How One Foundation Is Laying the Groundwork to Advance Treatments for an Ultra-Rare Disease

A week before Deborah Ondrasik’s daughter Gabrielle turned 1, she suffered her first seizure. Within a year, Gabrielle was diagnosed with CACNA1A-related disorder, a rare, neurodegenerative condition. At the time she was the eighth known person to be diagnosed with the disorder. We spoke to Ondrasik, who is a pediatrician, along with CACNA1A Foundation Vice President Sunitha Malepati about the CACNA1A-related disorders, how it progresses, and what the CACNA1A Foundation is doing to advance research to speed the development of treatments and a cure.

Daniel Levine: Deb, Sunita, thanks for joining us.

Sunita Malepati: Thanks for having us. Danny,

Daniel Levine: We’re going to talk about CACNA1A, your experience with the neurodevelopment disorder and the work that the CACNA1A Foundation is doing to accelerate research and therapeutic development for the condition. Deb, I wanted to begin with you and your daughter, Gabrielle, who was born in 2013. When did you first notice a problem?

Deb Ondrasik: I’ll start by saying that I’m a general pediatrician, but there’s nothing like being a first time parent. And so, when I welcomed my first daughter, Gabrielle, I started to notice some delays in her first year, but I mostly wasn’t sure what to do about that. As she got older, they became more and more obvious. So, at two months, I noticed that she didn’t make great eye contact. At four months, she wasn’t rolling over. At six months, she wasn’t sitting. But then she would start to roll and start to do a tripod sit and give me hope. But by 10 months it was really obvious that she had pretty significant delays. And so, I actually started out with early intervention and had them evaluate her and was just devastated to get the results that she just was globally delayed. I think I just had my mom eyes on and didn’t realize how significantly she was behind on gross motor, fine motor, social, and communication milestones.

Daniel Levine: What was done to follow her progress and perhaps get a diagnosis?

Deb Ondrasik: Yeah, interestingly enough, I was seeing a pediatrician in her first year of life who didn’t do standard developmental screening. And so, I think that’s partially why her first year of milestones were somewhat missed. But then after that first year of her delays being obvious by her first birthday, she also had a really significant seizure. She just, out of the blue, had an hour long seizure that landed us in a hospital and then a brain MRI that had some abnormal findings. At the time we were told, well, first of all, we had to push for the brain MRI. They didn’t want to do an MRI because they were thinking it was a simple febrile seizure, which is a common pediatric condition that you really don’t get too concerned about. But Gabby didn’t have fever and her seizure was an hour long and she had global delays. So, I did push to get the MRI, which I think as a pediatrician I knew to push for that. They found the abnormal brain findings but then still felt like maybe this was just a one-time seizure.

Daniel Levine: The fact that you’re trained as a pediatrician, did that change the way health professionals interacted with you or the way you may have reacted to the professionals you consulted? Told you?

Deb Ondrasik: I think it definitely changed probably everything in our plan, in our progress that year, because she started having seizures and we really wanted to have the best care for her. And we were in the military system, both working as military physicians, my husband and myself. And so, within six months of her getting her abnormal brain MRI, her global delay diagnosis in her now epilepsy, because she had multiple seizures, we were sent to a specialized center where I had worked previously. So, as a department I had worked in, within a couple of days [she] had an EEG, neurology, developmental pediatrics, and genetics all evaluating Gabrielle, and genetics went ahead and offered the whole exome sequencing. And if you remember, this was back in 2015 when that was really mostly not covered by insurance. but we had Tricare insurance so it was covered. So, we were able to be one of the first in the country really to get that whole exome sequencing. And I think being a pediatrician and working in a system where I actually was working was a huge benefit. Unfortunately, I think a very different odyssey, a planned journey, for other families where other families usually are on many years of an odyssey trying to get a diagnosis.

Daniel Levine: Listening to you now you, you speak very calmly and you even talk about febrile seizures not being all that unusual in a young patient. But being a mother, what was it like to see your daughter go into a seizure?

