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Seventeen Minutes of Science: Rare Disease Drug Development

Tune in weekly to our virtual series “Seventeen Minutes of Science” every Tuesday at 11am PST / 2pm ET where we go live on Facebook with a new guest each week to talk about how science and biotechnology is woven into their lives for (you guessed it) 17 minutes!

For episode 43 of 17 Minutes of Science we are joined by Dr. Ethan Perlstein of Perlara PBC.

Dr. Perlstein is the CEO and founder of Perlara, a company on a mission to accelerate the discovery of cures for rare genetic diseases and uncover underlying mechanisms that enable the development of treatments that work across a range of diseases and individuals.

Ethan has been passionate about Rare Disease for more than a decade. Starting with PhD in Harvard’s Stuart Schreiber lab. Then, as a postdoctoral fellow in the Lewis-Sigler Institute at Princeton, Ethan has been championing finding new purpose in old drugs. 19 peer-reviewed has culminated in his involvement in multiple startups, all focusing on Rare Disease. He has become a tireless champion for helping families of Rare Disease to solve their Diagnostic Odyssey and find new drug. His big focus, how to you find the most cost efficiently repurpose old drugs for new use in Rare Disease.

Tune in to episode 43 to learn more about Dr. Perlstein, Perlara, and developing treatment options for rare diseases.


Dr. Chris Hopkins (Host): [00:00:10] Well, hello, thanks for attending this meeting today. Today, we’re going to have 17 minutes of science and we’re going to talk about some therapeutic discovery in rare disease. And my guest speaker is Dr. Ethan Perlstein. Hello, how’s it going?


Dr. Ethan Perlstein (Guest): [00:00:25] Hi Chris, thanks for having me on.


Dr. Chris Hopkins (Host): [00:00:26] Oh, it’s a pleasure. Well, I’d like to give everybody a little bit of background before I sort of start the timer on 17 minutes of Science. You know, Ethan, I’ve known for now for about a couple of years. We’ve been collaborating together a bit, you know, and I found that Ethan is incredibly passionate about rare disease. And he’s been in that space for more than a decade. He got his PhD at Harvard University in Stuart Schreiber’s lab. And then as a postdoc in the  Lewis-Sigler Institute at Princeton, Ethan was a champion for finding, repurposing and old drugs. And so he’s had 19 peer reviewed publications that are culminated in his involvement in the startups that focus in rare disease. You know, he’s become a tireless champion to help families in rare disease and help them solve their diagnostic odyssey by finding new drugs. And his big focus recently has been to find cost efficient methods to repurpose old drugs. So we’ll go through – Ethan, so your first question here, your first biotech back in 2014 was Perlara.


Dr. Ethan Perlstein (Guest): [00:01:30] Yep.


Dr. Chris Hopkins (Host): [00:01:31] You know, can you tell me a little about what that journey has been like and what you’ve learned on that journey?


Dr. Ethan Perlstein (Guest): [00:01:36] I learned so, so much. I mean, Perlara really started with a simple concept that the most entrepreneurial and most motivated families that are battling a long tail genetic disease make great business partners, even though those families don’t have any scientific background or, you know, didn’t want to be involved in in therapeutics, did not choose that fate. But they step up to the occasion and – you just see it over and over again where you talk to a parent, with a child with a genetic disease and it sounds like you’re often talking to a scientist who’s been studying this particular disease for their career. That’s how well, you know, these highly motivated families kind of soak up the science and just kind of step into this role that they didn’t ask to to be in. And so I kind of just realized that that would be, you know, they would be such great people to build businesses with and to do research with. And that was really the germ of Pelara. And the major learning was that you really can go quite a distance with the family that’s, you know, never been involved in R&D before. And in fact, you know, I think the biggest learning actually is that underestimating these families is sort of something you do at your peril and that, you know, pharma and the industry as a whole sort of looks at these cases as sort of edge cases and looks at these groups and families as well. You know, they’re just often some tiny little corner battling their disease. But I think underestimating them is a mistake. And I hope to kind of prove that that that highly motivated parents and families can become biotech entrepreneurs and company builders in their own right.


Dr. Chris Hopkins (Host): [00:03:27] That’s excellent and you know, I’ve observed the same thing with families, they’re incredibly passionate and it’s amazing to see the moms and dads get so educated that we’re getting informed as scientists know more about the subject matter often than we do.


