MED13L Research Update: Where We Are and Where We’re Headed.

In this special research update episode of Voices of MED13L, Rowan Dias opens with reflections from the World Orphan Drug Congress and the MED13L Foundation’s first year participating in the Million Dollar Bike Ride before introducing a recorded community update with Dr. Ricardo Ramirez, Chief Scientific Officer of The MED13L Foundation.

Dr. Ramirez walks families through the Foundation’s current research priorities, including natural history studies, adult outcomes, community surveys, biomarkers, drug repurposing, gene therapy, and the path toward future observational studies. He also addresses questions from the MED13L community about speech development, treatment timing, variant types, long-term care, sleep, the gut-brain connection, and how families can participate in research.

This episode offers an accessible overview of where MED13L research stands today, why community participation matters, and how the Foundation is working to move science forward with urgency, safety, and the voices of families at the center.

Transcript

Voices of MED13L - June 2026 Research Update

Rowan Dias: [00:00:00] Hey everyone. Welcome back to the Voices of MED13L. I'm Rowan Dias, a MED13L sibling working with the foundation this summer as a research affiliate, and I'm starting off this episode for the MED13L Foundation. Before we get into it, I wanna share a couple of updates from this past week. This past week, I was in Boston for the World Orphan Drug Congress.

It is one of the larger gatherings in the rare disease world. It brings researchers, pharmaceutical companies, and patient advocacy groups together to share what is happening across rare disease, from the science to the treatments, to the obstacles that are still in the way. I was there to present my research poster, The Invisible Investors.

The point of it is something our family knows firsthand. Almost all of the progress in MED13L has been funded by our own community. So far, families and supporters have raised nearly $1.5 million towards research. The Invisible Investors is about those people, the families and donors who quietly [00:01:00] pay for the work that could change our kids' futures.

Dr. Ricardo Ramirez, the chief scientific officer of the MED13L Foundation, was in Boston with me for the week. Then this past weekend, we headed down to Philadelphia for the Million Dollar Bike Ride. It was the foundation's first time taking part. Christian and I co-captained our team and two other families rode with us, all representing MED13L.

Together, we raised nearly $1,000. It was good to be there in person with other families who understand what this is like. What you're about to hear is a recording of our recent community update in case you missed it live. In it, Dr. Ramirez walks through where the foundation is in its research right now, what we have accomplished and where we are headed.

So let's get started

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Okay. It's my [00:02:00] pleasure to meet all of the MED13L community, both in the US and outside of the US. Thank you all for joining. This is the first of many installments of this kind of forum. The idea was really to level set and get an understanding of what the community is thinking, your voice, your questions, and talk about our research.

There's gonna be more to follow up as we have this. And again, like I mentioned, this is really a conversation we wanna have because we wanna understand where are-- where we need to develop certain areas or focus on specific areas. So again, thank you all for showing up today. This is really important.

This is a first step. And just as a reminder, without your participation, your dedication, and your involvement, we actually can't move things forward, right? We need this community to work with us as a partner and so that we can drive research forward patient advocacy forward and get us to actionable therapeutics in some way or some way, shape, or form [00:03:00] I also wanna stop and just thank my team.

This is, these are the people that drive the foundation. You may know them by email. You may now see them as a face. Katie, who's our president, Stephanie, Sue, Vanessa, who you just met, Michael, Diana, and all the board members, thank you to all of them for fostering this community and really engaging.

I'm Ricardo. I joined in January as a CSO, and I'm looking forward to really diving in. So I just wanted to-- before we get started, I just also wanted to call some reminders that we think are important areas for you guys to all be aware of. So we do have some upcoming surveys. We do have a three to five-minute, very short survey on NSAIDs, so these are like ibuprofen, aspirin.

And I-- we wanted to understand the general usage across our community. The reason why we're asking specifically for these drugs and compounds is that we have seen some anecdotal data and evidence that these types of drugs could be important for [00:04:00] MED13L drug repurposing. So the more that we understand this could inform our next steps in potential observational trials or observational studies if we think that NSAIDs are a drug we should think about for drug repurposing and has mutual benefits.

So this survey is absolutely important for the foundation to gauge whether or not that is a step that the community wants as much as we're willing to invest. We have a community priority survey as well. This should hopefully roll out in July. There'll be-- there, there will be more details on that as well.

Again, gauging what the community wants all in alignment with these kinds of discussions. And then as Belinda and I and others had discussed earlier, really our over eighteen community survey and engagement. And part of this is really an outreach to the older population because we want to understand where the demographics in-- of the MED13L syndrome patients are moving towards and understand the windows of opportunity that we can learn from all [00:05:00] ages and all ranges in terms of MED13L syndrome severity as well as change over life.

Some additional reminders and updates. Please participate in research. You can do that directly. Example, you want to further understand your genetic variant, you can upload your gene report to the Census 2026. The link is here. These slides will be provided as well as in four additional languages after this.

And this call will... The Zoom call will also be recorded so that you can have all the necessary material. Please visit the website, which also has a lot of information that's useful, and please reach out if if you have any questions. Another plug for Citizen Health. Please enroll with Citizen Health.

This will also appear on our website as a as a potential link in the future. And we are also working on optimizing and rolling out development of simple and streamlined system for all surveys coming soon. So we are focused on how to make the [00:06:00] life of surveys much easier, which I know can be taxing and can be difficult with so many different surveys.

So we're working together as a foundation to better streamline this approach and make this less of a challenge for our community

So how this will work today I'm gonna walk through the Q&A survey responses. The idea here is everyone took the same survey, and I wanna just put back the data as to how everybody participated and what their responses are. This gives you an understanding of what others are thinking, where are you in that alignment and we can discuss from that point.

Please type in your questions in the chat. Stephanie will log them. Hopefully, there'll be time at the end that we can address them, or I can address them as we go, or I can address them in a follow-up. Again, we want to hear from all of you, and without this, we are unable to progress. So this is a two-way partnership [00:07:00] Okay, let's jump into the actual data.

