Global Genes Rare Leader: FOXG1 Research Foundation Co-Founder & Executive Director

The Basics
Name: Nicole Johnson

Title: Co-founder and Executive Director

Organization: FOXG1 Research Foundation

Social Media Links:

Disease focus: FOXG1 syndrome is a rare, pediatric, neurological disorder that greatly impacts brain development and causes severe physical and cognitive disabilities. FOXG1 syndrome is caused by a mutation to the FOXG1 gene, which is one of the first and most critical genes in brain development. There are currently about 900 known individuals with FOXG1 syndrome worldwide, with the diagnosis rate climbing steadily year-over-year. FOXG1 syndrome is typically a de novo (spontaneous, non-inherited) mutation, with multiple variants that affect individuals differently along the spectrum of severity. Most children born with FOXG1 syndrome are nonverbal, have severe cognitive and physical disabilities, experience intractable seizures, respiratory distress, cortical vision impairment, feeding difficulties, reflux, movement disorders, and more. Less-severely-affected FOXG1 patients present with autism spectrum disorder.

Headquarters: Sands Point, New York

How did you become involved in rare disease: Becoming involved in rare disease, science, and even medicine is the last thing in the world I would ever have expected or chosen as a career path. But, when my daughter Josie was diagnosed in 2014 at 2 years old with FOXG1 syndrome, it became the only area I was interested in dedicating my time to. There was just very little known about FOXG1 syndrome. At the time, there was not a concerted research effort underway for FOXG1 syndrome. It was lumped under Rett syndrome. On her genetics report it said congenital variant of Rett syndrome, but it’s not Rett syndrome. It’s a completely different gene with a variety of variants that all present somewhat differently. At that time, I knew that a real effort centered on FOXG1 syndrome had to begin and that I was at ground zero for what would grow into a much larger organization.

Previous career: Television producer for CNN, NBC, and worked in corporate communications. Founding partner for Qello Concerts streaming service, now called Qello Stingray.

Education: B.S. from Towson University in Maryland

The Organization
FOXG1 Organization’s mission: We are the parent-led, global, rare disease patient organization driving the research to find successful, precise therapeutics and ultimately a cure for every individual in the world with FOXG1 syndrome while deeply focusing on patient advocacy and support. It’s our mission to accelerate research to find successful therapeutics for FOXG1 syndrome and related neurological disorders.

Organization’s strategy: We’re centered in three main areas that are integral to driving drug development. We have a three-pronged approach. One is research. The second is data. Third is the patient community. We’re building a consortium of brilliant scientists to work together to deeply characterize the disease, answer the critical scientific unknowns, and test potential treatments ranging from cutting-edge gene therapy to nascent technologies. We have a ‘leave-no-stone unturned’ mentality. At the same time, our strategy is centered on covering all variants of the disease with a suite of assets that represent all the mutation categories, and then matching them to the coordinating patient data. That’s particular to how we go about things. Having mouse models, cell models for the missense mutation, the nonsense mutation, the deletion, and to be able to layer that over the data from the patients of those exact mutation types, is helping us to provide rich data on our patients and the disease.

Funding strategy: Since we launched in 2017, it’s been a grassroot roots effort with family and friends pulling everyone together. We do as much fundraising as we can, applying for grants, putting together our grants team, building strong teams within our organization. We have a fundraising committee now and we’re looking at all the different opportunities. Fundraising is one of the hardest things about this. We need millions of dollars, and we need people to care about a rare disease. Our fundraising strategy is to do everything we possibly can to raise money and we’re always trying to think outside the box for different ways to do it.

What’s changing at your organization in the next year: We’re just growing so fast. We’re building our team to meet our needs. I’m basically working 60 hours a week right now with a to-do list that would double those hours. We’re hosting the first-ever FOXG1 parents conference in November. We’ve had two science symposiums in the past, but this is the first time that we’re bringing FOXG1 parents from all over the world together. We’re hosting it on the beach in Florida so that we can provide parents and caregivers with a retreat-like experience and an opportunity to relax while we all connect and learn. Our worldwide foundation chapters are growing. We have a FOXG1 Research Foundation in Australia. We have an affiliate association in Spain and in France, and we have more in the works. We’re also about to announce the very first clinical trial for FOXG1 syndrome. This is for an epilepsy medication that is showing very good results for other epilepsy rare diseases.

Management Style
Management philosophy: I’m a producer at heart, coming from CNN, I can see everything that has to come together and all the elements to make it a success. I have somewhat of a positive, perhaps even spiritual, management philosophy. We don’t get the minutes of our lives back. And for our children, we don’t have time to waste. No matter what we’re doing, no matter who we’re working with, it’s imperative that we work smart, efficiently, innovatively, and carefully. But, most importantly, you need to feel good while you’re doing it. At the end of the day, for me, the most important thing for everyone is that the work we do feels good. Our lives are very hard as FOXG1 parents. Growing a global organization from the ground up, building it like a startup, working with industry, academia, parents, and more, with the goal to cure a rare disease in our children’s lifetime, is a stressful role to take on. Protecting our good energy is so important and you must identify what is draining that good energy and know when to call it. You must remove what’s draining you. And once you do, you open the door for much more productive and uplifting things. My management philosophy is not to be too rigid and allow for free-flowing communication because that is where the best ideas come. Stay organized and constantly maintain all the verticals but be nimble to change where change is needed.

Guiding principles for running an effective organization: We’re guided by these shared principles: Never feel locked into one way of doing things. Never think you know it all. Always challenge yourself/us to do better.

Our guiding principles are these questions: How can we do this better? What can we learn to improve ourselves? How is our current process working? What are the gaps that are slowing us down? How can we identify and solve them? What do we need to? What do we need to perform better?

Back to my spiritual style, I personally ask, are we leading with gratitude? I come back to this question often in my life and it always delivers. Breathe through the stress and come back to gratitude, and then and only then can you focus. And never lead with ego. I think this is common in our space, in business, and in life. I’ve seen how it’s the most counterproductive aspect in business. The goal is always, what can we do to help FOXG1 children live the healthy and able lives they deserve.

That means working as a team and seeing the big, holistic picture. And one more is just to value everyone and don’t forget your purpose. Every person, every touchpoint of this organization, is integral to our success. If you’re putting in one hour a month, or 60 hours a week, your time is valuable and appreciated. I want everyone to know this. I want everyone to smile knowing we’re here to change the landscape and to improve human life. We have a tremendous purpose, and it should always feel good.

Best way to keep your organization relevant: Be innovative. Be creative. Always reach out to people. Always make that connection. Always think, what can I be doing to keep my organization relevant. But you must be present. You must be out there. You found me to write this article. You found us. When you’re thinking innovation and you’re connecting with the greater rare disease space, and you’re seeing 10 steps ahead to reach your goal, you will be relevant.

