Physicians Fight for Their Daughter and All Children with Single Gene Disorders - Dr. Geri Landman, Co-Founder of Moonshots for Unicorns

Michael Carrese: Hi, everybody, I'm Michael Carrese and today we're going to bring you another heartbreaking but also heartwarming story of a family racing against time to find a treatment for their child's rare disorder. As in every other episode we've done with parents of these children, my guest today is also striving to help all the other kids with the same challenge. But, unlike our other parent guests, she and her husband are both physicians, which obviously adds a pretty interesting dimension to the story. So, I'm delighted to welcome Dr. Geri Landman to Raise the Line today. Her baby daughter, Lucy, is one of only a few children known worldwide to have a genetic disorder called PGAP3, in which a single missing gene causes seizures and severe physical and cognitive limitations. We're going to find out about Lucy struggles and the efforts Geri and her husband Zach are making to help her and many other children through the nonprofit they created called Moonshots for Unicorns, which is funding research into PGAP3 treatments and other single gene disorders, and there's an interesting connection to autism in all of this that we'll be learning about as well. So, thanks very much for being with us today. Dr. Landman,

Dr. Geri Landman: Thank you so much for having me. We love the opportunity to talk about rare disease.

Michael Carrese: Let's start as we always do with learning more about our guests' personal and professional background. What first got you interested in medicine, and then why pediatrics?

Dr. Geri Landman: I always knew I wanted to do medicine from a very early age. I loved the idea of being able to help others in moments of need, when you're sick yourself, or you have a sick family member, you just really want someone who will empower you. Then in medical school, you know, I just loved pediatrics. I loved the idea of treating the patient and the family as well, and kids are just so much fun on a daily basis that I knew I'd never get burned out doing pediatrics.

Michael Carrese: And has that proven to be the case?

Dr. Geri Landman: (laughs)For the most part. My life is busier than planned on at the moment. But I still really derive a lot of joy from the three days a week I spend in the office.

Michael Carrese: As I mentioned, your husband, Zach, is a pain specialist. I think most folks can understand how having those medical backgrounds would be a big help in dealing with Lucy's situation but can you give us some detail on what having that expertise has meant in her situation?

Dr. Geri Landman: I think it really meant earlier diagnosis for her for a couple of different reasons. You know, as a pediatrician, I think subtle signs were obvious to me a little bit earlier than they might have been to other parents and we had more ability to advocate for her. Like many rare disease parents, we were reassured many times. Lots of test results were normal and so that reassurance wasn't inappropriate. But we still just had this nagging feeling that something was wrong. It was because of connections that I had at Stanford and other places that got Lucy admitted to the hospital when she was eight and a half months old and got an expedited workup. It happened to be that someone who I trained with at UCSF was the neuro geneticist on service that week who sort of said, "Okay, I know this mom. She's not crazy. Let's get some broader genetic testing, even though all the other tests are coming back normal."

Michael Carrese: Yeah, that is pretty key. I would say.

Dr. Geri Landman: Yes.

Michael Carrese: You can probably understand then, for parents who don't have this expertise, just how much more challenging this whole situation could be, right?

Dr. Geri Landman: Absolutely. Absolutely, and I think it's really challenging for families especially when doctors are telling you everything's okay. My husband and I, even as physicians, probably had the hardest time in the month and a half prior to her diagnosis, when we were kind of alternately reassured on different days. On a Monday when I thought everything was okay, Zach was like, "No, something's clearly wrong. " That was true the opposite days as well. I think that would be really challenging for a family that didn't have the kind of support system to bounce things off of, and the ability to actually do something about it when you're having those feelings.

Michael Carrese: Absolutely. So, it'd be great to get an understanding from you of PGAP3... the clinical explanation of it and then how it affects Lucy on a day-to-day basis.

Dr. Geri Landman: We first started to notice something was amiss with Lucy at around four months old when she was just a little bit floppier than other babies. But she continued to make progress with physical therapy and everything until she got some sort of illness when she was about eight and a half months old. This is pretty classic for lots of kids with genetic disorders that illness really brings out the symptoms of the disorder in a major way.  So, at around eight and a half months old, she had learned to sit up but then stopped being able to sit up. She stopped babbling, she started refusing all solid food and she just was less interactive. She stopped making eye contact and was really, really fussy and those are pretty typical of the symptoms of PGAP3. There's hypotonia, or low tone, floppiness, lifelong ataxia or sort of inability to be steady and know where your body is. Many kids with PGAP3 don't walk. Lucy's just learning to walk right now. 

And then there's intellectual disability as well and some autistic features. Lucy has no expressive speech. There were maybe a couple times that she said a word with meaning, but it's not really reproducible and she has a lot longer processing time. If you ask Lucy, "Where's your head?" you look back thirty seconds later and she's touching your head when you think she didn't get it at all. It affects every system in her body, her gut is as low as her mind is, so she has bad reflux and constipation and suffers a lot from tummy troubles that, luckily, as a pediatrician, I am somewhat good at treating, but it still definitely impacts her on a daily basis. And then, about 70% of kids with PGAP3 get refractory seizures at some point in their life. Lucy, luckily, does not have seizures yet.

