How a Family Raced from Diagnosis to Experimental Gene Therapy in Three Years

Michael Pirovolakis, a four-year-old with the ultra-rare, neurodevelopmental condition SPG50 disease, earlier this year became the first person to be dosed with an experimental gene therapy developed to treat the disorder. The gene therapy was the result of a relentless pursuit by his parents, Terry and Georgia, to raise money and engage scientists and others in the development of a treatment for SPG50. We spoke to Michael’s father and founder of CureSPG50 Terry Pirovolakis and associate professor at UT Southwestern Medical Center Steven Gray, about SPG50, the work to develop and advance an experimental gene therapy for the condition into the clinic, and why Pirovolakis says his work is not yet done.

Daniel Levine: Terry, Steve. Thanks for joining us.

Terry Pirovolakis: Thank you.

Steven Gray: Dan, great to be here.

Daniel Levine: We’re going to talk about the ultra-rare neurodegenerative condition, SPG50, the work the two of you have done to advance an experimental therapy into the clinic, and where we go from here. Terry, perhaps we can start with your son Michael. Listeners may remember an episode we did with you early in your journey. How did Michael come to be diagnosed with SPG50?

Terry Pirovolakis: Around six months of age, Michael wasn’t lifting his hands. He wasn’t reaching his milestones and my wife noticed something was going on, so we went to the doctor’s office and they were like, you know, “he’ll catch up, don’t worry about it.” So then, what happened was we waited about 12 months, well, nine months actually, and he still wasn’t raising his hands and they started noticing that he was starting to get microcephaly, a slowing down of his head growth. And then around 12 months of age, we were in the infectious disease unit because I was in Latin America and they thought he had Zika or CMV. Those came back negative and we got transferred to neurology. They did a bunch of panels and a bunch of tests and they found that he had the thinning of the corpus collosum, to an MRI. All the panels came back negative and then they did a WES report and on April 2nd, 2019, he was diagnosed with SPG50.

Daniel Levine: And what is SPG50? How does it manifest itself and progress?

Terry Pirovolakis: Yeah, so SPG type 50, basically what happens is it’s a slowly progressing paralysis of spasticity that starts in the toes and it works its way up in the first decade of life to the waist and the second and third decade of life up to the shoulders and the arms and causes severe cognition impairment.

Daniel Levine: This is an ultra-rare condition. What were you told about it? When Michael was diagnosed?

Terry Pirovolakis: We were told that there’s less than 50 kids in the world, that they really knew nothing about the disease other than it causes severe cognition delays and growth and developmental delays. And that was it. They said, go home, love him, do physiotherapy and that kind of stuff, but there’s very little that we know about it.

Daniel Levine: It’s remarkable to think about the speed at which you were able to work to get a gene therapy developed and Michael dosed, but how did you come to work with Steve?

Terry Pirovolakis: So, I went to a conference called ASGCT in Boston and I met with six of the seven world experts. I met the NIH, the FDA, and a bunch of companies, and actually, Dr. Gray won an award that day that was for, I think, it was geneticist of the year. And right after that presentation, he was kind enough to meet with me and I pleaded with him to take on the program because he was super busy with other ones, obviously, and he agreed to, and that’s where this journey started.

Daniel Levine: Steve, many of our listeners will be familiar with you and your work to develop gene therapies for ultra-rare conditions. What led you to believe a gene therapy was a viable strategy for SPG50?

Steven Gray: Yeah, we looked at SPG50 like we’d look at a lot of other diseases and genes and there are certain characteristics of it that looked like it might be amenable to gene therapy. I think the size of the gene, worries about over-expression or under-expression seemed favorable, and I think that the type of the disease itself kind of matched somewhat other disorders that we’d had success with. So, all in all, it looked like it could be a good candidate for gene therapy. And really, Terry was very convincing as being a good partner on the patient advocacy side and we decided to take the leap.

Daniel Levine: What does it take to move a gene therapy from concept to a clinical trial in the context of an ultra-rare condition?