Why people like working with you: I’m a good listener. I have a good way of hearing what people want to do and then turning it into action. I’m compassionate and most of all, it’s clear that I’m passionate about what we’re doing.  

Mentor: Orrin Devinsky, NYU Epilepsy. Bruce Leuchter, CEO of Neurvati, Daniel Fisher CEO of Tevard and Dravet father, John Crowley was an original mentor when Josie was first diagnosed. My cofounder Nasha Fitter is also a mentor, the Angelman FAST Foundation, Terry Jo Bichell from CombinedBrain. Mike Graglia from Syngap Research Fund. Those are just some of my mentors in this space. I’ve had mentors throughout my career in different areas. Myron Kandel from CNN financial news will always hold a special place. There is a new Netflix documentary out now about my writing mentor and friend, Ben Fong Torres.

On the Job
What inspires you: What inspires me most on the job is the FOXG1 children and their parents. Every single one of us is living an extremely difficult life. Every single parent that I come across just has this incredible, unique ability to advocate for their children. It’s the most inspiring love and passion that I get to see every day. The parents inspire me so much, but our FOXG1 children inspire me so much because they’re just amazing. I always say for the things that our children cannot do because of their disabilities, they make up for in this incredible, pure love and joy that comes out in every photo I see. I just want to give them the abilities and the healthy life that they deserve.

What makes you hopeful: The SMA story makes me very hopeful—that there is a gene therapy story out there for a rare disease that is working. While there are few actual approved cures out there right now, I believe we’re living in a time of scientific breakthroughs and that there will be a tipping point when we go from just a few successful gene therapies and just a small number of therapeutics approved for rare diseases to many. I’m keeping this mentality to prepare our organization for that many, for this tipping point, for precision medicine to treat the many symptoms our children experience, as well as to ultimately fix the gene.

Best organization decision: Starting the organization. We got together a team and we never looked back. I will also say having a strategy from the start to focus on every mutation category was one of our strongest decisions early on.

Hardest lesson learned: I went into it thinking that everyone would be very cooperative and learned that people think differently. Not everyone will understand the value of working as a team to help all FOXG1 children. It was hard for me to accept that there were people who have more need for control and they operate from a different place, a place of pride, rather than doing what is productive, helpful, and holistic. I’ve learned to remove any disappointing or counterproductive emotions about this and just put my head down and work as hard and smart as possible to always focus on the goal. I’ll always do what I can to find a cure for every child and adult in the world with FOXG1 syndrome. I know that I’m here for children that I won’t even meet one day, for children who aren’t even born yet. Keeping that in focus removes any disappointments we’ve encountered along the way.

Toughest organization decision: Choosing the research projects to fund is not always an easy decision. We receive proposals from many brilliant scientists at leading academic centers. Oftentimes parents on our team bring forward a scientist whose research proposal is meaningful to them. They’ve been talking for a while. Proposals can seem very promising to us and we get excited about them. But we know we cannot make decisions based on our parent-driven emotions. This is why we have a multi-disciplinary Scientific Advisory Board. They spend time vetting and evaluating research proposals. They find the holes, they ask the tough questions, they give great feedback. We value every single dollar that is donated to help us drive this science. It is our duty to be shrewd with the science we fund.

Biggest missed opportunity: I like to believe that anything that felt like a missed opportunity was just a redirection in the right direction. We recently spent so many hours trying to hire a director of development. We’re ready to bring someone with years of experience to help our non-for-profit development holistically. We must have gone through 60 applications and got down to two candidates. We underestimated the current competitive job market, and both candidates took other positions. Again, is this just a redirection to the right person to help us grow? I’m going to say yes. So, we are continuing to search for a great director of development to join our team.      

Like best about the job: The purpose. I never felt what it meant to have such a purpose in life before. I certainly loved being in the music industry and I loved working in television, but knowing that the work I’m doing here is going to impact human life is unlike anything I’ve ever imagined.

Like least about the job: The purpose. The fact that I’m here because Josie has FOXG1 syndrome is my least favorite thing about the job. I would love nothing more than to have a typical life for her and for my family. I would love for her to be running off the school bus right now, telling me about her day, grabbing food out of the pantry, and running off to her dance class and all these simple things that everyone around me experiences. She had a big seizure yesterday. She’s tube fed. She can’t talk to me. We’re having discussions wondering if she’s having migraines from her new seizure medicine. It’s a heavy life and I’m just so sorry for her that she suffers. And yet, I could start singing “The wheels on the bus” and she’ll smile. She’s so sweet and precious. It’s so hard for her. I would give anything to not be talking to you right now because the term rare disease doesn’t impact me in my life. That’s what I like least about my job.

Pet peeve: Hearing people chew. I was happy to hear this was a genetic condition called misophonia. That makes sense because my sister suffers from it much more than I do. Something happens to us when we hear people chewing. Chewing gum is the worst offender.

First choice for a new career: I’d be a singer in a band, I just have to learn how to sing first. I’d play the guitar too. It may or may not be true that my Josie’s name is inspired from Josie and the Pussycats from Archie comics.

Personal Taste
Most influential book: The Universe Has Your Back by Gabrielle Bernstein. I must have gifted this book to at least 20 people and also Deepak Chopra‘s Seven Spiritual Laws of Success is a guide for me.

Favorite movie: My son will tell you that every movie is my favorite movie. We just watched CODA, and that’s my favorite movie of the week. I have a 15-year-old son, Tanner, and we’re going through the list of all-time best movies, which is fun to do with your kid. Some of my favorites include Forrest Gump, Almost Famous, True Romance, and Dead Poets Society.

Favorite music: My favorite band of all time is Phish, but I love everything from Motown to the Beatles. Bill Withers is a favorite, jazz, Bowie, classic rock, reggae, indie music, old school rap, A Tribe Called Quest—there’s nothing I don’t love.

Favorite food: New York pizza

Guilty pleasure: New York pizza and DIY Instagram videos. When you watch someone just do things themselves, like home renovation, they’re mesmerizing to me.

Favorite way to spend free time: First is just being with my family. I didn’t mind being stuck at home for two years with my people. Second is seeing live music, especially with the friends I love. Third is walking in nature.

Global Genes Podcast: Empowering Rare Disease patients With Their Own Health Recods

Health records can be a rich source of data that can help provide an understanding of a rare disease and drive the development of therapies to treat them. But the siloing of this data, the use of inconsistent terminology, and the unstructured nature of aspects of these records all stand as barriers to harnessing their potential. The consumer health technology company Ciitizen is working to give patients greater control over their own health data and enable its sharing with researchers and providers. We spoke to Nasha Fitter, vice president of rare disease for Ciitizen, about her own experience as a mother of a child with a rare neurologic condition, her work as a rare disease advocate, and a collaboration between a group of rare neurologic disease advocacy organizations to build a natural history study on the Ciitizen platform.