Michael Carrese: And can you tell us, for the clinicians in the audience, what the mechanism is that's at work here? What's missing? What the problem is?

Dr. Geri Landman: Yes, so it's an autosomal recessive disorder, meaning Lucy doesn't have a single working copy of her PGAP3 gene. Zach and I are both carriers for one faulty copy, and she had the bad luck of getting both so she doesn't make any functional PGAP3 protein. The function of the PGAP3 protein is to modify the GPI anchor, which if you know anything about cells, you know there are many cell signaling molecules anchored to the outside of cells. The upshot is that Lucy's GPI anchors, the anchor that anchors all those little cell signaling molecules, is quite loose. Her cells don't communicate very well because the cell signaling molecules just sort of float off into the ether. 

Alkaline phosphatase is a lab that we check on pretty much every comprehensive metabolic panel in the country, and alkaline phosphatase happens to be a GPI-anchored molecule. So, a hallmark of this disease is very high alkaline phosphatase because her alkaline phosphatase just floats off into her serum. And that was something we always noticed about her labs going through, although that's also very common in infancy so didn't mean anything all by itself.

Michael Carrese: That's very helpful. Thanks for explaining that. So, as I understand it, there is some good news, potentially. Nationwide Children's Hospital in Ohio is working on a potential treatment. Can you fill us in on what's happening there?

Dr. Geri Landman: Yeah, they are a very famous center for gene therapy. That was the center that developed the first gene therapy for spinal muscular atrophy, which is also a devastating pediatric disease. That's been an incredibly effective and transformative therapy for families affected by that disease. When Lucy first got diagnosed, we sent off ten thousand emails to lots of different researchers across the world, and never expected to hear anything back but thankfully did hear back from Dr. Kathrin Meyer, who runs the center for gene therapy there, and she agreed to take on Lucy's case. 

She said, "Yeah, actually, PGAP3 is a pretty great fit for gene therapy. The gene is missing so if you put it back, it should work well." The size of the gene is important. It fits well inside the AAV vector that they use for most gene therapies at this point, and so Moonshots for Unicorns signed a contract with Nationwide Children's and the progress has been great.

Michael Carrese: That's fantastic. So, why don't we get into Moonshots for Unicorns and have you give us the backstory on that and tell us what kind of progress you've been making?

Dr. Geri Landman: I think, you know, like all parents -- all physician parents and all non-physician parents -- when we first got this diagnosis, we were devastated. Lucy had actually begun to do a bit better after her initial hospitalization as she kind of recovered from whatever that little virus was. When we got the text from her neuro geneticist on April 18, Lucy was sort of standing at our living room coffee table smiling at us and it seems so discordant with the conversation we were having that, you know, we had a baby who would probably never walk and never talk and would probably develop severe seizures. So, we took our requisite week and cried a lot, and went on a lot of hikes, and then we said, “We can't do this forever.” And so we got to work. 

Luckily, we have a huge number of friends who are very helpful, lawyer friends and nonprofit friends and everything who helped us within a month set up a 501C3. We call it Moonshots for Unicorns because we know this is a moonshot, right? There are not a lot of neurodevelopmental diseases out there that have cures in a meaningful way. There's a lot of treatments that are out there, but not a lot of things that are really transformative, and we said, "Gosh, you know, there are so many of these single gene disorders that should be amenable to things like gene therapy and drug repurposing and everything." We don't want this just to be a focus of PGAP3. Eventually we want this to be an organization that carves a path to help lots of families who are affected by single gene disorders. So, we set up Moonshots for Unicorns because all our kids are unicorns and we started fundraising.

Michael Carrese: Well, it's amazing that you've been able to get that off the ground and be so involved with everything else on your plate. So, my hat's off to you. I mentioned at the beginning that there is a connection to autism in all of this. Can you fill us in?

Dr. Geri Landman: When the proteins function in the brain, the final common pathway is fairly common across these single gene disorders so that expressive speech is very often affected, muscle tone is very often affected, seizures are a common feature, and then autistic features are really common, too. I wonder how much autism out there is really due to single-gene disorders. There are very many of our families in the PGAP3 world who were given either just an autism diagnosis, or maybe an Angelman Syndrome diagnosis, but didn't have the genetic reports to back it up. 

I think had genetic testing been sent earlier for those families, they would have had an underlying diagnosis. I think a lot of times until those kids develop seizures, which often isn't until later childhood, no one thinks to send genetic testing. And so, one question that we have is with all of these disorders out there, if you can sort of fix the underlying gene, how much can you really affects those kinds of autistic features for those kids going forward and I think there's really promising data on this. There's some new ASL therapy for Angelman Syndrome, which also has autistic features as part of it, coming out of some groups in the Bay Area here that have shown that kids who are in their teens getting this for the first time are developing expressive speech. So, it's incredibly encouraging.