Steven Gray: It’s a long and difficult road. I think that this went relatively quickly for SPG50, but you need certain pieces in place. You need an appropriate animal model or cell models to test a treatment. And you’ve got to initially design your best idea of what that gene therapy approach could look like. It really helps if you can lean on past experience and past successful programs to guide that design and initial approach and then this combination of you’re trying to do studies to test whether that treatment is effective in kind preclinical models—cells and animals, and at the same time, you’re trying to gauge, the safety of it. Then that leads into, if you do see positive treatment results in the laboratory, then doing formal toxicology studies, which is where the cost starts to increase substantially. And then, really the biggest limitation is typically around the manufacturing of the drug. It’s sometimes hard to find access to manufacturing facilities and it’s incredibly expensive. But Terry’s organization was just an unbelievable partner in that whole process and he opened doors and made things happen. That’s really very unique. Then, after you do all that, if all of the safety and efficacy studies look favorable and you’re able to manufacture the drug, then it’s a process of applying to the regulatory agencies and getting permission to start the clinical trial.

Daniel Levine: Terry, I want to follow up on that with you and the things you did. But before that, Steve, are there ways you’ve been able to compress the time? Are there common vectors you’re using for neurological diseases or other things you’re able to do to speed the development of a gene therapy?

Steven Gray: Oh, yes, absolutely. I mean my lab and other labs have been developing approaches and moving them into clinical trials, taken a similar approach. So, in the past, we had initial experience with a disease called giant axonal neuropathy. We moved that into clinical trials in 2015 using a AAV9 vector. And the approach that we took for SPG50 was almost a copy and paste from that in terms of the overall design and then the pathway from concept to clinic. So, we really relied on that past experience and yeah, I think that kept us from having to go down uncharted paths, fail, restart. We were basically able to chart a path from the beginning and follow it, and luck was with us that we didn’t really reach any insurmountable hurdles.

Daniel Levine: So how long did it actually take you from the time you started working on this to getting an IND?

Steven Gray: So, this started actually with a clinical trial agreement in Canada with Health Canada, rather than an IND with the FDA, but from concept, like that first conversation with Terry, to dosing the first patient was less than a year—sorry, less than three years.

Daniel Levine: Still. Amazing.

Steven Gray: I think in the field of any kind of drug development, that’s kind of lightning fast.

Daniel Levine: Terry, what were the things you were able to do to open doors and get the process accelerated?

Terry Pirovolakis: You know, we did a lot of investigating and finding the right teams, and when we found the right team, we would usually go to the CEO or someone very senior and explain that time is of the essence, that we’re not a company, that we’re moving very fast and we need their help. And always, we got a responsive “absolutely we’re here to help you.” An example was we applied to Health Canada, and they came back and were adamant that we use a larger animal. We were on the phone pretty much right after the call was done and in two months we were starting a larger animal study. Other things that we did are we took a lot of financial risk. So, before the efficacy animals were even dosed, we were starting our rat tox in the GLP lab. Before we even finished or started our non-human primate or our larger animal study, we had manufactured our clinical batch. So, we took a lot of financial risks, but we never took any safety risks or shortcuts. Everything that we did was a discussion between me and Dr. Gray and the team. We decided what was the best course of action and nothing was done with a single decision. I think that’s the most important thing: that we were aligned along the way. And if Dr. Gray felt that I was doing something that didn’t seem to work, or this partner was the wrong partner, we just moved on. Right. And that was extremely successful. And on top of that during COVID, the team didn’t stop. I mean, we could have shut down, they could have shut down the animal core, like a lot of other labs did, but they went in every day to continue to work. And that’s a testament to how dedicated the team was.

Steven Gray: Well, I was just going to jump in and really emphasize the point that Terry made because, he did take a lot of risks. I mean, they were calculated risks, but they were financial risks and the traditional sort of safe approach is to do one step, wait for the results, do the next step, wait for the results and so on, and so forth. And that way you can cut your losses and kind of restart, before you get to the biggest ticket costs. In this case, a lot of things went in parallel and we’re lucky that it came out good and we were able to move forward, but I mean, it also could have ended in disaster if we had findings in our toxicology studies that stopped us going forward, and then we essentially had to would’ve had to discard a whole GMP drug batch and start over.