So these are the twenty-seven families who responded. I think it ended up being slightly a bit more, but I captured it at twenty-seven families. Ninety-six percent were parents and guardians. Fifty-nine percent had previously participated, and there's six countries represented. So again, this really helps to call out that multiple countries are part of our foundation, even though we're in the United States, and that's amazing.

We want to reach broader jurisdictions. Below you'll find the age of the individuals with MED13L. You can see that a lot of the population is pediatric. We know that there are individuals over eighteen that we would love to include in our community and really monitor and understand what are some of the developing symptoms.

And so really want to increase the plus eighteen category here in the next phase 'cause we think that's very important for the earlier generations. In terms of research activities that you all have participated in, I'm really happy to [00:08:00] see this. There's a lot of genetic testing.

Obviously most of the genetic testing helps to identify the MED13L specific variant that your child has. Thank you for participating in foundation surveys. Again, this is really helps us to move things forward and get data so that we can design trials and studies. Thank you for those of you who've also participated in our Natural History Study.

There'll be a separate update that I will be providing, what I call a spring update, that talks about what natural history studies are, why they're important, and why they will help move the needle forward for the foundation. Thank you to those of you who have also donated your biorepository and have performed clinical evaluations.

So this is in general a snapshot as to where our community participates and most of you are doing some form of participation, if not multiple. So thank you again

Okay. Okay. So the question, what do you want to learn about? What [00:09:00] topics would you like most expanded? Adult outcomes and long-term expectations. I think this is a re- a key theme for our community that you all all-- you are all aligning on is to what will my child face in the future? Without knowing that, we can only guess.

And so this relies on our older community, Belen and many others, to come back and say, "Here's what my child has experienced during adolescence. Here's where my child is today." In order to inform not only the younger generation, but inform us as a foundation, is there research for and therapeutics that are geared more for the older population that are not present in the younger population?

Because that's something we still don't understand. For example is vision more impaired as you get older? Or is it just impaired early and then it stays? Cognitive delay and impairment, other neurological or psychiatric developments that [00:10:00] occur throughout the life of the individual. So we need more of that, and it sounds like the community wants more of that.

So there's really gonna be a strong call to action from our foundation to bring in the older community. A lot of you asked, what does MED13L do in the brain or in the body? And that's a great biological question. I'll come back to answer that in the next coming slide. I think there's a just a general misconception of what is this protein and why is it so important.

Current research progress. Again you will all hear about the different types of research we're doing in the spring release, which will be out next week in the newsletter. So please keep your eyes on that. Again, I will do specific research progress updates in the future. Right now, it's just getting a holistic view of our community.

Behavioral development and support. I think that our community has also done quite well in identifying areas that can be helpful for the community in terms of behavioral or development. Clinical trials. In order [00:11:00] to get to clinical trials, we need a drug. In order to get a drug, we need to make sure that it's safe, that it's doing what we expect it to do.

That's really an endeavor of twenty twenty-seven going forward. We think we have our eyes set on an observational trial. We'll see how that goes, but we're very hopeful that we can start to move a bit more progressively on this front Therapeutic development and timelines. So having joined the foundation with, which already had early work in dir- in terms of different therapies my focus as the CSO is to really drive therapies that are not only actionable today, but are gonna be safe.

And so really working with partnerships with different biotech industries as well as academic partners will get us there. The timeline will, I will say for this, to be honest, it really depends on the type of therapy and the safety, right? We don't want to rush a therapeutic forward, and we don't wanna cause harm more than what we need to.

And so in line with how [00:12:00] we think about therapy development needs to come a safety component, which is what we're really focusing on, and that really ties into gene therapy and precision medicine. So those two go hand in hand. We wanna make sure that if we have a gene therapy, it's safe that we can administer to our child, and they're gonna be fine.

And that it's not gonna lead to adverse effects. We don't wanna make the quality of lice w- life worse, right? How can families contribute to research? There are lots of ways that the communities can contribute to research, and I highlighted them on the previous slide, right? Natural history studies, biorepositories.

We know that samples are hard to give. I know g- giving blood is very challenging. It's very hard. But without having those bio samples, we actually can't learn about proteins in the body or the DNA, or we can't really understand biomarkers. And again, a biomarker is just a signal that we use in a clinical trial to make sure that the individual is improving or not improving.

So [00:13:00] we need samples in order to move things forward because we need to get data in order to evaluate. Again, a two-way street, and we're th- very thankful and appreciative of having to go through that process, which I know is not simple and not easy. Why symptoms vary between individuals? That's a great question.

And part of it is we don't really understand yet th- that component. There's some severities and differences. We think it's genetically linked, but perhaps there are genetic types of MED13L mutations or variants that lead to certain symptoms. The more data we collect, the more information we have, the better resolution I can say with some certainty or with some confidence that, yes, if you have this type of mu- variant, you're likely to have this range of symptoms.

But again, we're building this out, and we're doing as much as we can with what we have today[00:14:00] 

Okay. I'm gonna go, just go through a few of these. If you could ask one question, and I wanna highlight a few of them. So this individual asked: Can gene therapy truly lead to speech development in older children and adults? That is a million-dollar question, right? When to treat is absolutely a fair question here.

We know that brain development happens throughout the early stages of life, but also throughout adulthood, right? Our brains are constantly changing. They're making different connections. We're able to learn at certain points of our life, and then that also changes as we get into our late 30s or early 40s.

It's harder to learn. And yes, absolutely when to treat is a key question we are asking as a foundation, as a scientific organization as well. I do believe that there are ways to understand when that could be improved, and we think, at least my hope is that, yes, [00:15:00] gene therapies could help restore speech development in some capacity.

The question is when to treat, and is there such a window of not being able to treat? That is still something we are trying to tease out today

Do we have any likelihood to modify the proteins that have not been produced correctly? Yes, absolutely. We are looking at technologies today where we can replace a fully disrupted protein with a completely fixed new protein that would restore the normal levels of MED13L in the body. Yes, that is achievable.