Michael Carrese: Yeah, that's quite amazing. So, on the Moonshots for Unicorns page, you talk about not being able to meet your child. Can you explain more about what you mean by that?

Dr. Geri Landman: Yeah. Lucy has two older sisters who are neurotypical and you can just sort of look at them and listen to them play and then look at Lucy and just wonder who she would have been. Because when your first two kids are so different from each other, but still both so cool, when you have a third child, you sort of wonder who are they going to be, right? And Lucy is this incredible human being herself -- and obviously we've met and love Lucy -- but who would she have been if she didn't have this one missing protein, this one, you know, C to G transition and her DNA? What would her personality have been like? How would she have interacted with her sisters and everything? And that's what we mean by we would love to meet the Lucy that had that PGAP3 as part of her, too.

Michael Carrese: That makes sense. And I'm so sorry. You know, it's so hard to listen to this as the parent of two daughters. I can't imagine what it's like to go through all of this and I'm just so amazed at how you've been able to obviously take great care of Lucy, but also do things that are going to potentially help so many other children.

Dr. Geri Landman: Thanks. You know, it’s not a community that anyone chooses to be a part of, but I will say that the community of rare disease parents is just an incredible community of everyone being willing to help each other and everyone realizing that the more we can help each other, the more we help our own kids, too.

Michael Carrese: Yeah, absolutely. Shiv and I had been so honored to speak to people like you and the many rare disease parents and family members we’ve met over the last couple of months and what you're saying is absolutely true. The rare disease community is just full of remarkable and impressive and wonderful people. 

So, we just have a couple of minutes left, but I did want to give you a shot at one of our favorite questions, which is focused on the fact that we're a medical education company. Is there a myth or a gap or something along those lines on a topic that you care deeply about and you would say, "Osmosis, it would be great if you could make a video about that." What would that be?

Dr. Geri Landman: Yeah, I think one key takeaway that I've had is we need a better way to do rare disease research in this country. The idea that we ask parents who are dealing with a rare disease child and trying to go to physical therapy and occupational therapy and speech therapy and figure out ketogenic diets and deal with insurance companies...to ask those parents to also do fundraising and find researchers and build a team is just not a feasible model. This is not a good way to make sure that rare diseases are getting cured in our country. I don't know exactly what the answer is. I'm not a politician. But we've had some conversations with a team at the White House about kind of building a better structure for how we can get this research funded. 

And then the second takeaway that I would say to trainees and everyone out there is that in medical school, we're taught that “when you hear hoofbeats, think horses, not zebras.” In other words, don't always think of the rarest of the rare and most of the time, things are okay. And I think that while that's true, you should sometimes think of the zebra. The other thing that's been a theme is if there's not a treatment, why test for it if it's not going to change your management? But I think in the world of genetic disorders, that advice should just go out the window because the power of diagnosis for families dealing with rare diseases -- even if there's no treatment -- is it allows those families to mobilize, to find other families who are dealing with the same conditions, to just not feel crazy, that something is actually wrong with their child. Lucy was so constipated and uncomfortable reflux wise, and I was trying all those conservative pediatrician things like prunes and pears and water. But once I found out there was a really good reason that her tummy was so backed up and hurt, we started aggressively treating her constipation, and she was a lot more comfortable because of it. 

I think that that happens for a lot of families...that it allows them to say, "Okay, I'm not working with a child who's neurotypical here. So my approach needs to be different." And so it's really transformative to have the diagnosis, even if there is no treatment. I look forward to a world where the newborn screen is just a whole exome sequence so that parents can get these diagnoses early and do as much about them as they can.

Michael Carrese: Yes, talk about information being power. I mean, it's extraordinarily powerful in that case.

Dr. Geri Landman: Absolutely.

Michael Carrese: I'll send you some information on this, but you and Shiv are in a mind meld about the zebra situation. He has spearheaded a big effort here at Osmosis and Elsevier to launch what we're calling The Year of the Zebra, which is basically a big educational push to raise awareness about rare diseases and it includes drawing a spotlight on particular rare diseases throughout the course of the year. It's all very exciting. 

Dr. Geri Landman: Sounds fantastic. I'm so glad you guys are doing this. Thank you.

Michael Carrese: Oh, you're welcome, and it's certainly an honor for us to do whatever we can to help out with this really, really important cause. So, we're gonna have to leave it there but I want to thank you very much Dr. Landman for taking the time to join us today and we just wish you all the luck in the world with Moonshots for Unicorns and with Lucy. 

Dr. Geri Landman: Thank you so much. Really appreciate it.

Michael Carrese: I'm Michael Carrese. Thanks for checking out today's show, and remember to do your part to raise the line and strengthen the healthcare system. We're all in this together.