Daniel Levine: Nasha. Thanks for joining us.

Nasha Fitter: Thank you for having me.

Daniel Levine: We’re going to talk about Ciitizen, its healthcare technology platform, and the potential to leverage the data available in electronic health records to drive faster diagnoses and new treatments for rare diseases. Listeners may know you through your work with the FoxG1 Research Foundation, which you co-founded. You became involved in the world of rare disease after your daughter began having seizures. What happened and how was she diagnosed?

Nasha Fitter: Luckily, the fact that she started having seizures got her a diagnosis much faster. She was diagnosed through the epilepsy panel from GeneDx and we found that she had a FoxG1 mutation about three months after she started having seizures. We always think that if she hadn’t had those seizures, it would have taken us years to get to a diagnosis because she would have just had an intellectual disability and we wouldn’t have been offered the ability to get genetic testing.

Daniel Levine: What were you told about FoxG1 at the time she was diagnosed?

Nasha Fitter: Interestingly, I was told not to go online because it would scare me. What I was told is that it affects gross motor, fine motor, communication, most children don’t walk or talk, they eat with a feeding tube, they have hundreds of seizures a day, and movement disorders. This was my first, kind of, information overload and I thought, God, life is over. What can I even do here? I learned going forward that there is a spectrum and there are many things that we can do. That was my first information overload and I think is what most parents receive.

Daniel Levine: How well understood is the condition today and how does it manifest itself and progress?

Nasha Fitter: It’s not understood. That’s why I’ve become so incredibly passionate about the need for data and making that data accessible. There’s not much known about FoxG1 syndrome. There are a limited number of patients. There has been a few research reports published, but it’s always a very small number. It’s a spectrum, like most diseases, and we need more data. We need more information on more patients to get a sense of how this disease manifests change over time.

Daniel Levine: What was the decision you made when you decided to launch the FoxG1 Research Foundation?

Nasha Fitter: It was simply that we need to accelerate finding a cure. Everything I learned is that if you want something done in a rare disease, you’ve got to get together with a group of other parents or patients and do it yourself. No one will care unless you care. It really wasn’t even a decision. I don’t think I even had a choice. It was just something we had to do.

Daniel Levine: The FoxG1 Research Foundation, in my mind, has a very clear strategy and is rather methodical in the way it goes about things. What’s the approach it’s been taking?

Nasha Fitter: That has actually been our number one approach, to be very strategic and very clear on what we’re doing and why we’re doing it. We get flooded with research requests from different scientists. Unless we really know what is absolutely necessary, you can start funding projects that may not necessarily help you get to your end goal. What we did is speak to biotechnology companies and biopharma to understand what it takes to get a drug developed in our children in a way that’s safe. With that understanding, we were able to work backwards on what are the different steps that are necessary for us to get to that point. We’re very ruthless with that. We don’t do anything if it doesn’t fit in that paradigm.

Daniel Levine: It seems to me, a lot of the thinking that’s driven your approach has been to de-risk drug development, so that companies would come into the space. How have you gone about doing that?

Nasha Fitter: That’s what it’s all about. It’s hard and it’s expensive. De-risking means understanding the disease. Companies don’t want to spend endless amounts of money on a disease that is not well understood. To understand a disease, you look at it in a forked approach. One is, to understand it from a biological pathways perspective, and that’s where you need to know the non-human ways that you can model a disease, animal models, stem cell models, et cetera. Then on the flip side is, how we can document what children or patients are going through in a very systematic way. With that combination, and with some proof of concepts, you’ve hopefully de-risked it enough for someone to invest millions of dollars to develop a drug.

Daniel Levine: In that context, how did you come to view the need to gather data and the role it would play in the process?

Nasha Fitter: I was very lucky that early on one of our SAB members, who runs a biotech company, told me if there’s one thing you do, conduct a natural history study. That is something that is really difficult for biopharma to do. It’s hard for biotech companies to access patients and contact patients but as an advocacy group we can do that. I took that to heart and plunged into how we collect good data. There were mistakes we made along the way. We started a registry and we created our own survey, and then later I learned that if it’s not an FDA validated survey, that information is useful internally but won’t be taken seriously. We, kind of, had to start over and get validated surveys, and we’re lucky to be on the Ciitizen platform where we can get rich clinical data, which is really what moves the needle.

Daniel Levine: In addition to your role as CEO of FoxG1, you also serve as the director of rare neurological diseases for Ciitizen. The FoxG1 Research Foundation received a $500,000 grant from Chan-Zuckerberg Initiative to allow groups like yours to use machine learning to accelerate rare disease drug development. This has funded a digital natural history program that FoxG1 syndrome launched with three other rare neurological disease groups in partnership with Ciitizen. Let’s start with Ciitizen. What is Ciitizen for people who are not familiar with the company? What’s the problem it’s trying to solve?

Nasha Fitter: The problem Ciitizen is trying to solve is, can we create an accessible platform where patients can access their own medical records, your raw medical records or your MRIs, and then can share it easily with whomever they want, it’s totally in the patient’s control. Then, can we use those raw medical records to extract relevant information to create natural histories that can then be shared freely and easily with researchers, academic or biotech. That’s kind of what it does. Then, I would say the problems we’re trying to solve are getting second opinions quickly for patients, getting matched to clinical trials, and further developing natural history studies for rare groups and larger groups.

Daniel Levine: How are the various organizations working together on the digital natural history study and what does it ultimately seek to do?

Nasha Fitter: I could not have done this without our pilot groups, the SynGAP Research Fund and TESS Research Foundation. We came together to figure out how we could utilize this platform. Ciitizen started in the oncology space due to our founder’s own personal story of losing his sister to metastatic breast cancer. I really felt that this platform is the future for rare diseases because we need this deep clinical data and we need it fast. We can’t wait three to five years to collect rich natural history data from in-person studies. It was perfect for the problem that we have in rare diseases. It was really TESS Research Foundation and SynGAP that joined us, FoxG1 Research, and, thankfully, CZI believed in us and gave us the grant to do this work. To actually have the first cohorts come onto the platform, sign up, have patients trust us, we’ve collected their medical records, and we’re now in the process of extracting information and creating these rich studies. SynGAP research fund will have data from a rich natural history study on a hundred patients in six months. That’s never been done before in the rare disease space. There’s already a plethora of researchers that are utilizing this data. I’m excited that this year we can showcase how this platform is a game changer for groups like ours.

Daniel Levine: Have you learned anything in the process of doing this about gathering data and improving the way it’s done?