Deb Ondrasik: Well, Danny, that’s a funny question. I was not calm at all with that first seizure. It was quite dramatic. I still feel like it was like a movie. We were on a dirt road in El Paso drinking wine, and she started having a seizure, and I just yelled out, like, call 911. By the time the ambulance got there, the seizure had progressed and was looking more significant. And I was actually so hysterical they would not allow me in the ambulance. It was just the worst thing to see your child have a seizure. And yeah, you could know everything medically, but when it’s your own child seizing, it’s just horrific. And I wouldn’t wish it on any parent. So, we were behind her rushing to the ambulance or rushing to the hospital, and then when we arrived at the hospital, they did not let us back with her because she was still seizing. They then had to give her so much medicine to stop the seizure that she stopped breathing and they had to intubate her. And it was really hard to see a 12 month old infant. The first time I saw her, she was intubated and it reminded me so much of the training we do in pediatrics where we train pediatric advanced life support on these little mannequins. And she looked exactly like that mannequin with, you know, intubated at the time and on a machine—it was frightening.

Daniel Levine: How was she ultimately diagnosed?

Deb Ondrasik: Through whole exome sequencing, yeah. So, when she was 18 months old they did the genetic testing and we got a result just a couple months later that she had this de novo abnormality in her calcium channels, the CACNA1A mutation.

Daniel Levine: This is a condition listeners may have heard of because of the activity of theFoundation, but at the time she was one of a handful of patients known to have this diagnosis. What were you told about it?

Deb Ondrasik: We were told that it was a known cause of epileptic encephalopathy, which she was diagnosed with epileptic encephalopathy, but that it was more commonly known as causing some ataxias and other things. And it was just coming to light that it maybe caused some other conditions as well. And they told me that really she was the first in the U.S. that they were aware of—at least this geneticist and this genetic testing company, and that there were just a couple of others in Australia and throughout the world. But there certainly was no foundation to go to and there was very little information about what the prognosis would be for her.

Daniel Levine: What have been the effects of the condition on Gabrielle?

Deb Ondrasik: They’ve been quite significant. She’s had really difficult to control or intractable epilepsy. Her seizures have initially really progressed where they were happening to the point of every month lasting two to three hour long seizures that we could not control at home. So, we would end up in the ER and have to get IV medication to stop the seizures. In addition to that, she didn’t start walking until she was three and a half, and her walking is still very limited. She has an ataxic gate and her walking is very unusual and she isn’t very stable. She also has autism and so she has very limited eye contact and social skills. And she is nonverbal as well, with limited forms of communication. So, she has major delays. She’s nine now and I would say that she mostly acts like a one-year-old and has difficult to control epilepsy.

Daniel Levine: What therapy or treatments does she receive and how does her experience line up with other people with the condition?

Deb Ondrasik: Yeah, I’ll share the story of how the foundation impacted Gabby’s treatments. She was diagnosed with CACNA1A, but even at the time she was diagnosed, we didn’t know if there was too much calcium or too little calcium in her neurons, because we know it’s an issue with the calcium channels. And so, about three years ago we moved to Boston and started seeing Dr. Anna Poduri, who’s a, a genetic epileptologist at Boston Children’s. And she was able to tell me that research had been done, that we now knew that for Gabby’s specific mutation that there was too much calcium. And so, she recommended that we try verapamil, which is an off-label use of this medicine that’s usually used for blood pressure. It’s a calcium channel blocker. And wow, Gabby just had a really amazing response to this verapamil. So, we started it two and a half years ago, and she went two and a half years without having to go to the hospital. Her status epilepticus has resolved with this medication, which is only because we know the underlying root cause of her epilepsy. Interestingly enough, I’m connected with three other kiddos in the world that have the same point mutation as her that I’m in contact with. One is in Sydney, Australia, and her daughter also is having these debilitating long seizures lasting one to two hours and she now is on verapamil as well because myself and my daughter’s neurologist have spoken with her neurologist and her daughter has had a really good response to the verapamil. And then we’ve been able to talk to a researcher up in Canada, Dr. Elsa Rossignol, who actually has a mouse model with Gabrielle’s specific point mutation, and she’s trialing verapamil on those mice. And what we’re seeing in my daughter and this little girl, Emagen, and the mice is very interesting where it seems to limit status epilepticus, but it increases the daily seizures. And so, Gabby has had less status events, but she has had a major increase in daily seizures. She has seizures every single day at this point.

Daniel Levine: Well, let’s bring Sunita into this. Sunita, how typical is Gabrielle’s experience and how well understood is the condition today? How heterogeneous is it?

Sunita Malepati: Yeah, thanks, Danny. The condition is quite heterogeneous, but there are a cohort of patients in our community that have an experience very much similar to Gabrielle’s experience. We know a lot about the condition from the sense of we know what this gene does, we know what it’s responsible for, and we know when there’s variance along this gene, the sort of symptoms that patients will experience. But the condition itself affects people differently depending on (a) where the mutation is, maybe whether it lets too much calcium in or too little calcium into the neurons. So, the community is quite heterogeneous, but there is a lot that we know about it.

