This week I am talking to Geri Landman, MD, MPH a pediatric urgent care physician, and Zach Landman, MD, MPH Interventional Pain Medicine Fellow at Stanford University. Their daughter Lucy (@lucythepgap3goose) has a rare single-gene disorder – she has two bad copies of the PGAP3 gene, one of the many genes involved in cell communication. In Lucy’s case, one tiny amino acid difference in one protein molecule (Phospholipase C).
Any parent will recognize the anguish of this and the challenge of finding answers, made especially hard in this case with the parents both physicians and mom a pediatrician. Their journey to a diagnosis was not straightforward and as you will hear involved a degree of luck with one of the neurologists they saw being trained in Neuro-genetics and ordering tests that ultimately confirmed her diagnosis.
Personalized Medicine for Everyone
While this condition is rare it represents a major part of our future of medicine and the next frontier of personalized medicine. Our understanding of the human body has moved from the very granular disease and organ-based approach to a much more individualized, cellular, and personalized breakdown of disease. We classify many or most cancers based on the organ affected in the body but it is becoming clear that cancer cells have their own taxonomy that is perhaps better built on the cell type. As our understanding improves we find ourselves dealing with smaller and smaller subsets of patient groups. From a treatment perspective that can mean that therapies developed may apply to smaller numbers of patients and diseases. Our current economic mechanisms and approach to therapies do not support this new frontier very well creating gaps in the resources necessary to advance research and we are in need of new models and approaches.
Listen in to hear how Geri and Zach describe the various treatment options open to Lucy and others like her and the work they have done to establish research organizations and accelerate the work to create not just a treatment for Lucy but for many other people. They are determined to create a new class of therapies and approval processes that would allow for accelerated development and use of individualized treatments that would expand access and bring down the costs to make it accessible to more people
Lucy turned one just recently and time is not on her side. They and Lucy need your help in any form – you can email info@moonshotsforunicorns.org and learn more from Moonshots for Unicorns and support Lucy, Geri, and Zach at Lucy’s GoFundMe page.
Listen live at 4:00 AM, 12:00 Noon, or 8:00 PM ET, Monday through Friday for the next week at HealthcareNOW Radio. After that, you can listen on demand (See podcast information below.) Join the conversation on Twitter at #TheIncrementalist.
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Raw Transcript
Nick van Terheyden
Today I’m delighted to be joined by Jerry and Zack Landman they are both physicians in the Bay Area. Jerry exact. Thanks for joining me today.
Geri Landman
Thank you so much for having us, NEC.
Zach Landman
Happy to be here.
Nick van Terheyden
So if you would I always start every show the same way. I think it’s important in your case. Interesting story, but the background is always relevant. I find, tell, tell the listeners, if you would, what your story is to this point how you arrived here, and what the steps were in getting here.
Geri Landman
Great, let’s so I’m Gerry Landman, I’m a pediatrician in the Bay Area, I changed at Boston Children’s and got an MPH at Berkeley. And you know, was going about my private practice until I got pregnant with our third daughter Lucy, who is now 12 months old, Lucy’s had quite an odyssey already in her short life. There were some potential abnormalities on prenatal ultrasounds that we were very reassured about. She was breech, she was the first of my daughters to be breached. And that seemed a little concerning. But she was born healthy and thriving. Around four months old, I noticed being a pediatrician, that Lucy was a little hypotonic, that she had a little lower muscle tone than other than our other daughters. And she, like our other daughters loved food, she watched the spoon go back and forth from my plate to my mouth. And so I tried to set her up in the Buffy chair, and she just sort of off to the side a little bit. I said, Okay, you’re not ready for this. The same was true at five months. And so we went to the pediatrician and said, you know, what, maybe some of those prenatal concerns would it be a good idea for us to see neurology got into the neurology around six months started physical therapy, the neurologist was very reassured by Lucy’s exam, and she was improving greatly with physical therapy, the whole time being at smiley, interactive, you know, laughing, chatting, baby. She achieved sitting independently a little later than her sisters around seven months versus six months, but still. And then I went on this family vacation to Panama, and Lucy was about eight and a half months old. And she got a little cold, some sort of viral illness, maybe a tummy bug, and things really went downhill. So whereas previously, she could fit for 15 minutes, you know, I’m playing with her sisters, you’d sit her down, and she just fell over to the side. And she stopped eating solid foods. She’d previously been eating solid foods for about two months and just refused to turn her head to the side extra head backward. And probably most Concerningly just stopped making good eye contact, which was really worrisome. So we came home and then talk to the neurologist, we actually wound up in the Sanford er once just concerned that maybe there was something like an interception, a telescoping of her bowel going on and got a little workup, then, you know, got sent home with follow up. And I think, you know, one one thing that’s a little bit important here is just as a pediatrician, I, I always sort of questioned myself. And as I think many moms do, you know, am I crazy? Am I just being overly worried here? I think postpartum anxiety is a real thing, you know, and there’s a lot of parents who worry about a lot of things. And so I tried to kind of check myself and keep my own worries in mind, and in check, but I I emailed our neurologists finally and said, Something seems very wrong here.