Nasha Fitter: I think Ciitizen has completely gotten down how to collect data quickly. The most challenging part, I learned, is getting patients to come onto the platform. You have your early adopters who are invested in research and will come on. We have a chance with platforms like this to get our entire communities on. All caregivers and patients have to understand that this is a community effort. In rare diseases, you cannot hope that someone else is going to come and solve your problem. This isn’t breast cancer. Everyone has to do their bit. That means joining studies such as these, so we can collect a large cohort of data, as large as possible, to do a really rich study.

Daniel Levine: Is there any insight you’ve gotten into the resistance of patients to participate?

Nasha Fitter: I think this is a new innovative method. People haven’t heard about it before. So, there is a lot of education that’s necessary. Then, rare disease families are busy, they’re exhausted, and they think, is this one more study that I have to do? Will it go anywhere? Will it result in anything? There’s a lot of apathy to do things, which is completely understandable. Unfortunately, we have to work through that apathy to get something done. That’s what we’re hearing and seeing.

Daniel Levine: Because Ciitizen is actually pulling data from electronic health records, how is the burden of participation compared to a more typical natural history study?

Nasha Fitter: It’s a night and day difference. Here, all patients have to do is come onto a platform, get some of their documentation like their child’s birth certificates, et cetera, and take a picture of them so we have it. [This is] versus an in-person study where you’re having to get your special needs child in a car, drive to an academic center, spend half a day there, you may not live near a center and have to fly there, and you have to take days off work. It’s a huge difference in terms of time burden. But I think, many people are wary of technology. They’re wary of data privacy. These are important questions and there’s a lot of education that’s necessary.

Daniel Levine: How was the quality of the information that can be gleaned from electronic health records relative to the typical surveys that make up a natural history study?

Nasha Fitter: That’s a great question. One of the benefits of a platform like Ciitizen is that we can go back and collect 10 years of the data. You’re looking at 10 years of really rich natural history data because everything is collected, every progress report, every clinical note, every MRI, every EEG report. So, we’re able to piece together what is the continuum and true natural history of these patients. There’s not a lot of holes in the data because most patients have been seeing their neurologist or specialists in a consecutive way in order to get services. We’re able to actually pull a very large and deep amount of data. Also, we can normalize it because a physician in one institution may term something differently. I learned myself that there’s 40 different ways you can say heart attack. That normalization is also something that’s very valuable. Our goal is to look at data at the aggregate level. There is still a role for in-person studies and in-person visits because you can ask further questions. I’m really excited about, if there’s things that we want to further ask patients, can we use technology? Can we do video interviews, are there other ways that we can gather data without a patient having to necessarily go into a center? For me, the data can either supplement a current in-person study, or it could be a study in itself.

Daniel Levine: It strikes me that the other thing that’s possible here is, you normally think of groups doing these types of studies in isolation. You’ve got four groups focused on different neurological conditions working together here. Is the expectation that insights gleaned from one will help elucidate the other?

Nasha Fitter: Yes, exactly. We learned so much and there’s a lot we have in common and there are differences. That’s really been the eye-opener—that there is so much in common. We can scale faster through neurodevelopmental disorders. There’s a few things that we’re learning that are different and are very helpful to understand how these diseases differ from each other. That’s why when our foundation wrote the grant we wanted to include a few different groups that were similar in some ways, but also quite different in the types of genes, gene locations on different chromosomes, et cetera, so we could build something that was holistic.

Daniel Levine: You mentioned the challenges of getting patients to participate in the natural history study. What control do patients have over their data and how it’s used and what’s the incentive for them to make use of the Ciitizen platform?

Nasha Fitter: They have complete and total control of their medical records, as well as where the extracted data goes. It’s a completely patient-centric platform. Patients consent, yes I want to share my data with academic and biopharma researchers or I don’t, or I just want to be contacted on a study by study basis. It is completely up to the patient and they can pull their consent at a later date as well. It is very much a patient directed platform. The other thing that sometimes I think gets overlooked is, normally when you have biopharma that are creating these natural history studies, they do them individually. You’ll have company A doing a study for, I’m just going to make up a disease group, like SCN2A patients, and then company B may do a similar study. You’ve got a very small patient pool to begin with and then they have to enroll in two separate studies. That’s what we’re trying to break away from. We can just gather this data and put it on one platform. Then, however many companies that want to access the data can do so. It’s not owned by any one company or any one academic institution.

Daniel Levine: As a matter of disclosure for listeners, I perform work for the collaborative data sharing platform RARE-X. Listeners can hear a discussion that you and I recently had along with Vanessa Vogel-Farley about a partnership that Ciitizen and RARE-X recently entered. While I have you, what will that partnership do, and what does that mean for rare disease patients looking to drive research into their conditions?

Nasha Fitter: The future, how we’re thinking is how do we just accelerate, accelerate, accelerate, getting all this rich information. RARE-X is amazing because they have thought through very carefully, what are the right survey questions that caregivers and patients should take? This is a distinction that there’s some confusion over. There’s two types of data. There’s something called a PRO, which is a patient reported outcome, like a survey that we fill, and then there’s clinical, clinician reported outcomes, which is information that we glean from a medical record. There are two types of data and why the partnership with RARE-X is so powerful is we’re able to combine the expertise of both of those. Information that’s gleaned from PROs and then information that is gleaned from electronic medical records. One of the things I love about RARE-X is they realize that no one platform is going to own everything and be great at everything. The idea here is, we have our expertise, but the only way we’re going to accelerate rare disease is if we can open these pipelines. RARE-X may work with other companies like Ciitizen, and we may work with other organizations like RARE-X, and that is fine. It’s up to the patient or the advocacy group where they want to go. The goal is our platforms should really talk to one another.

Daniel Levine: As you think about the new ways that information technology is enabling people to gather and share information about rare diseases? How do you see this ultimately altering the landscape for patients?

Nasha Fitter: I think this is going to be one of the biggest game changers that we will see in our lifetime because over the next 10 years we will see a massive movement towards precision medicine. That will only work if there’s very granular information on a per patient basis. So, very granular genetic genomic information as well as very granular clinical information that also can be compared to other cohorts. I see the future of medicine very differently than how it is now. I see treatments that are going to be much more effective. We’re going to see better treatments. We’re going to see more transformational treatments. None of that is going to be possible without rich data, easily accessible by everyone in the spectrum.

Daniel Levine: Nasha Fitter, co-founder and CEO FoxG1 Research Foundation and director of rare neurological diseases for Ciitizen. Nasha, thanks as always.

Nasha Fitter: Thank you so much for having me for this important topic. I appreciate it.