There are technologies that are available. We are partnering with individuals that allow us to do those capabilities. And yes, I think this is a, an avenue that we are invested in and we see potential

Does MED13L affect life expectancy? Again, without having this data from the older [00:16:00] populations we don't really know. We don't think that there is an issue with life expectancy. I think as a foundation, we're more generally concerned as to what happens to the brain as these individuals get older.

Are there changes in cognitive impairments in other areas? Are there psychiatric differences and challenges there? We wanna understand those considerations which could alter life expectancy, but we don't know if there's a, for example, a change in dementia or likelihood in dementia or memory-related types of challenges.

And so we are building this up to give this to fully understand life expectancy for MED13L specifically This ties back into the first question, timing of treatment. If a gene therapy will be found in a few years, will a now four-year-old benefit or will she have missed the train?

Absolutely brilliant question. That is still something we, we don't fully understand. What we are doing is we actually have [00:17:00] mouse models where we can type- try to model this in a mouse and ask, do mice that have MED13L fi- being fixed in certain stages of its development, does that change anything or not?

One of the key caveats, it's a mouse, it's not a human. So whatever we learn from the mouse, it's a key question to ask, is it directly translatable to the human? That's something we have... We only have a tool. It's the best tool we have because, we can only do that. We're also looking at neurons in a dish.

We can take a MED13L patient's cells. We can put them on a dish, and we can change them into brain-specific cell types, and we can model disease in a dish. And so there are ways that we are working on trying to understand timing of treatment and safety simultaneously

Adult transition. Again, what does a transition into teen and adult look like for, and how can we prepare for that? Given that there's just so much [00:18:00] interest in understanding the trajectory of MED13L syndrome along age, this is an area that I feel we really need to invest in as a community because we can learn a lot from the individuals that are in the adult stages, and that will really truly inform what's happening in the transition between adolescent into teen into early adult years and even older generations if they're if they're able to come forward

Severity. Why is the spectrum so wide? My daughter can't sit, talk, crawl, or walk. I will say in my early view of the population as a whole, the MED13L population as a whole, a lot of the same impairments are quite similar. There's definitely intab- intellectual disability disorder that's very common across the entire population.

I think the one that is not is epilepsy, for example. Epilepsy is not persistent across all the different MED13L syndrome variants. But the spectrum is wide because genetically there's some [00:19:00] component we don't fully understand. And so I think as we get... as we build that resource of identifying all of the different MED13L variants that exist, we can tie them to severity, and we can understand, okay, if you are in this particular range of MED13L variants, you're likely to have or exhibit these spectrums.

And so again, these are driven by surveys. The only way we can elect collect this data is you tell us what's happening, we know the variant that you have, and we can start to map out essentially these variants lead to these spectrums of syndromes sorry, of symptoms Long-term care. What happens to my daughter when me and sorry, when me and my husband are gone?

Absolutely fair. I think that is a key consideration for a lot of the demographic of our community, which are on the younger side. What happens later, right? How can they take care of themselves? I think there are lots of [00:20:00] ways that we can provide support in understanding long-term care, and we'll do that through the patient advocacy side on promoting that more specifically through identifying partners or identifying services that really help facilitate long-term care Speech and development.

How can I make the most impact on my son's development, especially speech? I think that's a great question and a really hard one. I would still like to learn and understand from our community if speech therapy has made improvements. I know Vanessa and maybe others might have experience in, in, in having speech therapy and really diagnose whether or not it is truly helping or not truly helping.

Obviously the repurposing of drugs and the therapeutics that we're building are really to promote changes in the brain that would effectively lead to a better outcome in speech and development. And so I think there are multiple ways to think about how to evaluate on a per individual basis.

Remember, because we have so many [00:21:00] different MED13L variants and s- the spectrum is very broad, we won't know what's gonna be successful for one variant versus the other. And I think for us to share what has worked and especially what has not worked, is also just as important. The negative results really help us too and help our community.

So the more that you can share your experiences the more that we can glean and really focus

Okay. So there were some additional questions on gene therapy and timing. So just one example, and I'll touch upon this in the May spring update or the spring update, is that we have a gene therapy that we are working right now with in collaboration with the University of San Francisco. The way that this technology works is that it turns up your child's existing copy of MED13L and it does not change the DNA of your child.

It actually just turns up. So think of it as like a knob. [00:22:00] You wanna turn the knob up on MED13L specifically, and it just turns it up. And there's been success already. So SCN2A, which is another disorder they've been able to show that it restores function even at later stages in life. And so essentially we...

to put it in the, "Has my child missed the train?" is I don't think necessarily we've missed the train. I think we just need to understand a little bit more about how this mechanism imparts or really relays to speech differences or brain development. Again, we are working as fast as the science and safely allows us to do and so that's something that we really wanna consider when thinking about gene therapy specifically.

So again, speech and development, and here speech was the common... most commonly raised concern. And as most of you will know from the update is the natural history studies which track over the course of years they track speech and communication outcomes. The idea is to understand what the trajectories look like in our [00:23:00] population.

Now, it'd be great to have a natural history study that crosses into adulthood as well. So as we think about that population of over eighteen individuals with MED13L, we would like to think about a natural history study in those populations as well and ask, "How do they compare to the natural history studies on our pediatric cohort?"

So I think it's something to think about, and this really ties into drug repurposing and gene therapy because they target the underlying biology that contributes to, developmental delays as well as speech Severity and vari-variability. I touched upon this a little bit, why symptoms vary.

There are different types of mutations, as I mentioned. So we have measured DNA... We have measured proteins in blood which is called proteomics here, and the idea there is that we want to understand whether these proteins that are in your child or circulating in your child identify a particular signal that tells us that they're MED13L versus a non-MED13L [00:24:00] individual, and we can use that in clinical diagnosis, in, in diagnostics going forward, as well as our natural history studies that helps us.