Daniel Levine: Despite the financial risk, you were able to do this for what I would say is a jaw dropping amount. Terry, how much did you raise? How did you go about raising money and what did it ultimately cost to do what you did?

Terry Pirovolakis: Yeah, so we had an amazing team of support in my local community. I mean, we had people set up golf tournaments and galas and barbecues and lemonade stands, and we just showed up. We didn’t organize any of these events. And then people were putting out lawn signs with Cure SPG50 in the front of the street. And we just had an amazing group of people. Then our story went viral and we had 23,000 donations from around the world and then what happened was that allowed us to not have to worry about things until we got very serious. At one point we had to manufacture or lose a slot for a year. And we were very fortunate that a silent donor gave us $800,000 to continue because he felt that our program was doing everything correctly.  Then when we got to toxicology, again we were stuck. We couldn’t raise the money fast enough, and we found a partner that needed the data anyways, or felt that the value of the data would be acceptable and they paid for our tox program. So, we were very fortunate, like Dr. Gray saying, we had a lot of luck and we had a lot of amazing people and we made a lot of good decisions along the way, and everything just fell into place. And we were able to move forward.

Daniel Levine: Well, give listeners a sense of the range of scientific and technical talent you needed to engage to carry this through.

Terry Pirovolakis: Well, we needed about three and a half million dollars in total. And we needed a team of hundreds of people. People think that the scientists and everybody else are important, but everybody along this food chain as I call it is important. For example, we were shipping a tox batch from Spain to Quebec, and it went through Texas during the snowstorm and trying to get a hold of someone in the shipping group to say, “hey, you need to replenish this dry ice for the next four days” or we’re going to lose this batch of product that will take months to remake, and the gentleman at Charles River that manages shipping was on the phone for hours talking to them, making sure that someone replenished it and then called back every day for confirmation. This is the type of dedication that is along the whole pipeline that you have to get to, because if you lose anything along the way, you’re set back potentially a year. Right. So, we were just fortunate. We had this amazing group of people that just fully understood that we’re trying to save kids, not Michael, but kids, right.

Daniel Levine: Michael was treated with the experimental gene therapy as the first patient in a clinical trial. How was the gene therapy administered?

Steven Gray: So again, this is pulling on the precedent of a protocol that we developed for giant axonal neuropathy and started seven years ago in 2015. And it’s basically injecting the viral vector, the AAV vector, into the cerebral spinal fluid. And we’ve been doing it via a lumbar puncture. So it’s similar to a spinal tap and there are other clinical trials that are injecting into the same fluid space, kind of by other routes, but that’s the approach that we’re taking.

Daniel Levine: And this is a viral vector you’re using. So, you get one shot at it. How do you go about determining proper dosing?

Steven Gray: Yeah, all that starts with the laboratory studies and animals where you’re testing a range of doses in an animal model of the disease to find what the minimum therapeutic dose is. Then you’re also doing the same thing in formal toxicology studies, kind of seeing what’s the highest safe dose that you can go to. So, you look at that, you try to mesh that effective dose with the safe dose and ultimately, extrapolate from the animals to humans and that sets your human dose.

Daniel Levine: Is the expectation that in a best case scenario, this will halt the condition, or is there reason to think it might actually reverse progression?

Steven Gray: Well, I can only speak to our animal studies, so far in the mouse model of SPG50. In those studies, we showed significant preservation of a lot of their motor function, their movement. Those studies are still ongoing for the end of the life of the mice. But out to a year, I think things have looked pretty encouraging. It’s always difficult to compare mice to humans. I think that we’re encouraged that there should be a benefit, but that’s also when we start treating humans, that’s the experiment too.

Daniel Levine: Terry, when was Michael treated and has there been any noticeable change yet?

Terry Pirovolakis: Yeah, what we did was we actually applied at both regulators at the same time because we wanted to treat more kids, but Michael was treated in Toronto Sick Kids Hospital on March 24^th, and we’re seeing some things, but I think the reality is because he is on a really strict immunosuppressant regimen you don’t know if it’s the drug that’s causing a reduction in inflammation in the brain or the steroids that he is on. So, it’s really hard to tell at this point what those gains are and if they’re because of other things, but we’re optimistic that things will improve.

