Neurology researcher and parent advocate: Dr. Luis Oliviera and the v-ATPase Alliance

Dr. Luis Oliviera is parent to a son with an ultra-rare developmental and epileptic encephalopathy.  He's also a researcher with the Michael J. Fox Foundation.  He created an organization bringing parents and researchers together to better understand his son's disorder, which is part of a  group of disorders caused by rare mutations in v-ATPase genes. Dr. Oliviera was interviewed by Dr. Alina Ivaniuk.

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What is v-ATPase?

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Transcript

[00:00:00] Dr. Alina Ivaniuk: Hello, everyone. This is Alina from the YES-ILAE, bringing you another episode of the Sharp Waves podcast, and I can foresee that our episode today will be full of insights. It might sound trivial if I just told you that I'm interviewing a scientist and the interview will be wrapped around an ultra-rare disorder.

However, the scientist is also the parent of the child with that rare disorder and started an alliance to bring together families and researchers working on the topic. Here today with me is Luis Oliviera. Welcome Luis. And could you please briefly introduce yourself to our audience and tell us a bit about what you do.

[00:00:44] Dr. Luis Oliviera: Absolutely well, first, thank you so much for the invitation to speak with you today. It's really a pleasure. I'm a scientist at heart and by training. My academic career has been mostly dedicated to research in degenerative diseases, especially Parkinson's disease.

I did my training in Portugal and then some postdoctoral research in the Max Planck Institute in Germany and Columbia University, New York. And during the past five years or so I've been an associate director of research programs at the Michael J. Fox Foundation for Parkinson's Research, where I oversee multiple projects and initiatives to develop biomarkers and novel treatments, focused on the main genetic targets in Parkinson's disease.

And these are highly collaborative projects with both academic institutions and pharmaceutical companies, and this year we published a major research advancement in Lancet Neurology reporting the first validated biomarker for Parkinson's disease, which notably comes up years before the onset of the classical motor symptoms of the disease and is transforming the way people now look forward to a more biological definition of the disease, resulting in smarter clinical trials and enabling testing of prevention therapies. 

In parallel, and more recently with my partner in life, I would say, we started an organization called v-ATPase Alliance to support children and families diagnosed with developmental and epileptic encephalopathies caused by genetic mutations in the v-ATPase genes.

This has been something we're moving forward with immense dedication and a great deal of personal effort, but something we believe can have a big impact in the development of treatments that can improve the lives of the affected children. 

[00:02:42] Dr. Alina Ivaniuk: Well, that's fantastic work. You do a lot and everything that you do or have been doing so far until very recently, in all of that, v-ATPase has not been coming across that much, right? This is just something recent that you encountered. Could you share with us how do you meet that disorder and how did you come up with the overall concept of what it is and how it functions? 

[00:03:12] Dr. Luis Oliviera: Yeah, absolutely. I mean, we got to know this disorder after a very challenging one-and-a-half years of, you know, seeing our little boy failing to meet multiple developmental milestones really at all levels, motor, cognitive, social.

And with nothing that could really justify what was happening, despite a battery of clinical, metabolic, neurological tests including MRI, EEG, and it wasn't until earlier this year that we were able to do full exome sequencing and found the de novo mutation in ATP6V0C, which is one of the genes composing the v-ATPases.

You are right that things around this gene are very recent. There’s a couple papers in the past two, three years describing that microdeletions in the chromosomal region encompassing the ATP6V0C gene resulted in a pediatric neurological syndrome. But the first paper clearly associating variations of this gene as causing developmental and epileptic encephalopathies was published just in September of last year. Which was really shocking to me, because we not only had the misfortune of having our baby carrying this novel genetic disease, but also that research available is so recent that the condition is essentially unknown to most researchers and medical professionals.

And I mean you asked me to talk a bit about what v-ATPase is, right? 

[00:04:50] Dr. Alina Ivaniuk: Yeah, if you could briefly explain to us what that protein is and how it functions. 

[00:04:57] Dr. Luis Oliviera: v-ATPase is a large protein complex that is expressed in all cells and highly expressed in the brain. And it plays a crucial role in regulating the acidic pH in the lysosomes and vesicles of the endo-lysosomal pathway, as well as synaptic vesicles. This complex is part of the membranes in these organelles, and it has one domain, the V1 domain, that faces the extravesicular space, and it generates energy by hydrolyzing ATP, and a second domain, the V0 domain, that is embedded in the membrane and uses the energy generated by the V1 domain to transfer protons inside the vesicles against its chemical gradient.