Daniel Levine: The CACNA1A Foundation has been around only since 2020, but it’s working to support translational research with the goal of having at least one treatment for the condition in the pipeline within the next five years. How is it going about doing that?

Sunita Malepati: Yeah, we have a very ambitious goal because as you can hear from Deb’s story, the children are quite severely affected and there’s a high unmet need to improve the children’s quality of life. So, the foundation is a parent led organization really focused on trying to bring treatments to the community. And we’re doing that in a variety of ways. We can get into the specifics around that. But one of the ways we’re doing this is funding translational research—so really focused on funding research that is going to bring a treatment to the clinic. We’re doing that by enrolling families in different natural history studies, so collecting data on patients’ lived experiences, and then we’re also developing assets that can help bring the community to clinical trials and de-risk an investment by a pharma/biotech company looking at this disease as a target.

Daniel Levine: So, you’ve been able to ramp this up quite quickly. How did the organization go about creating a research agenda?

Sunita Malepati: Sure. The group of parents that started the organization, and the leadership since then has basically built this collaborative team of not only families affected by this disease, but researchers and clinicians who are treating our families. And we basically have gotten together and built a research network and tried to do the analysis of where the gaps are, like what is preventing a treatment development in this area. And with the expertise of everyone around the table, we’ve come up with a sense of where we need to invest to unlock additional knowledge. And then we’ve tried to also get a sense of what types of treatment modalities exist that would work potentially on CACNA1A-related disorders. And we’ve essentially made targeted investments in those areas to either bring about more knowledge or to essentially fast track our proof of concept studies to hopefully bring about investments in this area.

Daniel Levine: A lot of the work CACNA1A has focused on is gathering data. It’s working with the Chung Lab at Columbia University on a natural history study. It also has its own CACNA1A data collection program with the RAREX, which is part of Global Genes, which produces this podcast. It’s also doing a natural history with Ciitizen, which uses electronic medical records to pull together a natural history. Can you explain why you have these different efforts concurrently? Do they seek to do different things?

Sunita Malepati: Yes. I think everyone, all the listeners, probably know that participating in research studies is a really important way for the community of researchers and families to really understand how CACNA1A families are affected by this disease. And each of these studies that we’ve promoted within our community as being important research opportunities collects different types of information, and they complement one another to really provide a comprehensive and robust understanding of CACNA1A-related disorders. They do a little bit different things in terms of the types of data that they’re collecting but they all complement each other and they’re all really important things to participate in.

Daniel Levine: Does having those three different efforts create any unusual burdens on the patient community or affect their willingness to participate in multiple data collection efforts at once?

Sunita Malepati: Yeah, I think there’s unfortunately a burden on families to have to fill out multiple surveys across a number of different research studies. And that is part of the burden that we all bear as rare disease families to get our data out there. But the data that patients provide is one of the most valuable pieces of information that researchers can use to advance therapeutic development for rare diseases. So, it’s really critical that families make the time to participate in these research efforts. And at the end of the day, the natural history study that we are collecting will hopefully help us create a clinical trial that doesn’t require a placebo arm because we have data on patients who are not on any sort of medication right now, and we’re starting to understand the natural progression of the disease. So, the hope is that by participating and by getting enough families to participate, we won’t have to have a control arm in the study.

Daniel Levine: And will data from all of these efforts be available to all researchers? Who controls access to the data?

Sunita Malepati: Yeah, we’ve been really intentional about creating these opportunities for families to participate in an open science manner. For example, with the Chung Lab, you know Wendy, while Dr. Chung is the PI on the study, or the principal investigator on the study, she is incredibly collaborative. She’s open to sharing the data with any researcher that wants to look at the data. She shares the data with the Foundation. Obviously all the data’s de-identified, but she’s incredibly collaborative and [that] is one of the reasons we’ve partnered with her. RAREX, which I know a lot of the listeners are familiar with is also an open science platform where they are basically getting the research and the data they’re collecting out there to as many eyes as possible. And that’s really important for conditions like CACNA1A where there may be researchers looking at a particular symptom or particular disorder, but they don’t necessarily know that CACNA1A has that disorder as part of its manifestation. So, it gets more eyes on our data and that’s good for everyone. And then in terms of Ciitizen, as well, they are putting data in the hands of patients and families and they’re combining medical records. So, a lot of these clinician medical notes, things that patients typically don’t see or don’t have access to, Ciitizen is now putting that on their platform so families can easily access that and share that. And they’re also creating these natural history study data insights from the medical records or collecting for our community. So, they’re all going to be accessible to anyone who wants to see them.