Zach Landman
So they decided to actually to admit Lucy to the hospital in March for an expedited workup and they did a very extensive workup MRI with a with and without contrast, and EEG to look for seizures for over 24 hours, nerve conduction and EMG study for muscles to see how the nerves are conducting electricity as well as actually multiple spinal taps LPS lumbar punctures, for neurotransmitters were possible infections and everything was completely reassuring. But the neurologist who happened to be on Sir Reverse was actually a neuro geneticist meaning trained in both neurology and genetics. And so, you know, Lucy was getting better the cold was going away, she was getting our strength back, not quite to our baseline. But they didn’t have any further tests that we really could do other than some genetic testing. So they sent out very, very broad genetic testing. And we went home, and she returned to physical therapy and looked like she was back on her path, gaining skills gaining ground, day by day. But we got a text message, actual text message from that doctor on April 18, on a Monday around 3pm, that said, the Lucy’s genetic tests are back, we need to have a zoom call. And what we learned in that call was that Lucy is missing a working good copy of something called her key gap three, Gene, it’s a gene that makes a protein that helps helps connect cells to another by placing things on the cell surface membrane, and that this condition was extremely rare. There’s probably fewer than 50 Kids Worldwide with this disorder. And the neurologist looked at us and said, Without treatment, Lucia will never walk, she’ll never talk. Then she’ll likely develop a refractory meeting untreatable seizures sometime in her childhood. And literally sitting on her lap was smiling, cute, laughing baby, that looked like all, all two of our older girls like like a carbon copies, just blond haired, blue eyed, smiley, chubby baby. And we just could not believe that to be true at the time. But they did follow up testing, obviously, and full sequencing. And they tested our genetics as well. And we were both carriers for for the two bad copies. And what we learned is that there because it was so rare, there was no research on PCAP, three treatments, or even things in development, no clinical trials. And through our connections, Jerry and I both trained at UCSF, Harvard, and myself at Stanford, were able to connect to literally every leading research scientist in the world. And nobody had something that they could offer as a potential drug or medicine or, or therapy. But we did understand the science, we did understand what was the problem. And we did understand that there’s a way to boost this protein, just the the current studies weren’t being done.
Nick van Terheyden
So first of all, thank you for sharing what is clearly a very difficult personal story. Obviously, huge impact for two physicians who deeply understand the background, the impact of all of the words, the terminology, you know, and what that means for for Lucy. So I really appreciate that. I think everybody really appreciates how you’ve come to this point, and are trying to do something great, out of what is a very challenging circumstance. So if you would help people understand just a little bit of the details. So I mean, you talked about the genetic defect. So this is a single genetic defect, and to be clear, discovered, almost by chance, because of the individual that happened to be there. Who would have progressed to that where others Absolutely, typically would not. So you know, fortune in that particular instance. Tell us if you can, what that means. What the not just the clinical outcome, but what can we do about it?