And so it acidifies these organelles. Specifically the V0C gene, or the C subunit, are part of the V0 domain and in the membrane and organize themselves as a rotor through which these protons are transferred. Now, why exactly mutations in this gene cause disease is not known, but we know that mutations in other genes that also encode for key subunits of the v-ATPase cause a similar phenotype.

And some examples are the V0A1 gene, which is the subunit actually responsible for transporting the proteins to the vesicles, or the genes V1A and V1B2, which are involved in the hydrolysis of the ATP that generates the energy to transport the proteins. Or even mutations in other proteins that are not technically part of the v-ATPase, so-called associated proteins, that stabilize the v-ATPase complex as a whole. So overall, this tells us that failure of this large protein complex in regulating the pH in these intracellular structures leads to developmental and epileptic encephalopathy.

In contrast with, let's say, genes involved in metabolic pathways where genetic mutations cause disruption of very well-defined pathways, in the case of v-ATPase, it's really more about a foundational role for overall cellular homeostasis. You need an acidic pH for these cellular structures to perform their functions, you need a pH gradient to signal where certain proteins need to migrate and be functional. In synaptic vesicles, you need the low pH for the storage and accumulation of neurotransmitters inside the vesicles. And so when that is not well maintained, there's a series of cellular processes that we probably don't even fully appreciate at this point that are affected. Probably two of those processes that are more directly affected include synaptic activity and autophagy, which is a major cellular mechanism for degradation and recycling of cellular materials.

But I would say there are likely others that we're just beginning to comprehend, such as aspects related to mitochondrial function and neuroinflammation. So I think we're just really scratching the surface here and there's a lot to be done to accelerate new treatments.

[00:08:18] Dr. Alina Ivaniuk: Thank you so much for this introduction to the biology of this protein. Also, clinical knowledge is also, I guess, not very well developed in this domain. And I think that it also gives some background for the creation of the Alliance, right? How the overall idea of creating an organization come and what steps did it take to bring it to life?

[00:08:42] Dr. Luis Oliviera: Yeah, I mean, it came to life through really an array of personal emotions, you know? This diagnosis is probably the biggest existential challenge I've ever been in. We were left with this diagnosis and that was pretty much it. Despite being followed in a medical center of excellence, my son's doctors, pediatricians, geneticists, neurologists, and so on, he has a very large care team, have never heard of v-ATPase disorders before. I would say there is essentially no care plan of action except the one that we as parents are putting together. And also at the time, not knowing anyone in the world with this condition, not finding a single resource that could help us orient ourselves in this new reality really left us with the anxiety of not understanding what the future might look like: for our son, for us. So that was really hard. 

And on the other hand, through my professional experience working on the Michael J. Fox Foundation, I've seen firsthand the beautiful impact this organization has in the lives of patients with Parkinson's and the tremendous influence as a catalyst for new discoveries and development of novel therapies. And so it quickly became clear for us that creating an organization like v-ATPase Alliance would represent and serve a community that was lacking this support, and that is likely dealing with this condition with a lot of uncertainty, and I might risk saying, you know, walking a very lonely path. 

In addition, we thought that to accelerate potential treatments, it is critical to put the human condition and the patient voice at the front and center of the research. Understanding the disease and its mechanisms starts with the patients. And so connecting the patients with the researchers not only allows for more impactful research, but it also underscores the urgency of getting the right answers. You know, so with all of this, me and my wife who has been a life force, not only directly building the structure of what v-ATPase Alliance is today but also being the mother of our special son and sort of the family glue of having all of this to be possible, we created a website called vATPaseAlliance.org and a social media presence on Facebook, Instagram, Twitter, LinkedIn, you name it, to generate relevant information about the condition and create a platform for the patient community to finally connect and share experiences.

And the response has been overwhelmingly positive. In the meantime, we started working with another mother of an affected child, who is an incredible advocate, to more formally expand our activities. We have already established important research collaborations with clinicians and investigators in Spain, Ireland, Italy, and the US. And that's really exciting. This is very much in the beginning, but I think we're off to a good start. 

[00:11:54] Dr. Alina Ivaniuk: Yeah, that's tremendous progress in a very short time. I can just imagine how hard it is to start something like that, but I can also see how your personal experience and the experience of your child powers you on that path. What do you see as the main goals of the Alliance? And what do you think is needed for reaching those goals?