Dr. Ethan Perlstein (Guest): [00:03:42] Right.


Dr. Chris Hopkins (Host): [00:03:42] Pretty amazing. Shout out to those family groups out there, amazing and passionate and we love what you’re doing. And, you know, we, Perlara and our company Invivo Biosystems, we’re passionate to help you and help you get there. You know, Ethan, can you tell me a little bit about sort of how you were doing this and creating these solutions, maybe even a little bit about your PMM2 example. Talk about how you went about that, how the model organisms helped you, how that sort of reduced the cost. You know, just give us a little bit about what’s the process that it takes for a family to go, “OK, I’m game, I want to play, I want to solve some disease. Let’s go.”


Dr. Ethan Perlstein (Guest): [00:04:28] Yeah. So you know, the cure odyssey, as I like to talk about, you know, kind of get started where you are able to create a set of patient avatars and so these would be simple model organisms where you can take specific genetic mutations and program them into these animals and create very specific versions of a disease, in fact, maybe even create a particular child’s version of a disease. And this is really, really useful in cases where, you know, you don’t have a mouse model. And when people talk about animal models, they almost always mean mouse models. Even though yeast and worms and flies are perfectly legitimate animals. But in the case of PMM2, phosphomannomutase deficiency, which is still, a you know, a rare disease. But, you know, it’s classified as an inborn error of metabolism. The challenge with PMM2, is that there was no viable mouse model. Like the mice were just embryonic, lethal. And so it was just very challenging to create. And then when they dialed in specific patient mutations that are common and in PMM2, then the mice kind of weren’t sick enough. So there was this problem of finding the just right kind of mouse model that was sick but not too sick. And and so what we did is just sort of flip the table and say, well, you know, PMM2, is a really old gene. It’s an ancient pathway. And you can you can kind of observe this pathway of glycosylation of protein. So sugar is being attached to proteins. That’s happening in a single celled yeast organism. It’s happening in all our cells at all times of life. And so taking advantage of that evolutionary conservation, we realize, OK, well, mice aren’t cooperating. Fine. Let’s start with yeast. And then and then they cooperated quite nicely. And then we moved up to kind of worms and we just go up the phylogenetic elevator here to more and more complex species. And then we found out that we didn’t even need to test a mouse. We had so much conviction based around this this drug that’s actually now in the clinic. And it’s a repurposed drug. As you said, we didn’t need a mouse model to give us a conviction. We were able to understand its mechanism. And because it was a known drug with a proven safety record, although not necessarily in kids, but we’ve now sort of said, OK, well, we’ll go to the patient because that’s the ultimate yes or no, or go or no go decision. And that that decision is proved to have worked out. And so sixteen months later, our first N of 1, our patient with PMM2, you know, is sort of experience amazing quality of life gains and is now sort of in a much stronger position and a higher baseline to start getting the next wave of therapies, because repurposing is just sort of a start. So, yeah, so making these patient avatars, you know, not fretting about not having a mouse model and saying “fine for some of these pathways that are super conserved, you can use simple organisms and you’ll do just fine” and you can even skip the mouse and you’re no worse for wear. So I think that that is kind of the example that I like to talk about, because it went all the way from yeast to the clinic. And it’s something that can be scaled because there are many other diseases that fit that profile of PMM2.


Dr. Chris Hopkins (Host): [00:07:31] Well, thank you for that great overview of this amazing success. You know, the success story got to these N of one trials. This is Maggie, right? She’s doing quite well. Can you tell us a little bit more about sort of how Maggie’s doing and maybe a little bit more about sort of the trials? I think they’re ongoing at Mayo. And you’ve got company now called Maggie’s Perl.


Dr. Ethan Perlstein (Guest): [00:07:55] Yeah.


Dr. Chris Hopkins (Host): [00:07:56] So tell us a little bit more about Maggie and her story and how this is helping other kids.