Geri Landman
Yeah. First of all, I mean, as a pediatrician, I have like I said, I trained at Boston Children’s I was a hospitalist at UCSF for six years. I had never even heard of this class Class of disorders, no less this individual gene, and this individual gene was first described to cause human pathology in late 2014. And so we had some learning to do. Basically, it’s an autosomal recessive mutation, meaning you only need one good copy of the gene to be neurotypical and live a normal life. Lucy doesn’t have a good copy. She has two bad copies, one of which probably retain some function because she seems to be milder overall, than some of the previously described cases in the literature.
Zach Landman
What the scientists think is that, you know, you need 50% of a working protein, that’s why it’s autosomal recessive to be normal and typical, Lucy may have 25 may have 30%, if she had zero, these kids are very, very ill and die within the first year of life and develop seizures and are very, very weak. So she clearly has some level of function because she has not yet developed any of the severe features of the of the disease, when we bring her to the playground or park, she looks very similar to all the other 12 months old in terms of her tone, her smiling, her babbling, all of that. And so the key is to really get this protein to a sufficient level or working level as as everybody else.
Nick van Terheyden
So if I can try and put it into simplistic terms and make sure that this is correct, but it’s a gene problem that is expressed with a single protein. And the absence of that protein is causing all of the downstream effects. And the replacement of that protein, if that were possible, is something that would be a fork in the road for Lucy and would mean essentially, as close to a normal life as possible, albeit with that supplementation if that were achievable, or some way Is that Is that a fair summary?
Zach Landman
I think that’s a fair summary. Just to expand off of that, we learned that there’s a similar gene that makes a similar protein, not the same one as Lucy’s, but on the same on the same clinical pathway, doing similar types of things within the cell, the girl named Maggie, and at eight years old, she could not walk she was wheelchair bound at significant metal medical issues. And they found actually a Japanese nerve pain medicine that just so happened to boost her protein by 400% or more in the cells if you give it to her just like if you happen to give, you know, Simba statin to something and yes, it helps your cholesterol but it also will boost this protein. Just incidentally, we found that with the COVID-19 drugs that, you know things that are made from for other things initially, actually turned out to work really well for other other aspects that maybe weren’t their initial intent. And so they gave that medicine to Maggie and also a few other kids with her disorder. And the consequences were astounding, she began to walk she began to her language exploded. And so that medicine went from never being used in the United States to a fast track phase, combined one in three trial, which is basically the last stage of a clinical trial at Mayo Clinic where they’re, you know, getting this approved. And that went in a matter of months from you know, nothing to, you know, potentially FDA approval and medicine.
Nick van Terheyden
So for those of you just joining, I’m Dr. Nick the incrementalist today I’m talking to Dr. Jerry Landon, and Dr. Zack Landman, we’re talking about Lucy Landon, who has a specific genetic condition, which causes an absence of a protein we were just talking about the challenge and the potential therapies. And what you described was essentially a groundbreaking life changing therapy in a similar kind of disease process where you replace using, essentially a drug that are being used for other purposes in medicine, you have essentially gone about a process and I think you have two threads to your approach. Obviously, one is very personal. And I think it’s important to understand this. For Lucy there, there is a need to find some solutions. Can you help people understand what what are the possible solutions that are available or could be available? And what’s that going to take?
Geri Landman
Yeah, I think there’s a there’s a few buckets for families that have found themselves in a similar situation. One is to sort of try to understand the underlying pathophysiology and think about are there any supplements that can help with this, you know, and mitochondrial disorders, things that may help with reactive oxygen, oxygen species, co Q, vitamin E, things like that can sometimes be helpful. And that’s, that’s sort of the easy box to check, right? We started the sixth the day after we got Lucy’s diagnosis because that’s a supplement with very few side effects that’s been shown to potentially help. The second bucket is the drug repurposing bucket that we’ve already talked about a little bit. And that’s an amazing solution. Then, because it’s really the beginning of personalized medicine, I think, you know, what we’re doing is we’ve undertaken a project with a company called Pur, Laura and Dr. Ethan Pearlstein, whose company is actually here in the Bay Area. And he was the one who discovered the Japanese nerve pain medicine that Zack talked about before, basically, by a via process, that’s, that’s somewhat plug and play. So you, you take a person with a genetic disorder, or you could do you know, cells from a person that maybe didn’t have an underlying genetic disorder, but had some other sort of pathophysiology. And you try to reproduce that defect using CRISPR, or other technologies. In simpler organisms, you know, this protein PCAP three is highly conserved throughout evolution, that’s how important it is that yeast habit. So you put it into yeast, you put it into worms, maybe zebrafish or Drosophila, you know, all these organisms that we sort of learned about in college college bio experiments. And you see if they look different than normal yeast or normal worms, or if they act differently, the zebrafish who have T gap three who live in Qatar having seizures, they don’t So normally, so there, there’s something similar going on there. And then you can test this this battery of drug known drugs known compounds against those kind of avatars, people call them you know, the these simpler organisms that have the same gene, and see if we can improve the phenotype. And then you can test them for safety.