One, one, key point, this is exactly why broader participation matters. Everybody matters in the community. Doesn't matter if you are older or too young. There's no b- There's... we are open and interested in taking everybody in because we need the full data. We need the full picture of what MED13L life looks like Adult outcomes and long-term care.

This is the number one topic that the families want addressed. And, there's limited data on adult outcomes, as I mentioned, for methylmalonic syndrome. The ACTION natural history study is building the first da- dataset. We think that we'd like to build a secondary dataset at some point for the older population.

And we hear you. This is a priority for you as much as it is for us going forward, so your participation is absolutely key here So I'll come back to this. This [00:25:00] is the slide I showed earlier, and I just wanted to touch upon, what MED13L does in the brain and body. It's what I haven't really touched upon so far.

So as we know, MED13L is a key protein. You need at least one-- We have two copies of MED13L in all of us. When one copy is disrupted, you have MED13L syndrome. When both copies of MED13L syndrome-- or both both copies of MED13L are disrupted, you actually cannot be born. It's not viable. It's important that at least one copy is expressed or maintained, and it's in...

this MED13L protein is expressed in all of the cell types we have in our body: eyes, skin, heart, intestines, hair, everywhere. And when there's a disruption, it not only leads to a disruption in the brain. We know that there are cardiac issues. We know that there are visual issues. We know that there are muscle issues, and all of them essentially contribute to MED13L syndrome.[00:26:00] 

Now, what we see in our community, in our individuals is that MED13L most generally disrupts cognitive impairment. So it's not ranking specifically that the brain is the most important. It's just what we see as a manifestation of having MED13L syndrome and what really as a community we really want to be able to mitigate or to work on.

That's not to say that we wouldn't work on cardiac or muscle problems or issues that may arise in the future. It's just the most prominent symptom that we're faced with and that I think most of the community is really concerned about, and that is fair. So that's why a lot of our therapies are really focused first on brain-centric aspects because we think that's where we can actually see a meaningful change.

So as we work on thinking about others-- what others are experiencing, for example, in the adult population, if psychiatrics or if we see, for example, there's a [00:27:00] propensity for, heart failure, for example we would say, "Wow, okay. We need to start looking at the heart earlier. Maybe there's a heart therapeutic we should think about so that in the future they don't face cardiac problems."

Again, we don't know where to point and shoot because we don't have the full data set. I hope that makes sense to everybody

Okay. In the survey I asked, what feels unclear and what worries you all. I'm gonna read a few of these out loud really to just get everybody the sense of what's confusing or unclear. All of it, and I get it. It's a lot of information. You're learning a lot as we're learning. We're updating you in real time as much as we can.

We're also learning as well, right? We're also learning about MED13L syndrome. It's been around since 2015 as its o- official identification, and the foundation was started in roughly 2017. So you have to think about where we have come [00:28:00] and where we are. This foundation has done a lot. We hear you. We are here.

This is why we're doing this. Gene therapies, what it is and how it works. At some point I'd like to do a deeper dive on gene therapy for our community. Not today, but at some point I would like to walk everybody through the stigmas, the, fact or fiction on gene therapies really to inform what it is and why it's safe or, what's been in the news and things like that.

Not today, but at some point I will do a specific primer or a specific talk on gene therapies. Variant types, right? A lot of you wanna understand what's a missense, what's a deletion, what's a VUS, which is a variant of unknown significance. Again, this is here tying to the actual MED13L type of mutation that the individual carries.

What's more important than the variant type is what does a variant type mean in the context of the life of my child, right? If they have a missense mutation, how severe is it compared to [00:29:00] other missense mutations? There are many different types of missense mutations. There are many types of deletions.

More than focusing on the variant, we wanna focus on what the, what do the symptoms actually mean, and that way we can inform on what symptoms we're trying to treat. We're not treating necessarily the variant. We're treating the symptoms. That's what we wanna do as a community. What MED13L does in the brain.

There's, we are on the cutting edge of understanding that as well. So as a foundation that's focused on patient advocacy and driving science, we're also learning and discovering what this protein does in the brain. It's not fully understood. We know that it controls the genes in, on, on how they're turned on and off, but that's about it.

It's a central, what we call a central regulator in the cell Can medications help a genetic condition? We think so. We don't know how much it can help, but we think help is a very broad term here. Any [00:30:00] change could be meaningful. A few words could be a change that is meaningful and profound. There is no limit to what is gonna be gained here.

And so I think with that in mind, we're pushing forward on all areas that are robust and safe so that we can achieve even a 1% change, even a 2% change. Full restoration, we don't know. But if we can see meaningful changes that impacts your life and impacts the life of your child, then that's a win.

Why severity varies so much? We talked about this earlier, different variants and expected outcomes for their specific child. Again, this is a case by case. It's hard to know, but the more data we have, the better we can start to at least guess or predict, here's a quality of life from other individuals that have similar symptoms, that maybe have the similar kinds of variants Our job is to make [00:31:00] the science and also the advocacy side very accessible, right?

If something is unclear, it's our fault, not yours. That's part of what today's dialogue is for. Today's session, and as I mentioned, other future updates, they're gonna break these topics down in, in much more simpler language with a forum and specific focus on what you wanna hear. And gene therapy sounds like one of them, as well as looking at what our adult population looks like We also asked you what worries you most.

What happens when we're gone? Long-term care. I think this is really important for us to also address. What is existing out there for our community in the future? Are there services that we can start to look at now? I think that's very fair, and we're gonna need to address that. Unknown future, lack of clarity.

Of course, this is normal given you don't know what you're expecting. Adult autonomy and independence, again, ties into what do we see [00:32:00] in our adult populations? How much autonomy is there? How much have you seen a decline in that? How much have you seen a decline in speech and communication? Can we measure that, right?