Eine Zusammenfassung des FOXG1 Wissenschafts-Symposiums 2020

www.Foxg1research.Buzzcast.com

Am 17. Und 18 August 2020 haben wir das ursprünglich an der „University of Buffalo“ geplante „FOXG1 Wissenschafts-Symposium“ als virtuelle Veranstaltung durchgeführt.

Zwar hatten wir nicht die Gelegenheit, alle Teilnehmer persönlich zu treffen, aber wir hatten trotz allem ein tolles Publikum, welches mit mehr als 300 Teilnehmern unsere Erwartungen bei weitem übertroffen hat.

Es war eine wirklich bemerkenswerte Veranstaltung mit neuen und ergiebigen Informationen und einem wachsenden Konsortium von Wissenschaftlern, Industrievorständen, Betreuern und vielen anderen Gruppen, alle auf krankheitsmodifizierte Therapien des FOXG1 Syndroms fokussiert.

Viele der Themen, einschließlich der Q&A ́s, können Sie hier anschauen. Allerdings mussten wir einen Teil der Präsentationen aufgrund sensibler, nicht veröffentlichter Daten, entfernen.

Ich habe TAG 1 mit einer Übersicht des einzigartigen Zieles der „FOXG1 Research Foundation“ begonnen: Eine Heilmethode für alle weltweit betroffenen Kinder des FOXG1 Syndroms zu finden. Seit dem Start im Jahr 2017 haben wir bereits viel geschafft.

Klicken Sie auf <my welcome> um sich einen Überblick über unsere Strategie und Forschung zu verschaffen.

Wir sind stolz darauf, von den besten Forschern aus dem Bereich der seltenen Krankheiten lernen zu können. Klicken Sie auf on the Day One Keynote um sich die Präsentation von Dr. Art Beaudet bzgl. der Erforschung eines Heilmittels für das Angelman Syndrom anzuschauen.

Unser erstes Diskussionsforum, Phänotypen des klinischem FOXG1 Syndroms widmete sich vor veröffentlichten Informationen der „FOXG1 Patientenregistrierung“, welches sich darauf fokussiert, das Spektrum der FOXG1 Phänotypen (Symptome) in Kindern zu erfassen. Erkennbar sind leicht unterschiedliche Symptome, in Abhängigkeit von der spezifischen genetischen FOXG1 Mutation (Deletion, Missense) etc.

Die Eltern in dieser Gesprächsrunde berichteten über medizinische Symptome, entwicklungsorientierte Symptome und Verhaltensprobleme, mit denen sich ihre Kinder auseinandersetzen müssen. Wir haben einen Artikel mit diesen Themen zur Veröffentlichung in Fachzeitschriften mit dem Titel „Expanding genotype- phenotype correlations in FOXG1 syndrome resulting from a patient registry“ (Erweiternde Zusammenhänge zwischen Genotyps und Phänotyps im FOXG1 Syndrom, entstanden aus einer Patientenregistrierung)

Die folgenden führenden Kliniker und Wissenschaftler haben zu dieser Studie beigetragen:

Elise Brimble, MS

Kathryn G Reyes, BS

Orrin Devinsky, MD

Maura Ruzhnikov, MD

Xilma Ortiz-Gonzalez, MD

Ingrid Scheffer, MBBS, PhD

Nadia Bahi-Buisson, MD, PhD

In der Vortragsreihe Grundlagen der FOXG1 Biologie sprachen

Heather Olsen, MD, MSNext

Dr. Soo-Kyung Lee

Dr. John Mason

Dr. Michael C. Yu

and Dr. Priya Banerjee

Wir erfuhren, dass das FOXG1 Gen in verschiedenen Zelltypen des Gehirns aktiv ist.

Weiterhin tragen die meisten Tiere das Gen in sich (die meisten Tiere haben eine ähnliche FOXG1 Sequenz wie Menschen), demnach wissen wir, dass wir tierische Vorlagen als Studienplattform für die FOXG1 Biologie nutzen können.

Die Vortragenden referierten über die Protein-Arginin-Methylierung und die Liquid-Liquid Phase Separation – LLPS (Flüssig-Flüssig-Phasentrennung) als neuartigen Weg die FOXG1 Gen-Biologie zu verstehen, um Behandlungswege zu entwickeln. Diese Behandlungswege könnten helfen, die FOXG1 Protein Funktion zu kontrollieren.

Danach tauchten wir in FOXG1 Cellular Modelling (FOXG1 Zellmodellierung) Diskussion ein mit Dr. Robin Kleiman, Dr. Flora Vaccarino, Dr. Alysson Muotri and Dr. Aparna Bhaduri als Referenten. Aus dieser Präsentationsreihe nahmen wir 3 wesentliche Erkenntnisse mit:

1.  Die Höhe der FOXG1 Dosierung ist ausschlaggebend und es gibt eindeutige Hinweise darauf, dass verschiedene Gene durch unterschiedliche Dosierungen reguliert werden. Dies kann hilfreich dabei sein, die verschiedenen Phänotypen in Patienten zu verstehen

2.  Die Modellierung von Patientenorganoiden ist im Gange und verspricht spannende Einblicke in die patientenspezifische Biologie und ermöglicht ein Medikamenten- Screening

3.  Da Organoide eine hervorragende Ressource sind, um das menschliche Gehirn zu modellieren, ist es wichtig den Gesundheits- und Differenzierungsstatus der entsprechenden Zelltypen vorsichtig zu beurteilen und sicher zu stellen, dass wir eine solide Repräsentation von dem erschaffen, was wir versuchen zu modellieren.

Dr. Jessica Mariani ist für Dr. Vaccarino während der Q&A Session eingesprungen, Sie können dies hier anschauen.

Unsere letzte Gesprächsrunde am ersten Tag, FOXG1 Animal Modeling (FOXG1 Tiermodellierung) wurde von Dr. Rodney Samaco, Dr. Jae Lee, Dr. Goichi Miyoshi und Dr. Corinne Houart, moderiert. Frühe Informationen aus unseren sechs heterozygotischen Mausmodellen und des heterozygotischen Zebrafischmodelles wurde geteilt.

Die wichtigste Erkenntnis war, dass die neuesten Daten dieser Modelle einen klaren Phänotyp (Symptome) im Gegensatz zur Kontrollgruppe nachweisen konnten.

Dies ist ein wichtiger Aspekt, da die Modelle gezeigt haben, dass die Tiere ausgezeichnete Modelle für Medikamenten-Tests sind. Das ist der erste Schritt im Hinblick auf einen Medikamententest, da wir ohne geeignetes Modell nicht in der Lage sind, irgendetwas zu testen. Wir haben ebenfalls gelernt, dass man beides anpeilen kann: Das FOXG1 Gen selbst als auch Faktoren wie Stimulierung/ Hemmung neuronales Ungleichgewicht. Dies ist ein wichtiger Punkt, da er uns viele Wege aufzeigt, um unseren Kindern die Symptome zu erleichtern.