Zach Landman
Yeah, and it’s it’s kind of cool that we’re in this position where we have truly Lucy yeasts. So we put you know, Lucy’s gene into a yeast and we have a Lucy worm, and they’re missing called avatars are, they’re meant to replicate Lucy’s problem and other simpler to study species. And then you can, like Jerry said, tested the all those medicines, those 5000 compounds, or even more to see which ones make Lucy yeast look like normal yeast, again, which ones make Lucy worms look and act like normal worms. And you get a few hits from that they’re called, you know, hits that you get maybe three or four different medicines that can be as simple as like Pepcid, AC over the counter, or they can be something as methotrexate or cancer medicines. So you kind of hope you get one that’s safe and easy to take. And then you take Lucy’s own cells called her fibroblasts, which are kind of like pseudo stem cells, and you test them on Lucy’s actually own cells and do those, Lucy neurons start looking and acting like normal Lucy neurons. And then once you get ones that kind of hit all three, you feel pretty comfortable that yeah, you this medicine works in yeast works and worms and works and Lucy cells. So that’s what we’re doing today. And you don’t need a big academic center or a giant lab to do it, you can get pop up lab space in San Francisco, that’s what we’re doing of a rent a bench space, or you get a placement Oregon, or you talk to a scientist in New Zealand and do this technology, and they can do it. And the cost is in 10s of 1000s of dollars that, you know, we’re not millionaires or billionaires. And so for, you know, 150 or $200,000, you could potentially identify, you know, cure for your child or your family member. Yeah, that’s the first bucket. That’s a second bucket. And
Geri Landman
then I think that’s there’s two advantages to this bucket. One is speed. Right. So it’s really important, I think, Lucy, one thing I know as a pediatrician is that there’s critical periods for things and sure, there’s neuroplasticity, meaning like the brain can kind of heal after an injury. But Lucy shouldn’t be acquiring language right now, she should be learning to walk right now. And if we can give her something during those critical periods, that helps boost her protein so that she’s able to acquire those skills at a more natural time period, I think her outcomes will be so much better. And really, the sky’s the limit. So speed and then you know, accessibility, not that not that $200,000 is accessible to everyone in the world by any means. But I think, you know, here in the Bay Area, the average middle class family could sort of do this kind of personalized medicine. And the third bucket is gene therapy. And that’s probably the wave of the future for disorders like this, you know, missing a single protein, give that gene back that makes that protein and and you cure the baby. And they’ve done this with other disorders that are amazing to me as a pediatrician. So spinal muscular atrophy is One prime example right? This is a disorder where if you had SMA one, you used to die within the first year of life because you’re right respiratory muscles got paralyzed in 2017. That was the first trial of gene therapy for SMA that those kids are walking now, which I mean, that brings tears to my eyes as a pediatrician to think about that. It’s still new technology. It’s really I mean, we all know that in science as processes become more automated, they get cheaper. And I think if Lucy were born 10 to 20 years from now, that that would be the easy answer. But Lucy doesn’t have that kind of time right now. And so what we’ve done to sort of fill that bucket is we’ve started our foundation called moonshots for unicorns. Moonshot being, you know, a Hail Mary pass, right? Shoot for the moon land among the stars. Kind of effort. And Lucy’s always been our unicorn since she was born, you know, she was she was different from the start. And I think that’s true for for a lot of kids with single gene disorders that, you know, gene therapy is the wave of the future. But getting that process to be a little bit more plug and play will make it way more accessible to everyone, because it’s at least 10x, the cost of the drug repurposing bucket.