[00:12:21] Dr. Luis Oliviera: Yeah, I mean, we're small, and very much in the beginning, but we have very ambitious goals and a great deal of enthusiasm and energy to accomplish them. I can highlight three goals just to keep myself on time. First, we want to make sure that every family is empowered with information to discuss their case with their care teams and that we leverage each family's journey to better inform those care plans.

I can give you one example. All these children are dependent on various therapies to improve their quality of life: Occupational therapies, speech therapies, physical therapies, et cetera. Currently, there are no strategies that are tailored to these conditions. Children, especially in the first years of life, end up having some general approach that very much depends on the therapist's experience with cases that have a different etiology than the v-ATPase disorders. There is poor characterization of what might be a limitation caused by this specific disease versus what might be more related to behavioral issues. There's no understanding of if and when assistive technology might be implemented and for what, and more importantly, there is no shared knowledge of success stories that people might learn from.

And so that collective learning from the community is an important and very tangible goal in my opinion. And by the way, a similar example could be given in relation to the medications used to manage the epileptic syndrome as well, which differs a lot from case to case, and we don't fully understand why.

A second goal is we want to learn more about what the disease looks like and advance our knowledge of the underlying biology causing it. And again, here, you know, things start with a patient and we hope to be able to start a patient registry, conduct cross-sectional and longitudinal studies based on patient-reported outcomes to better understand the natural history of the disease, and also coordinate the research community to establish collaborative efforts to address the main gaps we have on our understanding of the disease mechanisms, which I think is key. 

And finally, the last, but certainly the biggest goal of all, is to develop effective treatments. These disorders are very well explained by genetics. And so there is an obvious, although challenging, path for treatment with gene therapy or other modalities that modulate gene expression.

But also given how recently reported these cases have been, I think there is value in investigating the repurposing or repositioning of drugs developed for other neurological conditions, with particular emphasis on lysosomal storage disorders and compounds that might have a broad neuroprotective and anti-inflammatory mechanism of action. These might be beneficial and we really don't want to leave any stone unturned.

[00:15:36] Dr. Alina Ivaniuk: Sounds indeed very ambitious, but it also sounds like you have a plan, and the goals are well defined. This is the best way to reach those goals. You have been mentioning community so many times. I wonder how big the community actually is, how many people with vATPase-related disorders are there, and how do you bring them to your organization?

[00:16:01] Dr. Luis Oliviera: Yeah, absolutely. I mean, it's hard to be accurate at this point, but I would say with an educated, although not that much, guesstimate that there are probably 40 to 50 people per v-ATPase which, for the total of the neurological condition, so the total of the genes that cause neurological conditions we could probably count between 150 to 200 patients in the world.

So far, we have connected with about 30 to 35 families. These families that have connected with us have done so organically upon finding us through the resources we have put together online. And I feel this is likely to continue as we create more relevant content. But I think as we expand, there are other opportunities to explore. One would be to work with clinicians and be present at relevant conferences to introduce ourselves and share our mission so that they can direct patients to us. 

Another potentially very powerful way to engage with more patients would be to partner with larger and more established organizations like the International League Against Epilepsy, where most likely these families have found important information even though that might not be necessarily directed and specific for their condition, but to let the patient community know that we exist and are specifically working on the v-ATPase conditions.

 So I think there are certainly more opportunities to explore and bring the community together.

[00:17:43] Dr. Alina Ivaniuk: Besides bringing the community together, what are challenges that you face now running the organization? Anything that is an obstacle that prevents you from doing something meaningful? Is there anything on your mind? 

[00:17:57] Dr. Luis Oliviera: I mean, the main challenge so far has been lack of time. A genetic disease, obviously, it doesn't happen in isolation. And so all the other components of daily life, such as work, household affairs, being a present parent, are as present as they were before, or maybe even more.

And so, you know, we're a team of three so far directly managing the various activities with some help from friends. As we connect with the community and put ourselves out there, I'm hoping that more people will share our vision and might be able to push alongside us to make things happen.

So actually, let me take this opportunity to say to our listeners that if you have a relative or a friend who has a v-ATPase disorder, or if you simply feel inspired by what we're trying to accomplish here and the way we want to impact the lives of these children and you believe you have a skill set that might help us get one more step forward, please reach out. Join us. We welcome all hearts and hands for this mission. But of course, once we move more from this ideation and strategy exercising to actually implementing these ideas more formally, I think financial resources will be key. You know, these things are not cheap to accomplish.

And we will have to work on ways to raise more awareness, fundraise, partner with other organizations to execute this vision. So that will certainly be a big challenge. 