Dr. Ethan Perlstein (Guest): [00:08:01] Yes. So Maggie started getting this drug called epalrestat back in January of 2020. So while 2020 was sort of a pretty lousy year for the world, was actually a pretty solid year for Maggie. And she made many, many strides. So from real world evidence, you know, things like being able to compare videos of her sitting and doing kind of call and response exercises, learning exercises with her mom and noticing, you know, that she’s just sitting more stably. Normally, she was very unstable with her core. And then after three months of treatment, she was sort of able to sit for stretches of time without moving or jerking around and having core stability. So that was pretty interesting. She stopped face planting within, I think, even the first few days of taking the drug. And that was like the first sign that the parents noticed that something’s different, something’s going on. And it can’t just be explained by the natural history. Like, you know, kids don’t spontaneously just improve with with this disease. And then other things started to crop up like conversations Maggie wasn’t able to have before because she just didn’t produce the volume of words or was doing more kind of parroting speech. And she started to actually open up and have conversations. And her mom, her parents, described having legitimate conversations with their child kind of for the first time. And that’s something – I have a six year old and have always sort of taken that for granted. And then I have a 20 month old coming up behind him and just take for granted that, you know, they’ll reach these milestones. But, you know, that wasn’t the case for this disease and for many kids like that. Another piece of evidence was Maggie started to color. Before she didn’t really know how to color within the lines. It wasn’t even something she was able to do. Now she can spend a long period of time doing very careful drawings and is much more artistic, and has more artistic ability that my six year old, you know, who’s sort of sort of quote unquote, typical. So I think that all those pieces of evidence started to, you know, make it seem that the drug was doing something. And then we got like quantitative data to back it up. So in the case of this disease, there’s a marker called  transferrin, which is used to sort of diagnose the disease, actually. And that marker, that biomarker normalized. It went from the abnormal range to the normal range and it stayed there. Maggie’s weight has improved. She gained weight literally. And it’s part of a big challenge for these kids who would normally have to take in lots of calories and basically have a very difficult time of putting on weight. And now she’s got muscle mass and her braces, her orthotic braces weren’t fitting in. So all across the board, there were just improvements. From cognition to things that we can measure in her blood and things we can measure her urine and and so forth that told us that the drug is having a positive effect. Now, to be clear, it’s not a cure, but it’s certainly a major series of levels up from where she was pre-treatment. And we think it puts her body and mind in a position to then be more receptive to the next wave of therapies that we want coming down the pike. Because, again, this is just the beginning of a cure odyssey. And we, we’re off to a great start, but we’re by no means finished.


Dr. Chris Hopkins (Host): [00:11:09] That is excellent to hear about Maggie’s progress. That is fantastic. We have about five more minutes left. Maybe we can – to inspire the families that might be listening, let them kind of know where the journey is going to go. Like where are we going to go with Maggie’s Perl? You know, what are we going.


Dr. Ethan Perlstein (Guest): [00:11:27] Yeah.


Dr. Chris Hopkins (Host): [00:11:27] The other kids out there, how are we going to – you know, what’s going to be the next steps?


Dr. Ethan Perlstein (Guest): [00:11:32] Yeah, the next steps are currently underway. So we’re going to be hopefully able to launch a phase 2 v 3 trial, an open label study at Mayo Clinic, a single site under the direction of Dr. Eva Morava-Kozicz. And we hope to enroll up to 30 kids in this trial. We’re just finishing up the IND paperwork sort of as we speak and getting a hold of the drug supply and all those other things you have to do to actually go from an N of one to to a proper multi-patient IND. And so all that’s in the works right now, we’re really hopeful that we’ll be able to send off our IND very, very shortly. And if we get the green light within 30 days, which is sort of what the expectation would be, then we’ve already started to talk to families. In fact, we’ve been holding a series of virtual town hall meetings with interested PMM2 families to just go through what the trial would involve to to read, to retell Maggie’s journey. And so, yeah, we’re very excited that we’ve identified more than 30 PMM2 families already who who have expressed interest in their kids enrolling in this pediatric trial. So, yeah, we’re just getting all of our ducks in a row. And and we’re really hopeful that within the next four to six weeks, we’re able to announce that the trial has been given a green light and that we’ll begin dosing patients soon thereafter. So we’re very excited. And, of course, as you mentioned before, Maggie’s Perl is this entity that’s kind of now in place and that was always by design. So Perlara and Maggie’s Cure, which is the foundation, which is a not even a foundation, it’s just an LLC that the Carmichael family established to work with Perlara on a quest that has now essentially blossomed into this joint venture that we call Maggie’s Perl, which is owned by Maggie’s Cure and Perlara and also our partner, Mayo Clinic. We’re just wrapping up a deal with them that we’ll be able to formalize. And we’re very excited to have them as a partner, too. So, yeah, I would say stay tuned. You can follow Maggie’s Perl’s journey on Twitter at @eperlste. And we also have a Facebook page. And we’ll be just sort of going to the airwaves and social media to provide further announcements on Maggie’s Perl and as the eperlste trial comes together.


