in their expertise. And if you think about this to a ultra-rare disease that is considered not commercially viable, no one wanted us, and we are now at the brink of potentially changing kids’ lives. And this is because of this really strong patient community. And I think this is also what’s really important that has made this so successful over the last seven years, is that we have incredible sister foundations, what we call sister foundations, that were founded by other MSD parents around the world. They helped to fundraise in their locales and invest in larger research projects. So while we say we’ve invested in over a million dollars, there’s other foundations that have also contributed hundreds of thousands of dollars to move research forward.

Daniel Levine: There are many patient groups like United MSD that would hope to see a gene therapy developed. What advice would each of you give for what patient organizations could do to pave the way for a gene therapy to be developed and advanced to the clinic in their own conditions?

Sarah Cortell Vandryspen: I’ll go from the nonprofit side, right? That’s my background. And what I would say is that you need to be sure that you develop a solid foundation for your organization. Put in those best practices for running your nonprofit organization, even if it’s a volunteer led with no paid staff, learn from other patient organizations about their growth, progress, mistakes, and wins. I have found that the rare disease community is so supportive. They’re willing to share and collaborate. So seek out those experts who know what they are doing. Amber found Dr. Gray and all those others that, I mean, literally some of our parents were chasing down experts at lysosomal storage conferences saying, please research MSD. And some of them said, okay, and gave their disease a chance. So, find those experts that know what they’re doing, everything from the preclinical space to patient engagement, to fundraising. Read, listen, attend conferences, ask questions. And this is the big thing: know that the timeline to clinic will never move fast enough. And I think Dr. Gray and I can agree on this, that even when you are right, you’re right at the door to clinic, right, moving, even moving to a gene therapy clinical trial, you’re right there. It will never move fast enough. But you can never stop pushing your patients. Our kids deserve it. So always be persistent. Always remind those that are working on your behalf, that there are people that are depending on them. So make it real. Share those stories because your patients, your kids, they deserve a chance.

Daniel Levine: Steven

Steven Gray: Yeah, and I guess I agree with everything that Sarah said, and maybe I’ll add from my perspective, is just, I guess, invest in the unity of your community. Try to keep the patient groups as organized, as cohesive as possible. So you’re working on a united front and also, as Sarah said, rely on the experts that are in your field. If you’re coming and you say, oh, I want to do gene therapy, and you seek out the gene therapy experts, well, you need to be looking at the disease experts in your field, the clinical experts in your field, the people that know the biology of it. And I think those people will be excited that somebody wants to help them move things into a treatment. And I hate that it’s kind of this way, but it’s educate yourself, understand what different pieces might be necessary. And you can educate yourself by asking experts, seeking them and asking. But if you’ve got your team of disease experts and clinicians that you’re assembling and you want to do a certain therapeutic modality, if nobody in your network really is an expert in that technology, then ask who is and seek them out and try to bring them in. And that’s really what pulled all of this together, and I think made it work, is there were some very, very committed clinicians and scientists that were studying this disease, and then they wanted to do gene therapy. They reached out to me. I said, I don’t have a mouse model for this, and I don’t have the bandwidth. So we sought out Jackson Laboratories, and then they were able to help out of doing work, developing the animal model, and doing all the dosing studies and everything. And it was a very, very open collaborative effort. And everybody was sharing information. And the patient foundations were really central to all of that. Funding is an obvious necessity, but in this case, United MSD, they didn’t have to fund everything all the way through a clinical trial. But I think that they were strategic. And one of the reasons why the grant, the application to the Bespoke Gene Therapy Consortium was successful is because the foundation had built that network of experts. They had built a strong scientific base, and they had spent their money very, very effectively. So that basically this could be presented through a grant mechanism to a company, to anything to make it very attractive that all the pieces were there. And I think that’s why it did attract some attention or some interest from companies. They turned away eventually because there weren’t enough patients. But I think that they became interested because all the pieces were there.

Daniel Levine: Sarah Cortell Vandryspen, executive director of the United MSD Foundation, and Steven Gray, associate professor at UT Southwestern Medical Center and director of the University’s translational gene therapy core. Sarah, Steven, thanks so much for your time today.

Sara Cortell Vandryspen: Thank you.

Steven Gray: Thank you so much for having us. This was good.

This transcript has been lightly edited for clarity and readability.

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