Als wir die FOXG1 Research Foundation gründeten, gab es keine gebündelten Anstrengungen, um in die translatorische Forschung des FOXG1 Syndroms zu investieren. Zu diesem Zeitpunkt war die gesamte Forschung auf die Rolle des FOXG1 Gens in Bezug auf die generelle Entwicklung des Gehirns fokussiert. Als eine „Foundation“ ist es sehr wichtig, gemeinschaftlich zu bleiben. Dr. Soo Kyung-Lee und Dr. Jae Lee sind Teil unserer FOXG1 Familie und wir sind gesegnet, dass sie weiterhin intensiv mit allen Wissenschaftlern in Kontakt sind und ihre vorveröffentlichten Arbeiten mit diesen teilen.

Heute sind wir näher als je zuvor an einem Heilmittel dran. Innerhalb der kommenden zwei Jahre werden wir Medikamente, Gen- und Antisense-Therapien prüfen. Ein Punkt der dabei offensichtlich wurde ist, wie komplex das FOXG1 Gen trotz seiner winzigen Größe ist, und wie wichtig es ist, die Biologie des FOXG1 auf dem molekularen und zellulären Level zu verstehen.

Aus dem Verständnis der FOXG1 Biologie werden Ideen und Erfindungen entspringen.

Unsere 2. Vorsitzende und Mitgründerin Nicole Johnson hat uns mit einer persönlichen Geschichte über ihre Tochter Josie in den 2. Tag geführt und danach den Fokus auf die translatorische Wissenschaft gelegt.

Unser Eröffnungsvortrag hatte den Schwerpunkt Medikamenten-Entwicklungs-Prozess für seltene Krankheiten. Wir wollen das „Tal des Todes“ vermeiden, in dem akademische Ideen stecken bleiben und niemals den Markt erreichen. Glücklicherweise unterstützt der „Orphan Disease Act“ nach wie vor die Entwicklung von Medikamenten für seltene Krankheiten. Wir sind begeistert, dass auch die FDA (Food & Drug Association) unsere Arbeit unterstützt.

Schauen sie sich die Plenar-Präsentationen über „Getting Orphan Drugs to Market“ von Dr. Lewis Fermaglich, FDA, und Dr. Diana Wetmore, Harrington Discovery Institute an.

Unsere erste Diskussionsrunde über das Thema „Potential Therapies for FOXG1 Syndrome“ (Potenzielle Therapien für das FOXG1 Syndrom) wurde von Dr. Yael Weiss, Dr. Antonello Mallamaci, Dr. Soo Lee and Dr. Sylvain Lengacher gehalten. Die wichtigsten Erkenntnisse sind:

1. Quer durch das Spektrum der FOXG1 Mutationen können wir verschiedene Auswirkungen auf den Protein-Level, Astro-Entstehung (astrogenesis) und andere Aktivitäten im Gehirn erkennen. Dies muss nicht zu verschiedenen Therapien pro Mutation führen, aber es könnte Einfluss auf unterschiedliche Dosierungen und kombinierbare Vorgehensweisen haben.

2. Die ideale Therapie wäre, Mutationsdefekte zu bearbeiten, aber da die Off-TargetEffekte immer noch Besorgnis erregend sind (unsere Kinder bekommen z. Bsp. durch die Behandlung Gehirntumore), könnten Mikro-RNA ́s ein Weg sein, das FOXG1 Protein und andere Level im Gehirn zu modelieren. Wir sehen, dass Experimente erfolgversprechend sind, in denen die MikroRNA ́s die FOXG1 Protein-Level ansteigen lassen.

3. Wir können ebenfalls erkennen, dass eine FOXG1 Überexpression einen Phänotyp des FOXG1 Syndroms verursachen kann, dies wird untersucht, um uns beim Verständnis der Dosierung zu helfen.

4. Gliazellen und Gehirnmetabolismus sind innovative Zielscheiben für FOXG1 Syndrome. Präklinische Daten belegen, dass siRNA-vermittelte Runter-Regulierung von FOXG1 in Astrozyten den Gehirn-Energie-Metabolismus dramatisch beeinträchtigen und kleine Moleküle GP-57 als Medikamente dienen könnten, um dies zu bewerkstelligen.

5. Um FOXG1 Protein-Levels nicht zu überaktivieren und noch mehr Schaden anzurichten, kann eine kombinierte Einstellung wichtig sein. Es könnte sein, dass wir Neuronen und Astrozyten stimulieren müssen, aber wenn ein Zelltyp stimuliert wird, könnte das eine Auswirkung auf einen anderen Zelltyp haben, dem wiederum entgegengewirkt werden müsste.

Dr. Soo-Kyung Lee, Dr. David Bedwell und Dr. Chris Ahern präsentierten unser letztes Forum „Potential Therapies for Nonsense Mutations“ (Potenzielle Therapien für Nonsense Mutationen). 30% unserer Kinder haben Nonsense Mutationen und es ist extrem interessant, dass wir zwei potenzielle vielversprechende Therapien in Aussicht haben.

1. Die erste mögliche Therapie besteht aus so genannten “Readthrough” (durchlesen) Wirkstoff, erhöht die Proteinproduktion von FoxG1. Zur Zeit erproben wir diese Wirkstoffe an HEK Linien (Nierenzellen) und SH-SY5Y Zellen Neuroplastomazellen. Erfolgversprechende Wirkstoffe werden weiter in Stammzellen und Mausmodellen angewendet. Ein wichtiger Aspekt dieser Forschung ist die Dosis, die wir damit erreichen können für jede Mutation. Dafür braucht man die Information wieviel FoxG1 wird benötigt? An dieser essentiellen Frage wird momentan von den Wissenschaftlern nach der Antwort gesucht.

2. Die zweite mögliche Therapie beinhaltet die Reparatur vorn „Stop-Codons“, in dem eine tRNA Gen-Therapie genutzt wird. In dem Fall würde die tRNA Sequenz verändert werden um „Stop-Codons“ zu unterdrücken. Was wir in Erfahrung bringen konnten ist, dass wenn die Reparatur robust ist, 40-80% der Wildtyp- Expression erreicht werden können, was viel höher ist als ein “Readthrough” Wirkstoff je erreichen könnte. Obwohl dies vielversprechend klingt, müssen noch alle Aspekte, wie z. Bsp. das Verständnis ob tRNAs andere ungewollte Nebenwirkungen hat, getestet werden.

3. Das Ziel könnte wiederum kombinierbar sein – die Verwendung von tRNA und Schichtung auf Nonsense-Verbindungen für den effektivsten Ansatz für unsere Kinder, die von Nonsense-Mutationen betroffen sind.