As scientists, we wanna be able to measure these things in a way that gives us some sort of a, an understanding as to how much of a decline. Is it ten percent? Is it fifty percent? We don't know. We need to build that. We can only build it with the community. Whether it will get worse, regression. We don't know yet.

We don't know what worse is. Is worse measurable? Can we say that there's a decline that's measurable? And how can we mitigate that? Lack of awareness and research funding. Yeah I think staying involved in the community through the website, through all of the social media components, keeps you informed.

We are doing the best to promote MED13L worldwide, going to conferences speaking to experts in the field. A lot of individuals have [00:33:00] learned about MED13L syndrome. A lot of biotechs and academics are interested, and we're building research funding as well internally, as well as externally to get us there.

Co-occurring conditions and complicating things. Fair. We don't know yet if we're gonna see a change in the in the genetic-- sorry, the behavioral makeup. Are there psychiatric disorders that are gonna also appear as our population gets older? So we'll have to monitor that, and we'll have to see what other diagnoses come up as well

So we hear every one of your concerns. They are valid. The research programs we are building, whether it's the natural history data, the biomarkers, the drug repurposing, gene therapies, they're all designed and they're all geared towards answering these questions and to reduce the uncertainty over time

What gives you hope [00:34:00] and motivates you? This was really important for us to learn, and I think it's important for all of you to reinforce this with each other. What gives you the most hope right now? The foundation and the research taking place. That means a lot to us because we are living, eating, and breathing MED13L syndrome all the time.

So thank you for acknowledging that we are doing our best, and we're trying to move things forward to change the life of your children. My son, he started to walk and is beginning to comprehend each more more each day. That is amazing. I would love to hear more about what you have done. So these kinds of improvements, please share them.

Please share what's working for you. If you're seeing changes, you can help provide us information, and we can share that to the broader community. Constant push toward gene therapy. Gene therapy among other therapeutics. We are pushing very hard. That is something that I am somewhat relentless over.

The efforts of the foundation [00:35:00] parents and the fact that the syndrome is not progressive. I think what I wanna say about this is yes, in general, the... i'm really happy that a lot of the parents are engaged. Our board is amazing and also driving a lot of and supporting a lot of what is being translated in terms of the community to me and to others.

With the concept of progressive, we don't really know if MED13L is progressive or not. I... We know that in general, there is likely some decline, but we don't know what that decline is. We don't know what progressive is here. So I would love to learn more about whether or not we can definitively say it's not progressive or it is progressive.

I'm glad that most of you find research in communities of support. That's great. We think that these kinds of opportunities as well as our in-person meetups roadshows any way of community engagement is really important. My daughter's growth and happiness. This is amazing to hear. I'm glad that this provides hope to you and I hope to many [00:36:00] others as well.

That research is ongoing and someone is actively working on it. We are actively working on it. This foundation is really dedicated to moving things forward. It may not always work. There will be things but... that we will work on that just doesn't get us there. We have to be able to move things forward that work and stop things that aren't working, right?

As a foundation, we need to prioritize as well. Seeing families with older children. Yes, please, we need more of this.

What motivates you to participate? Learning about my child's condition. I assume that's why you're all here today, and that's fantastic. Please keep attending. Please keep contributing. Helping future families, advancing therapies, and access to clinical insight. All of these are at the helm of what we're trying to do in this organization.

So I'll end with this part here saying, nearly every family shares the same motivators, as you can clearly see, learning [00:37:00] about their child or adult, helping others, contributing, advancing therapies. And this alignment really betw- you know, this alignment is what drives you and what drives our research.

It also is what makes this community very extraordinary, is the urgency, the patience with each other, and the willingness to contribute and help in any way possible. Even if it's a, an update, right? You're helping the community. Your children and adults are the motivation behind everything we do

I'll move on to barriers to participation. We also wanted to understand what makes it challenging for you to participate, and how can we help you to be more engaged? This is super obvious. Travel, right? We are all here on a remote call. We're not in one location. It'd be best to all meet in one place, and we know that is at times almost impossible.

So we hear you. Online participation [00:38:00] is still better than no participation. We hope to do more in, in-person meetups and support that as best as we can so that we can engage in person as a community and really get to meet in person. But the best that we can do is these kinds of forums Lack of information.

I would say that, most of what the barrier for participation is really based on travel. Lack of information, I think, the website does a pretty good job. Our newsletters do a pretty good job. We're always happy and engaged to respond. We get lots of Facebook questions that we help.

We field emails. So please reach out, find ways to, to navigate through the website as well. We're happy to walk you through if needed there. It's clear, time commitment. We all have other things going on, especially when you have children families, and so totally understand that. Language barriers.

We're also addressing this too. We-- we're starting here today and I've already started by making materials in multiple languages as best [00:39:00] as we can. It's hard to do it for everything, but we're really trying to do it to engage the contributions from other communities as well. So thank you for being patient, and please understand that we are doing our best here.

Child's comfort, trauma, and privacy concerns, I think these are very minimal in terms of barriers for participation. So we also ask you what would make participation easier. More roadshow-like options, so travel isn't as expensive. We're working with Combined Brain, which is the organizer of a lot of these roadshows, so that you can go and, contribute to the bio-repository.

Option to participate in Germany, for example, blood sample donation. We are, working internally within the US is already a challenge across states. Working across countries is a secondary layer of complexity. We are really doing our best. In terms of the European base, which ties into this, we have our international alliances, our global alliances, to really foster in the relationships with Spain the UK, with [00:40:00] Germany, with France and really trying to engage not only just the communities but also the science, right?

If you think about it, all these international organizations are trying to do the same thing. Why aren't we working together? And I think that's really our view is why not work together? Why are we duplicating efforts? It costs money to do therapies in France and Germany and the UK and Spain and the US.

Why are we not harmonizing? And that just takes a little bit of massaging, and we're working on that now If opportunities are available in the Pacific North-Northwest. Yes, we are heavily skewed towards central and the East Coast of the United States. We are working on broadening across the US.