Daniel Levine: Michael will be monitored for five years. How will you go about measuring the effectiveness of the gene therapy?

Terry Pirovolakis: Yeah. So, what we’re going to be doing is we’re going to be doing various efficacy endpoints, such as the MAS and Tardieu scale, which monitor spasticity and reflexes of the spasticity. And we’re also going be doing the Baileys and the [indistinguishable] scale in order for us to determine if there’s any cognition improvements, and then obviously safety. So, we come back every three months for the first 18 months for sick kids, and then every year after that for the next five years, and then there is some extension of that for the next 15 years.

Daniel Levine: Cure SPG50 received a rare pediatric disease designation for the gene therapy. You could continue treating kids through a clinical trial. How does the potential to get a priority review voucher change your strategy or the opportunity to potentially find a commercial partner?

Terry Pirovolakis: Well, the PRV helps you in order for you to figure out if you can make more drug or if you can create partnerships. We’re doing this as Cure SPG50 sponsor. We created six doses today. We have another batch being made, which is going to be a total of 10, thanks to the Columbus Children’s Foundation and Viralgen, who has been an amazing partner. And we’re hoping that this clinical trial will start in October, November. We got approval from the FDA August 11th to proceed with this clinical trial and our goal is to show efficacy over the 10 children and then hopefully to get that approved fully because the reality is there is no commercial partner that’s going to take on a program for 87 kids worldwide with nine in the U.S., considering we’re going to dose 10 altogether. So, we don’t have that many attempts and funding to get this going. We need to try to get it through one shot.

Daniel Levine: Steve, as people think about developing gene therapies for ultra-rare conditions like SPG50, is there an opportunity to scale that work?

Steven Gray: Yeah, I think that this is what the NIH has been trying to wrestle with, even the FDA has been weighing in and trying to help figure this out. And programs have been rolling out at the federal level to just try to start addressing that. But it’s a very, very difficult problem, because I’d say, 90-95 percent of the rare diseases out there have too few patients to really fit into the current commercial models. So, I think that the best that we can try to tackle that problem is to provide examples of hopefully successful therapies that can serve as a roadmap for others to follow just like we did with GAN and SPG50 carrying that torch behind it, and hopefully use platform type of approaches where we can copy and paste a lot to make things move smoother and faster. Hopefully over time, the regulatory burdens may come down. I think that there’s a lot of innovative thinking going on in terms of how to bring those treatments to patients maybe outside of the current commercial models or thinking up new commercial models.

Daniel Levine: Time is such a critical factor in progressive diseases like Michael’s. Are there barriers you think can be eliminated, ways to accelerate the process further?

Steven Gray: Yeah. There’s certain aspects, when you look at the safety and the efficacy in all of your laboratory studies, I don’t think that there’s really good ways to shortcut that because you have to show, even though it can be the same vector, it can be the same approach. You know, every gene is different. Every gene can have different levels of toxicity, and every disease might have different targets that sort of determine efficacy. So, unfortunately those are steps that just have to be done and those take time. But the things that hopefully can bring down the barriers are maybe to make improvements on the manufacturing in terms of access and cost and standard ability, because right now I’d say the drug manufacturer is probably the biggest barrier to a lot of these treatments moving forward.

Terry Pirovolakis: I also think like what Dr. Gray and Dr. Chen are doing, which is publishing all the data is also extremely important because a lot of these are being made by companies and they’re not going to publish the data, whereas if we continue publishing the data and showing our safety, our efficacy, then other programs can use that data to help move along their programs. So, maybe not in a direct way of saying, you’re going to take a transgene and just put into a different capsid, or the same capsid to put in a different slot. At least you can have the data to reference and say, look, we’re using the same promoter. And we did a rat and we’re seeing the same exact data and maybe will not need a larger animal, you know? So, I think what Dr. Gray and what Dr. Chen did by publishing this data will be extremely helpful in the industry.