Häufigkeit der Unterdrückung von Nonsense-Codons erhöhen.

Wir haben keine Zeit darauf verwendet über Gen-Therapien und Anti-Sense-Therapien für FOXG1 Syndrome zu sprechen. Diese sind in der ersten Phase und es gibt noch nicht genug Datenmaterial, über die man sprechen könnte. Wir hoffen, bei unserer nächsten Konferenz im Jahr 2021 ein solides Forum zu diesem Thema anbieten zu können.

Tag 2 endete mit zwei erfolgreichen und informativen Stunden in verschiedenen Breakout-Räumen mit Wissenschaftlern, Eltern und Pflegern. Der Austausch hätte noch stundenlang fortgeführt werden können und wir freuen uns darauf, noch weitere solche Diskussionen führen zu können.

In der Zwischenzeit werden wir alle Updates in diesem Blog und auf unserer FOXG1 Research Facebook Seite teilen.

Zu guter Letzt: 

Keine dieser Anstregungen ein Medikament zu finden, wäre ohne Spenden möglich. 80% unserer Arbeit beruht auf privaten Spenden und beinahe 100% der Spenden gehen in die Forschung. Bitte klicken Sie hier um zur Erforschung eines Medikaments für das FOXG1 Syndrom für eine bessere Zukunft unserer Kinder zu spenden. Vielen Dank! 

- Tina Kouemo-Burri 

Een samenvatting van het FOXG1 Science Symposium 2020

www.Foxg1research.Buzzcast.com

Een samenvatting van het FOXG1 Science Symposium 2020.

Op 17 en 18 augustus hielden we het FOXG1 Science Symposium 2020 als een virtueel evenement in plaats van op de Universiteit van Buffalo zoals oorspronkelijk gepland. Hoewel we het jammer vonden dat we niet persoonlijk samen konden komen, was het voordeel dat we een publiek hadden dat onze verwachtingen ver overtrof met meer dan 300 aanwezigen.

Het was een bijzonder event, met nieuwe en interessante data en een groeiend consortium van wetenschappers, leidinggevenden uit de industrie, zorgverleners en meer, allemaal gericht op het pad naar ziektemodificerende therapieën voor het FOXG1-syndroom.

Veel van de inhoud, inclusief vraag-en antwoord sessies, is hier te bekijken. Houd er rekening mee dat we de meeste presentaties van de wetenschappers niet kunnen laten zien vanwege gevoelige niet-gepubliceerde gegevens.

Nasha Fitter begon Dag Eén met een overzicht van het enige doel van The FOXG1 Research Foundation: een remedie vinden voor het FOXG1-syndroom voor alle getroffen kinderen wereldwijd. We hebben een lange weg afgelegd sinds we in september 2017 zijn begonnen!

Klik op mijn Welkom voor een overzicht van onze strategie en onderzoek.

We zijn er trots op te hebben geleerd van de beste communities voor zeldzame ziekten. Klik op de Day One Keynote om de presentatie van Dr. Art Beaudet te bekijken op de weg die is afgelegd om een ​​remedie te vinden voor het Angelmans-syndroom.

Ons eerste panel, Clinical FOXG1 Syndrome Phenotypes, deelde voorgepubliceerde gegevens van de FOXG1 Patient Registry die zich richt op het begrijpen van het spectrum van FOXG1-fenotypes (symptomen) die kinderen ervaren. We zien iets andere symptomen afhankelijk van de specifieke genetische FOXG1-mutatie (deletie, missense, enz.). Ouders in dit panel spraken over medische symptomen, ontwikkelingssymptomen en gedragsproblemen waarmee hun kinderen worden geconfronteerd. We hebben een wetenschappelijk artikel met deze informatie ingediend voor publicatie in wetenschappelijke tijdschriften met de titel "Uitbreiding van genotype-fenotype correlaties in FOXG1-syndroom resulterend uit een patiëntenregistratie."

De volgende vooraanstaande clinici en wetenschappers hebben bijgedragen aan deze studie:

Elise Brimble, MS

Kathryn G Reyes, BS

Orrin Devinsky, MD

Maura Ruzhnikov, MD

Xilma Ortiz-Gonzalez, MD

Ingrid Scheffer, MBBS, PhD

Nadia Bahi-Buisson, MD, PhD

Heather Olsen, MD, MS

Daarna was het de beurt aan Dr. Soo-Kyung Lee, Dr. John Mason, Dr. Michael C. Yu en Dr. Priya Banerjee tijdens het panel Basic FOXG1 Biology. We hoorden dat het FOXG1-gen tot expressie wordt gebracht in verschillende celtypen in de hersenen, en het gen is geconserveerd bij de meeste dieren (de meeste dieren hebben een vergelijkbaar FOXG1-gen als mensen), dus we weten dat we diermodellen kunnen gebruiken als een platform om het FOXG1-gen te bestuderen.

Sprekers bespraken Protein Arginine Methylation en Liquid-Liquid Phase Splitsing als nieuwe manieren om FOXG1-gen biologie te begrijpen om behandelingen te ontwikkelen. Deze behandelingen kunnen helpen om de FOXG1-eiwitfunctie te beheersen.

Vervolgens kwam het panel over FOXG1 Cellular Modeling, hier spraken Dr. Robin Kleiman, Dr. Flora Vaccarino, Dr. Alysson Muotri en Dr. Aparna Bhaduri. Er waren drie belangrijke aandachtspunten in dit panel:

1. Het niveau van de FOXG1-dosering is van cruciaal belang met duidelijk bewijs dat verschillende genen bij verschillende doses worden gereguleerd. Dit kan helpen om de variabele fenotypische uitkomst bij patiënten beter te begrijpen.

2. Er wordt momenteel gewerkt aan Patiënt-organoïde-modellering (het kweken van organen uit menselijk materiaal) en geeft hoopgevende inzichten in patiëntspecifieke biologie en maakt medicijn screening mogelijk.

3. Hoewel organoïden een uitstekende bron zijn voor het modelleren van het menselijk brein, is het belangrijk om de gezondheids- en differentiatie status van de celtypen van belang in de toekomst zorgvuldig te beoordelen en ervoor te zorgen dat er een gezonde weergave is van wat we proberen te modelleren.

Dr. Jessica Mariani verving Dr. Vaccarino voor de Q & A-discussie.