I believe that's also capable now. Clear instructions and local options. Again, this includes the Bay Area, the UK, Philippines. Expansion through these other areas is a work in progress. Just as a reminder, there are five of us. We're trying to, bring the whole world of MED13L together, and that is a lot for five people to do.

We need your help as [00:41:00] well. So please, if you find ways that you can participate or take on some of these roles with us, we'd be happy to welcome that opportunity. This session is recorded. Great. At least that's one thing I can make participation easier for. Providing options that won't be traumatic for my child.

Again, I would like to understand where this is coming from. It might be from donating blood, which is extremely traumatic. It's hard to source blood from a non-invasive kind of approach. There are some apparatuses that are being developed, but, if we need-- it's unfortunate if we have to, stick your child with a needle to get blood.

That's part of the burden, and we appreciate you being patient with us on that. Back to the language, German, Portuguese, and Spanish translations. As I mentioned, we also have that, and then via Zoom. We will do more of these via Zoom. This is also a plug for Vanessa. Please listen to all the podcasts that she does.

They're extremely helpful and informative. This is-- these are conversations that she drives with [00:42:00] others in our community, and there's a lot of information that's super rich. Put it on while you're driving, while you're running, whatever you're doing please. All right. We hear you.

Travel is challenging. We're working on that. We're working on expanding remote participation, as I mentioned, building partnerships with U- with sites outside of the US Northeast and providing translated materials for non-English speaking families and making research as low burden as possible for children where possible as well

Let's talk about priorities. Please rank the areas most important to your family. Again, many of you might agree, many of you might disagree with some of them. What we found is that therapy development is among the highest. Therapy development is your clear number one, and it's ours too. We also identify behavioral research, clinical care guidance, family networking, adult MED13L resources, [00:43:00] and lower on the end is the science side.

So if you look at the top part, which is what most of the families f- see as a priority, is behavior research, some sort of therapy development, and clinical care guidance, right? How do I take care of my loved one today? How can I work on certain behavioral cues, which I also see as a challenge. So we want to help, not just, we don't want to just help now, we want to also help for future treatments, right?

So we're building programs that address both near, what we call near-term clinical guidance and long-term therapeutic development. With the earlier-- because we have a lot of, a lot more data from our younger populations, really to build out the adult MED13L resources, that's gonna require the adult populations to come forward to be able to work with us, to be able to provide this information.

Which is why we're really thinking about a, an adult-centered excuse me, an adult-centered MED13L survey in the coming months[00:44:00] 

how you want to engage So the preferred format is this exactly what we're doing today, short presentation and some discussion, moderated questions. Open mic not so much, and breakout not so much. Anonymous questions, not so much. So based on today's feedback, we really took this into account and designed today's talk in this format that you can take with you that's gonna live forever.

As a short scientific overview is what we promised. This is where we stand. We have a moderated Q&A, so we'll also have questions and answers. Again, if you don't have a question today, but you have a question later, please submit it to info@med13l.org. Open discussion at the end for real-time questions.

An anonymous question option is available throughout our surveys

I just put this here because I think it's really amazing that we're able to reach outside of the US. [00:45:00] When I joined MED13L Foundation, I really didn't know how much interactions we had with with individuals outside the US, and I think it's amazing that we are reaching far and wide. And we want to essentially contribute and keep supporting other communities, even those outside of the United States.

And so thank you for being a part of that, and we are committed to expanding access to our international families as well, a- and provide, when possible, translated materials, participation like today, and partnerships with us So thank you to all of the families that participated. This has been a really amazing and eye-opening experience for not only myself, but us as a MED13L Foundation team.

I wanna open this up for discussion. We'll transition now to specific questions in the chat, as well as specific questions that you all may have. I'm gonna ask Stephanie now. Stephanie, if you could come on and help [00:46:00] me to start addressing some of the questions. Yeah. So the first question we have is from Vern.

How far away are we from seeing a MED13L patient trial for the gene therapy Ricardo was speaking about? Hey, Vern. Nice to see you. Thanks for the question. I think we are much closer to an observational study trial for a repurposing drug. We have enough data for a particular compound that has shown restoration of MED13L protein in neurons.

We also have identified it as a potential compound from the blood proteins or biomarkers study that we've performed across I believe it's twenty-seven MED13L individuals as well. So I think the first step is the observational study trial. It requires a lot of alignment with investigators who are willing to drive that trial, but we think that might be where we aim next as a twenty twenty-seven [00:47:00] endeavor.

Again, this requires participation from our community and we will keep you updated on the status as we start to formulate this process. As we as a foundation have never started a or led an observational study trial it's a new horizon, but we're excited about the prospect of it. In terms of gene therapy, just to answer that part, we are in the basic research of gene therapy specifically, or gene editing.

I would say those are two different things. Gene editing is what we're doing. For antisense oligos, which are a separate technology altogether, we're a little bit further along. And so I think, as we evaluate the feasibility of these compounds to work for restoring MED13L we'll have a better chance or better understanding of the timeline and the horizon for that.

But I would say it's definitely not... I think in twenty twenty-seven, we'll be able to understand or de-risk whether or not these are platforms or therapeutics that are viable for our community. That's really the goal of this next [00:48:00] year Thank you, Vern. Next question. 

Stephanie Khio: Next question we have from Belen. Any advances in the different investigations such as repurposed drugs, gene editing, which were taking place last year?

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: That's a great question. I believe those-- I believe one of the drug repurposing studies that I think you're referencing to is gonna be publishing some of their findings. We have not seen the publication yet. But once we do, we will share that to the community broadly. This was a very small number of MED13L individuals that participated in this study.

So in terms of the drug repurposing the drug compound that we're thinking about for twenty twenty-seven holds more data and more promise, and so we're excited about th-that prospect for twenty twenty-seven. In terms of the, I think it was the gene therapy it... I think we're still in basic research as of right [00:49:00] now.