Daniel Levine: You’re also working with COMBINEDBrain. Can you explain, for listeners, what CombinedBrain is and what you’re doing there?

Sunita Malepati: Sure. Yeah. COMBINEDBrain is a consortium I think now of 60 plus neurodevelopmental disorders. And the organization itself is really devoted to finding where there are synergies between the organizations and what efforts we can collectively do as a consortium of rare neurodevelopmental diseases to speed the pathway to clinical trials. They do a number of different initiatives that help all of us along, including hosting a biorepository, which is an area where families can donate biospecimens like blood or CSF fluid, and we can use that to develop research tools like IPSC neurons for different research studies. They’re also participating in a large study called Project FIND-OUT to increase or improve genetic testing accessibility for kiddos that may have these underlying neurodevelopmental conditions, but takes a long time to get them diagnosed. And so, all along the continuum from diagnosis to clinical trials, they have put efforts in that are meant to help all of us in our efforts to get to clinical trials.

Daniel Levine: You’ve also started the CACNA1A Research Network. What is that and how does it work?

Sunita Malepati: Sure. The CACNA1A Research Network is really something I alluded to earlier, which is a collaborative network of families, scientists, or researchers and clinicians who are seeing our CACNA1A families. And the idea behind it is really that all of us, each stakeholder is going to be at the table so that we can collaborate and think about how do we get to treatments and cures for this rare neurodevelopmental disorder using the expertise of everyone around the table. So, traditionally, knowledge has been siloed in different labs or different clinics or even in patients’ own homes. And the effort of the network is to bring all of those sources of information or knowledge or lived experience to the table so that we can understand how do we get where we are now, which is no treatment that’s specifically available for CACNA1A, to a time where there are multiple treatment options. So, when a kiddo’s diagnosed, instead of saying there’s nothing that we can do, a doctor can say, look, these are the options for your kid. And that’s really the goal of the foundation.

Daniel Levine: There are a number of neurodevelopmental disorders that might have underlying genetic causes, but share many of the same manifestations as CACNA1A. Are you doing anything to look across similar diseases?

Sunita Malepati: Yeah, I think that’s a really interesting question because we know that there’s overlap between a lot of these rare neurodevelopmental disorders, especially channelopathy diseases. So, ours is a calcium ion channel disorder. There are other calcium ion channel disorders, and then there are other ion channel disorders more broadly. And the one really remarkable thing about the rare disease community is just how open and collaborative everyone in the community is and has been since the organization was formed. And so, we’ve worked really closely just in terms of patient advocacy groups with other ion channel disorders. We’ve worked to create our own consortium of other calcium channelopathies, and we meet with those patient advocacy leaders and researchers in those areas on a monthly basis. And then through partnerships like COMBINEDBrain and RAREX, we are collaborating and sharing data across disorders so that any potential research finding that may apply to us is something that we will find out quickly and we will try to try to bring to our network to apply to our disease group.

Daniel Levine: And what’s the path forward? How hopeful are you about seeing potential treatments advanced to the clinic?

Sunita Malepati: I’m really hopeful. You know, I have a five year old daughter now who is diagnosed with a CACNA1A-related disorder at two and a half. And as devastating as it was to receive that diagnosis, I had no idea how much science has moved forward in the last 10 years in terms of finding treatments for rare monogenic conditions like CACNA1A, and now being part of the leadership team at the Foundation. I tell my families in the community all the time that I’ve never been more hopeful than I am now. Science really is moving at such a fast pace. We have seen some of these similar, rare genetic conditions cured. And I think in our kids’ lifetime we will absolutely have treatments available to them so that they will have a better quality of life. And really, the science is incredible and I think that with the team that we have at the Foundation, our families, and the research network, we’re going to get this done.

Daniel Levine: Deb Ondrasik, pediatrician and mother of a daughter with CACNA1A and Sunita Malepati, vice president of the CACNA1A Foundation. Deb, Sunita, thank you both for your time today.

Sunita Malepati: We appreciate it Danny. Thanks for having us. Thank you so much.

This transcript has been edited for clarity and readability.