[00:19:29] Dr. Alina Ivaniuk: You mentioned that of course you keep being a parent. Well more likely than not, it's even more challenging now as your son grows up. What it is like to raise a child with a rare disorder and how has your child's diagnosis changed your life and also how the creation of the alliance changed your vision of his disorder?

[00:19:59] Dr. Luis Oliviera: Yeah, that's a very difficult question. I think that time changes people's perspectives and I've seen beautiful and fulfilling stories with diseases like this. To me, this diagnosis entered my life just a few months ago, and it is very recent. And if I'm to be honest, you know, I cannot sugarcoat this. To me personally, you know, this was a horrendous tragedy met with a high level of resentfulness and sadness. It is this notion that the very basic wish that your son or daughter gets to have a fair start in the world and all the dreams that it enables are now just impossible to attain. And that is one of those things that breaks you up in some deep fundamental level, you know?

And being a scientist in the neurological disease space is also a double-edged sword. If it is true that I'm uniquely positioned to understand the disease, make sense of all the new developments, be a highly valuable contributor to my son's care, and obviously this, of course, on top of what a father can and should be, it also gives you the devastating realization that despite all the knowledge, all the training, all the network of experts, I cannot fix the problem for him, and you know, something that I'll have to learn how to live with. But I also must say that getting a smile or a laugh out of him every day completely melts my heart and shows me that despite all of the above, this doesn't have to be hell. There is a life worth living in all of this and, you know, together we'll live it. So yeah, I guess that's where I am currently. 

[00:22:03] Dr. Alina Ivaniuk: That's fantastic. Thank you so much for all your efforts and also for sharing your story. With regards to your son's care, you mentioned that it's a big team, it's a center of excellence, but still nobody knew about the disorder. Now you're an expert. How do you educate medical teams that care about your son about his disorder, and what do you convey to them, how, and are they teachable overall?

[00:22:33] Dr. Luis Oliviera: Yeah, I mean you're right. Like I said before, being a rare disease that most doctors have never heard of, my experience has been that most clinicians listen to you and are very willing to learn more, within the limits of their capacity, given that they, of course, see dozens of different patients every day.

But I also think that in order to insert yourself in this dialogue, I feel families need to be armed with valuable information that empowers them and allows them to elevate their language and arguments essentially to the level of the clinician or close to the level of the clinician. Otherwise, they will not pay attention to the right level. My personal efforts are mostly focused on making sure my son's clinicians are aware of the latest research developments that might have clinical relevance for my son, ensure that all the doctors are communicating the right information to each other, and of course, trying to have them engaging with the Alliance.

You know, actually that would be one take-home message for any listener that might be dealing with a v-ATPase disorder. Share our resources and contact information with your doctors, have them reach out to us. We can certainly provide them with curated information. But again, the benefits of building this community I feel will be long and lasting. We're a small community and each case is very valuable to understand the disease as a whole.

So we try to be very active on social media. So if you find one of our platforms or one of our pages in these multiple platforms and you simply write to us, we'll certainly respond. On our website, vatpaseAlliance.org, you can also drop your email or write a direct message. We'll get back to you. We'll have you on our contact list and we'll support you the best way possible with valuable information for your specific cases. 

[00:24:35] Dr. Alina Ivaniuk: Is there anything else that you would like to mention, to address? To tell either the patient or the clinician, to conclude? 

[00:24:46] Dr. Luis Oliviera: Yeah, I mean, my advice would be to get involved with organizations like the alliance, or if you have another rare disease, and assuming that organizations dedicated to that specific disease are already established, to engage with them on a fundamental level, make yourselves useful to that community. In a sense, they will become your extended family and you'll end up knowing most of those people throughout their whole lives because the communities are small. And so you have that opportunity to really connect. 

And also remember that better care, better treatments, personalized interventions, start with the patient. And in my opinion, there is also no better way to channel the patient voice into the research world than through organizations like the Alliance and many others dedicated to different rare diseases. 

And to clinicians, the advice is essentially the same. If you have patients with rare diseases, make an effort to actively engage with the relevant disease-specific organizations. The rare disease populations are small, often dispersed, and literally every case counts and informs each other. So, I think, including that aspect in the clinical practice would be very, very valuable for everyone. 

[00:26:08] Dr. Alina Ivaniuk: So thank you so much for all your efforts and for talking with me today. 

[00:26:13] Dr. Luis Oliviera: Absolutely. It has been my pleasure. And thank you so much for the invite and for supporting us as we get off the ground with this initiative that, as you said, hopefully will bring support to those in need.