Having joined in January- of evaluating with the team where we are and what term-- and, what science i-is being done is still ongoing. But we will report and share when we have clear, improvements or news to share. But keys-- Belen, please look out for the May update or the spring update

The next question we have is from Beth. We don't have an official diagnosis, but a variant of unknown significance has been found on MED13L. Is our experience useful at this stage, or do you prefer we wait for an official diagnosis? I'll also give you Katie's reply and then see if you have anything else to add, Ricardo.

Thank you. 

Stephanie Khio: Katie says, "Your experience is useful at this stage. Many members in our community have a variant of unknown significance diagnosis of VUS. We'd love to have you enroll in the Census, Rare-X, and Ciitizen to help provide clarity to your diagnosis." 

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Perfect. Katie did my job. Yes, it's important.

Please, everybody is important. Doesn't [00:50:00] matter if it's a VUS or not. We are working on collaborations and partnerships with others here in Boston on understanding VUS. So the more we have on VUSs, the more we can test that experimentally in a dish. So we need everybody. You are all welcome

Stephanie Khio: Okay, we have a question from Chase: If you had unlimited funding, what would you do? What is the moonshot? 

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Wow. That's a great question. If I had unlimited funding. Wow. I typically work on a budget, so the fact that you're asking me to think outside of the box is interesting. I think the two programs we have, I would push harder, but I- there's a few more modalities that I would throw money at that I think have a good prospect.

That's not to say we aren't in- investing in those already. We're working on partnerships and relationships with biotechs that are working in these spaces. But if we had unlimited funds, that's probably where I would go. I would go [00:51:00] to the, where there's been success-- where there's been success already, and there's companies that we are talking to that have done that.

It's just a matter of getting in line, unfortunately. And that line is also dependent on cash. So with more cash, you can buy your way through these situations and these doors. But as a scientist, that's where I would put my money in these technologies that I know are gonna, are likely gonna drive.

So I'm hopeful we can get there. It just may take us a little bit longer because of the constraints of capital. But I'm not concerned by it. Thank you for the question, Chase. 

Stephanie Khio: Hapa Aritz, I'm hoping pronouncing it correctly asks: Is it very difficult to gather information on MED13L for eighteen-plus years cases?

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Yeah. It's, I don't think it-- I don't think difficult is is the right word. I just think we haven't been getting a lot of of engagement. I think we, we would like more engagement from these population-- from this population of individuals. We are not a pediatric-centered organization.[00:52:00] 

We are a MED13L syndrome-centric organization, so all ages are necessary. And obviously from today's talk, we need all ages to participate because that informs where we go next. This is a, a verbal call to action. We need everybody, adults, variants, doesn't matter. We need everybody to participate because you're, you are helping.

Whether you think you aren't or you are, I think the data today shows you that you are helping. So please continue and, advocate where you can to get everybody to participate if possible.

Stephanie Khio: Vanessa asks, "Can you explain to the community what an observational study means?" 

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Yeah, sure. So an observational study is a study that's designed by usually an investigator, a clinician or an academic at an institute or hospital. The idea there is that they are, with government [00:53:00] permission, able to design a study on a small number of individuals, for example, MED13L syndrome, to test the efficacy of a particular compound or drug, in this case it would be an FDA-approved drug over some time.

So we would build a study that we would treat your child or adult with a compound X at a particular dose, and that we would set up particular surveys or measurements to capture what that drug does in each of these individuals over some time. This data then is used to understand whether or not we saw any improvement in any of the symptoms or measurements that the clinician or investigator are collecting.

For example, let's just say we built a test to pronounce certain words, ten words, and everyone has to do the same test. And you put them on the compound or the [00:54:00] drug, and every six weeks you ask, "Is there an improvement in the child or adult being able to say the word?" That is data that is used to ask wh- on the drug, was there an improvement or not?

It's a very simple example, but it's one way we can ask, did the drug improve speech, right? So these observational trials gives us a glimpse as to whether or not there's actually some benefit to taking these compounds. Thanks, Vanessa.

Stephanie Khio: Anna asks, "Do you believe that splicing platform may also be explored as a future option for treatment?" 

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Great question, Anna. So for those of you that are unaware of splicing is a particular mechanism in in DNA where you can you can recruit specific enzymes or proteins to change the way MED13L is made as a protein.

Because we have so many different variants in [00:55:00] MED13L, this particular approach will only help splicing specific variants. The technologies again, this is a nuanced component, but not all technologies can treat all variants. So one of the, one of the aspects of our foundation is we're trying to figure out a pan-therapeutic, a all-variants therapeutic.

Right? There are ways that you can fix one mutation, but only that type of mutation, and those are the technologies that exist. But we, as a foundation, are trying to be as holistic as we can to broaden the therapeutic potential of our entire community. Now, that's a lot, right? We wanna fix all MED13L variants instead of fixing one.

And splicing is an example where you can probably fix a few, but not all. So I hope that answers the question. A-at least from our perspective as we're trying to be holistic in terms of serving everyone, which is why we want everyone to be involved[00:56:00] 

Stephanie Khio: Ricardo Belen is asking, does naproxen help our loved ones, and how, and what about metformin? 

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Yeah. Great questions. So naproxen is a class of compound called an NSAID. NSAIDs like ibuprofen, aspirin these are pain relievers in a sense. We have some interesting data on NSAIDs. Nap- naproxen is one of them that we are looking at.

We are not prescribing naproxen or NSAIDs for use. We are evaluating whether or not there's the potential to understand whether they could be used as a repurposing drug. The NSAID survey that we are rolling out hopefully soon, is part of understanding how our community is using NSAIDs and whether or not we see any information.

It's just to understand how you all are... whether you all are using or whether there's any [00:57:00] benefit. So to date, Belen I can't necessarily prescribe or say that naproxen should be used for MED13L syndrome. I think we still have some data to collect which we're excited about, and doing so in, in today that will get us closer to understanding that.