Dr. Chris Hopkins (Host): [00:13:50] Ok, excellent. I mean, it’s such an amazing win-win story that we’re getting here with the effort going forward, the progress with Maggie. Exciting to be hearing what’s going to go on with this trial with the kids. Hopefully all those kids will see this great movement. This is starting to happen in rare disease. This is pretty amazing. Seven thousand genes that are potentially involved in rare disease. And this is just one of them. You know, so for the families that are out there listening, they may be asking the question, you know, OK, well, great for that gene, but how about my gene, what are we going to do about mine? It’s likely that there’s going to be a lot of solution there. So we’ve got about two more minutes left. Perhaps you could just sort of say, you know, almost what would you suggest is the way to engage and to utilize the power of model organisms, simple model organisms as a tool to jumpstart and repurpose drugs and get cures out to these kids?


Dr. Ethan Perlstein (Guest): [00:14:45] I mean, another major learning of Perlara scientifically was that certain kinds of diseases were going to be better modeled in lower – and I hate using the word lower, but in simple and I even hate used the word simple, but in terms of flies and and yeast and so forth. So I think the first step you have to do, and this is all something you can look up online, is really understand whether your gene is one of these genes that’s very conserved evolutionarily. In other words, what’s going on in the yeast and in the worms and in the flies is pretty much at the cell level and even at molecular level what’s going on in humans. So I think that – what you can do is and I can tell you that inborn errors of metabolism, for example, are a group of genetic diseases that fit really well with model organisms and where model organisms really shine. So core metabolism, not so surprising. I guess. There are other there are other swathes of biology where there is really good kind of compatibility and model ability in these organisms. But there are also going to be diseases where we also learned that it’s probably – you’re barking up the wrong tree because there’s simply not enough evolutionary conservation. And that’s OK. So I would say for families out there, you know, there’s so much information at your fingertips. And I think the first thing you can establish is, is my gene and my path in a conservative pathway? Is my gene, part of a very ancient evolutionary conserved pathway such that I can model what’s going on pathologically in a simple organism and not lose out on what’s really going on in the human case? So I think that, you know, you can reach out to me. It’s up to you. We can kind of give you that yes or no assessment about a gene as to whether it looks like it’s it smells like it’s a good fit. Cause it’s still kind of art as much as it’s science at this stage. But I hope that that that process of selecting genes and understanding: are they compatible for model organisms? We can have essentially a combination of AI and OI (organic intelligence),tell us, you know, basically rendering a verdict to say we think this is a go or no go. And then people can kind of be empowered from there. And I would tell people if it’s not a good fit for your disease. That’s OK. There are other experimental modalities and treatment modalities that are out there besides small molecule repurposing, and there will be an individualized path for you. So don’t worry. And there are resources like us out there to help guide you in those early moments to make sure that you understand what your choices are. I hope that helps.


Dr. Chris Hopkins (Host): [00:17:13] Excellent. And we have pretty much burned up our 17 minutes of science, and I’d like to thank the audience for listening and I’d like to thank Ethan for an excellent session here. And thank you, everybody, for attending.


Dr. Ethan Perlstein (Guest): [00:17:27] Yeah. Thanks, Chris. Thanks for inviting me. And yeah, looking forward to any feedback people want to send, send, send my way. And of course Perlara and I we are working together. So yeah, we’d love to be able to consider families if they look like they’re fit so reach out. Don’t hesitate to reach out.


Dr. Chris Hopkins (Host): [00:17:41] Yeah. Please don’t hesitate to reach out to either Ethan or I, or our company IVB, we’d love to be there for you to see if we can help guide you to the to the cures that will help your kids. Thank you.


Dr. Ethan Perlstein (Guest): [00:17:54] Thanks, everybody. Have a great day.

About The Author

InVivo Biosystems

InVivo Biosystems provides essential services to help pharmaceutical, nutraceutical, biotechnology companies and academic research institutions around the globe accelerate their research and drug development efforts. An expert in CRISPR genome editing, InVivo Biosystems creates custom genome edited C. elegans and zebrafish models to enable aging and other disease studies. In addition, InVivo Biosystems provides in-vivo analytical services to produce data and insights for companies that need to make go/no-go decisions quickly in early-stage development of new compounds.

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