Steven Gray: Yeah, and maybe I’ll follow up on that, because I think that’s good for bringing that up because it’s so important. We started a clinical trial for something called CLN7 Batten disease about a year and a half ago. And when we published all of the preclinical data, we included the toxicology report from our pivotal toxicology study as supplemental data in that paper. So, we basically published our complete set of efficacy and safety data and made it clear that was the entire package that went in for IND. So, I think that kind of serves as a very concrete roadmap for other people to follow, and even the design of a toxicology study and everything, how we did it, and we’re doing the same thing for SPG50.

Daniel Levine: I want to ask each of you for one final piece of advice. Steve, for advocates looking to engage a researcher like you, what advice would you give them for how to go about that?

Steven Gray: Oh boy. I think one of the interaction with Terry and Cure SPG50. I think that this can be held up as an example of how to do this, where it really does take a good partnership. Terry let me really focus on the research and moving everything forward and he handled all the fundraising. We never spent any time trying to write external grants and he was very active in engaging some of the contract research organizations, the manufacturers, so that my lab could really just focus on the technical aspects of moving this forward. And I think that the other piece of advice is try to organize your patient community. Cure SPG50 benefited a lot because there’s a group at Boston Children’s Hospital that’s been doing a natural history study on this disease for years. Most rare diseases don’t have that benefit. And I think the second best thing that they can do is organize the patient community, put together some type of a registry to at least start gathering information about the disease that can help with the eventual design of the clinical trial.

Daniel Levine: And Terry, what have you learned from this whole process that you would now use to advise other patient advocates looking to follow in your footsteps?

Terry Pirovolakis: Yeah. I get a phone call every week from a parent somewhere in the world and I spend about an hour or two on each of them. I tell them what they need to do and I kind of guide them and I tell them how dedicated they are. You have to be willing to give up your life, sell your home, do whatever you need to do to get this treatment going. And it may not even pay off, right? That’s the reality of it. And Dr. Gray set these ground rules to me at the very beginning and I understood them. I accepted them and we moved forward and there was never a question around them. Those rules are my commitment, because I would’ve sold my whole house in an instant, even if it was a slim chance. But what I do is, I walk them through it and I help them out and we find labs that are taking them in and I only move forward with programs and help them if they’re dedicated. And usually what happens is I’ll tell them this story and I’ll walk them through it. And then one out of the 10 people will call me back that are seriously committed to doing so. And I think that the reality is if it can fit into an AAV9 or people think it can be done and you really work super hard and you learn what you need to learn, you don’t have to be an expert in everything. We’re not doctors or scientists, we’re troubleshooters, right? And if we can clear the roadblocks for people like Dr. Gray so he can focus on what they need to do, and we can clear the path forward, we will see a treatment. And what I hope people will see from this is when we did this, we had a patient community, but no one helped us. Not a single family helped us, but we still made 10 doses. And I think if you’re listening to this and there’s a patient community out there and you’re thinking it’s research, there’s no way it’s ever going to happen, you can use me as an example. And if you jump on and you help that family out and it’s two or three or four families, you’re much stronger than an individual and you can actually see these therapies through. I think if that happens to one, two, 10, 20 programs, it’s going to be an influx of Terrys, and CLN7, and these amazing people that I followed in my footsteps to do my therapy.

Steven Gray: Yeah. And I just have to throw in, I think in our first meeting, Terry, I specifically told you don’t sell your house.

Terry Pirovolakis: Yeah. And on top of that, you also told me, we don’t do N-of-ones. And I took that to heart. And through this entire journey, it’s been Cure SPG50 journey to cure Michael, but the journey to cure Michael was meant to be a rally cry in Toronto. It was supposed to be “journey to cure Peter, or Samantha.” But I appreciated that Dr. Gray was like, we’re not going to do this for one kid. We’re going to do it for as many as we can, and that’s where we’re at now. Our goal is to treat as many as we can and move this forward so that every kid can see it.

Daniel Levine: Terry Pirovolakis, founder of cure S G 50 and Steven Gray, associate professor at UT Southwestern Medical Center. Terry, Steven, thanks so much for your time.

Terry Pirovolakis: Thank you.

Steven Gray: Thank you so much.