And the goal is if we're confident that naproxen is worth moving forward, for example, we would do an observational study with naproxen

We have a question from Christopher: AI is transforming nearly every industry. How is it being applied in the genetic therapy and ASO space specifically? And is it reasonable to expect that AI will meaningfully accelerate the timeline to potential treatments, whether by shortening 

research cycles, improving target identification, or reducing the burden of preclinical testing?

Great question. AI has revolutionized, like you mentioned, every industry. It has revolutionized [00:58:00] medicine already. The question I have is it gonna revolutionize it for MED13L? When I think about MED13L specifically, I think about ASO development, I think about gene therapy development. AI can only do so much.

I think AI is likely going to be much more able to identify new mechanisms for very complex disorders like Alzheimer's disease, where it's multiple genes that are involved. Here we're looking at one gene, MED13L. In some ways, we call this a monogenic disorder. One gene, mono. The idea is that we know exactly what we need to treat.

It's MED13L. That's the key gene that we know is disrupted in most cases. So I think AI will help us to shorten some of the research cycles that you had mentioned because it's gonna shorten the development of the therapeutic, or it's gonna shorten the commercialization component, or it's gonna shorten that.

It-- that then in [00:59:00] turn shortens the re-regulatory path. But at the end of the day, biology is still not solvable by AI, right? That's a very hard thing. So in order to test biology, we actually have to do the experiments in real time, not in silico or by AI. That's where we think our strength is on the biology side.

We will use and leverage AI where possible when it makes sense for us. But we aren't relying on AI just simply because AI isn't able to solve even some simple problems, let alone hard problems like MED13L I'm a proponent of AI. I just don't think it's gonna solve everything

Aritz is asking, "Is sleep disorder a common characteristic? Does anyone know how to address it?" 

Yeah, I'll I'll say from what I've heard, yes. I'll let maybe Katie or Vanessa who we've talked about this before. Do you guys wanna also just chime in, please?

Vanessa Dias: [01:00:00] Sure. For sleep disorders, it does seem to be a common thing within all neurodivergent individuals not necessarily just MED13L.

There are a lot of treatments that different families have tried that they've posted on Facebook. As just to piggyback off of what Ricardo is saying is that we as a foundation cannot recommend anything until we do a full clinical trial and can legally recommend something that it's been approved by the FDA.

Now, with that said, that's why I mentioned the Facebook group or in connecting with other families, is because other families can tell you what has worked for them, and I can speak to you not as a board member, but as a fellow MED13L parent, and I'm also a registered nurse by trade, so I'm-- anything I share with you has, is literally just as a fellow MED13L parent, that many families have seen some improvement in changing the kids' supplement.

We're [01:01:00] adding magnesium. Some families have added 5-HTP and some families have added melatonin all under the direction of their pediatric physicians or their physicians in general if their children are older. But those are the things that we've seen that has worked being a parent-reported treatment.

I know that there are, sleep habits that I'm sure everyone has tried that probably have failed too. But those are the top things that I've seen that people have chimed in and said is melatonin supplement magnesium supplementation as well as 5-HTP. But again, speak with your doctors first.

But as a foundation, we cannot recommend anything until we've done a clinical trial. Correct. Yeah.

Does that answer the question? 

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: I think so. Okay. 

Stephanie Khio: We're also asking what is FHTP? 

Vanessa Dias: 5-HTP is actually, it's a supplement that I'm [01:02:00] not sure where you're located, but in the US you can get it at pretty much any supplement store, at Whole Foods or, natural store. It's actually tryptophan. It's what the, when there's, most people think that when you eat turkey you get sleepy.

It's because of the tryptophan component within the turkey. That's all that it is. It's an amino acid that one of the side effects is it makes you sleepy

And it's tryptophan. Yeah. I can type it in The chat. Thank you. Bye. Thanks, Vanessa. 

Stephanie Khio: Anna is asking, "Some research shows that altering the gut-brain biome assists in certain symptoms in individuals with autism. Is there a crossover with patients with MED13L?" The gut-brain axis? That's a good question. I haven't seen any specific data that shows a gut-brain relationship [01:03:00] for MED13L specifically.

The gut-brain axis is super complex. Even in autism it's hard to know how therapeutic intervention works there. Like the gut is turning over all the time, right? Our intestines are constantly turning over all the time, and so therapeutics for the gut and the intestines are really hard. There could be relationships with types of foods, processing of metabolites in the intestine that could have secondary effects.

But I think we just don't know enough. It's not an area we've really looked into specifically. But it's something that that's, that, that exists so thank you for that. 

Vanessa Dias: Ricardo, may I chime in with that? Yeah. Just the neurologists that, different neurologists I've seen for my daughter, Elle, who's nine a lot of them have recommended probiotics to introduce to their diet, which are just the healthy gut bacteria.

To Ricardo's point, there, we haven't done an official study on it and no one else has, so [01:04:00] we can't speak to a correlation between, the gut-brain relationship with MED13L. But I think in general, neurologists recommend that for their neurodivergent children or their patients, is to have them on a probiotic, which is again, something you can get at a natural food store wherever you live.

Or if you don't have access to that, just increasing like yogurt intake. But, there's also that caveat of some people, thinking of gut and brain, they think, dairy causes inflammation, which then causes increased challenges for kids with neurodivergence.

But in the end, speak to your pediatrician. Probiotics are something that I, when I've spoken to many different families, they have their kids on probiotics

Stephanie Khio: That's all the questions we have now. If anyone else has any additional questions, please feel free to put it in the chat

Ricardo Ramirez, PhD, CSO of The MED13L Foundation: Thank you all. Yeah, we have a-- we [01:05:00] made it just in time. Please I'll s- I'll stay on and if you guys have any additional questions, I'd be happy to field them. You can come off of mic and talk openly. Again, thank you all for your participation, for doing the surveys. We're here all the time to help and and move this forward with as much urgency as you all have for seeing progress.