Nick van Terheyden
So, for the purposes of, you know, crystallizing this, whilst this sounds like it’s, you know, it doesn’t sound like it is rare. In this particular instance, this concept, you know, the three concepts that you describe are essential for the future of all of medicine. From a personalized standpoint, we’re moving towards this, you know, what helps Lucy helps many, many others, albeit with different so we have to find new processes, new tools, new techniques, and in the genetic bucket, which is obviously a higher cost at this point. But you know, we’ve seen the progress and the potential, you obviously have a compelling issue, you’ve started a GoFundMe. But this is not just about Lucy, and I think it’s important for everybody to understand that this is broader than that, tell people what they can do, and how they can help and what the sort of steps on
Zach Landman
exactly so the how gene therapy works is that you have a vector and this particular vector, it’s a viral vector, it’s called AAV nine. And you basically put the gene you want to give to the child that’s missing, or defective in that vector. And then it’s a one time infusion, either IV or intrathecal. It’s a one time thing and they get it and then the cells have that gene, and now they’re making that protein on themselves. And so, SMA is the one that Jerry talked about, but the SMA gene, they did a couple of different times with different genes. But right now, the FDA considers each one kind of as 100%, separate, and different app to start from scratch. And so but what we’ve learned from the scientists actually doing this is that if we can show a few more times to the FDA, you put a different gene in, it’s safe, it’s effective cures the child, then we can almost do it like the flu shot where you change it up a little bit a year, you do some safety studies, and you can kind of plug and play. And so moonshots is obviously starting with PCAP three, which is Lucy’s disorder. But our goal is to first do to pick out three, and then all the other kinds of single gene disorders until we can get the FDA to say yes, let’s plug and play. Because right now, the cost is about $2.5 million per gene therapy at a minimum, and so right now the gene therapists have Lucy cells, they’ve actually growing her pseudo stem cells, the fibroblast cells. And we’re in a race against time with moonshots for unicorns to raise that $2.5 million to approve this gene therapy. And then we’re not going to stop there, we’re going to go to next gene down the line until the FDA says okay, a v nine is a safe viral vector for gene therapy, let’s plug and play it because that would be you know, it cut the cost by 90% or more and the time by that much, because it takes you know, two to three years now 18 months at a minimum. And the actual process could actually be six months, four to six months, if we didn’t have to start from scratch every time. So those who want to help if they could go to moonshots for unicorns.org at five and 501 C three, nonprofit scientific organization you can learn about where we’re starting with the story is and how we’re on a mission to make gene therapy accessible and affordable for all because individually, each single gene disorder is extremely rare. There’s, you know, 50 kids in the world with the gap three, but cumulatively, they account for up to one person NSF have disorders. And that’s hundreds of 1000s of people suffering around the world that truly have a solution. It’s just a logistics problem at this point in time.
Nick van Terheyden
So solving the logistical problem for the gene therapy, there’s also the testing of other substances. And you know, for the clarity, flu, x 13, was one of the discoveries and COVID-19. It’s an antidepressant proved to be actually useful. That process of testing a little bit more or less costly, but that’s also something that you’re doing, you have a GoFundMe page for that. Obviously, there is no urgency in this domain. Unfortunately, we’ve run out of time, but for those of you listening, there’ll be links to those pages. If you can go to those pages help out. They’re always looking for support. And obviously moon shots for unicorns.org is the webpage. Zach. Jerry, thank you for joining me today.
Geri Landman
Thank you so much for having us. It’s been a pleasure to be on and I just wanted to offer to that you know if anyone wants more information about this, we do have an email address available on the website info at moonshots for unicorns.org. We love talking to scientists or researchers to anyone who just wants to learn more about single gene disorders, you know, people have jumped in to help us from all aspects of our lives in this and if we can be helpful to anyone we certainly want to want to give back in that realm as well. But we’re open to connections, funding, words of support. Everything helps.
Zach Landman
Thank you so much.