Ons laatste panel van dag één, FOXG1 Animal Modeling, bestond uit Dr. Rodney Samaco, Dr. Jae Lee, Dr. Goichi Miyoshi en Dr. Corinne Houart. De eerste gegevens werden gedeeld van de zes heterozygote muismodellen die werden ontwikkeld en onze heterozygote zebravis modellen. De belangrijkste uitkomsten waren de eerste gegevens die een duidelijk fenotype (symptomen) vaststelden uit deze modellen versus de controlegroep. Dit is belangrijk omdat het laat zien dat deze dieren uitstekende modellen zullen zijn voor het testen van geneesmiddelen. Dit is de eerste stap bij het testen van medicijnen, zonder een correct model zullen we geen medicijnen kunnen screenen. We hebben ook geleerd dat we zowel het FOXG1-gen direct kunnen aanpassen, bij bijvoorbeeld een remmende neuronale onbalans. Dit is belangrijk omdat het meerdere manieren biedt om symptomen van onze kinderen aan te pakken.

Dag twee:

Toen we de FOXG1 Research Foundation begonnen, was er geen translationeel onderzoek voor het FOXG1-syndroom. Al het onderzoek op dat moment was gericht op de rol van de FOXG1-genen in de algehele hersenontwikkeling. Als stichting is het enorm belangrijk dat we samenwerken, omdat het FOXG1 gen een klein gen betreft. Dr. Soo Kyung-Lee en Dr. Jae Lee maken deel uit van onze FOXG1-familie en we zijn gezegend dat ze wereldwijd samenwerken met alle wetenschappers en hun voorgepubliceerde werk delen.

Vandaag komen we dichter bij een genezing. De komende twee jaar zullen we medicijnen, gentherapieën, antisense-therapieën en meer screenen. Eén ding dat duidelijk is, is hoe complex het FOXG1-gen is. Het is een klein gen, maar enorm belangrijk om de biologie van FOXG1 op moleculair en cellulair niveau te begrijpen.

Dit begrip van FOXG1-biologie zal leiden tot uitvindingen en ideeën voor therapieën.

Onze president en medeoprichter Nicole Johnson begon Dag Twee met een persoonlijk verhaal over haar dochter Josie en richtte vervolgens de focus van de dag op translationele wetenschap.

Onze plenaire openingssessie was gericht op het ontwikkelingsproces van geneesmiddelen voor zeldzame ziekten. We willen de 'vallei des doods' vermijden, waar academische ideeën vastlopen en nooit op de markt komen. Gelukkig blijft de Orphan Disease Act de ontwikkeling van geneesmiddelen voor zeldzame ziekten ondersteunen. We zijn heel blij dat de FDA (US Food and Drug administration) ons werk zo steunt.

Bekijk de plenaire presentaties over Getting Orphan Drugs to Market van Dr. Lewis Fermaglich van de FDA en Dr. Diana Wetmore van het Harrington Discovery Institute.

Ons eerste panel over Potentiële therapieën voor het FOXG1-syndroom bestond uit Dr. Yael Weiss, Dr. Antonello Mallamaci, Dr. Soo Lee en Dr. Sylvain Lengacher. De belangrijkste conclusies zijn:

1. Over het hele spectrum van FOXG1-mutaties zien we verschillende effecten op het eiwitniveau, astrogenese en andere activiteiten in de hersenen. Dit hoeft niet te leiden tot verschillende therapieën per mutatie, maar het kan wel leiden tot verschillende doserings niveaus en combinatorische benaderingen.

2. De ideale therapie zou zijn om gen-mutatie defecten te bewerken, maar aangezien bij-effecten buiten het FOXG1-gen nog steeds een te grote zorg zijn (onze kinderen ontwikkelen hersenkanker door een behandeling bijvoorbeeld), zouden micro-RNA's een manier kunnen zijn om FOXG1-eiwit te moduleren en andere eiwit niveaus in de hersenen te bewerkstelligen. We zien succes in experimenten waar microRNA's de FOXG1-eiwitniveaus verhogen.

3. We zien ook dat FOXG1-overexpressie een fenotype van het FOXG1-syndroom kan veroorzaken en dit wordt bestudeerd om ons te helpen de dosering te begrijpen.

4. Gliacellen en hersenmetabolisme zijn innovatieve doelen voor het FOXG1-syndroom. Preklinische gegevens tonen aan dat siRNA-gemedieerde neerwaartse regulatie van FOXG1 in astrocyten een dramatische invloed heeft op het energiemetabolisme van de hersenen en GP-57 met een klein molecuul zou een medicijn kunnen zijn dat we gebruiken om dit te bereiken.

5. Om de FOXG1-eiwitniveaus niet te veel te activeren en meer schade aan te richten, kan een combinatorische benadering erg belangrijk zijn. Misschien moeten we neuronen en astrocyten stimuleren, maar door het ene celtype te stimuleren, kunnen we een impact hebben op een ander dat moet worden tegengegaan.

Dr. Soo-Kyung Lee, Dr. David Bedwell en Dr. Chris Ahern spraken in ons laatste panel, Potential Therapies for Nonsense Mutations. 30% van onze kinderen hebben een Nonsense mutatie en het is buitengewoon hoopgevend dat we twee potentiële therapieën aan de horizon hebben.

1. De eerste zijn readthrough verbindingen die de frequentie van nonsense codon onderdrukking verhogen. We screenen momenteel deze bibliotheek op FOXG1 HEK293 (niercellen) en SH-SY5Y (neuroblastoomcellen) reportercellen. Succesvolle treffers zullen verder worden getest in van patiënten afkomstige nonsense stamcellen en muismodellen. Een belangrijk aspect van dit onderzoek is het percentage onderdrukking dat we kunnen krijgen door mutatie. Hiervoor hebben we informatie nodig over hoeveel FOXG1-eiwit voldoende is. Dit is een vraag waar onze fundamentele wetenschappelijke onderzoekers aan werken.

2. De tweede mogelijke therapie omvat het repareren van stopcodons met behulp van tRNA-gentherapie. Hier zouden we de tRNA-sequentie veranderen om stopcodons te onderdrukken. Wat we hebben geleerd, is dat als reparatie robuust is, 40-80% van de wildtype-expressie kan worden verkregen, wat veel hoger is dan wat een readthrough-verbinding zou kunnen bereiken. Hoewel dit hoopgevend is, moeten we nog steeds alle aspecten testen, zoals het begrijpen of tRNA's andere ongewenste effecten veroorzaken.

3. Het doel kan opnieuw combinerend zijn - zowel tRNA gebruiken als gelaagdheid op nonsense verbindingen voor de meest effectieve aanpak voor onze kinderen met nonsense mutaties.

We hebben geen tijd besteed aan het bespreken van gentherapie en antisense therapie-inspanningen voor het FOXG1-syndroom. Die zitten in de voorbereidende fasen en er zijn niet genoeg gegevens aanwezig om te delen. Op onze volgende conferentie in 2021 hopen we een panel te hebben over deze therapeutische benaderingen.

Dag twee eindigde met twee uur boeiende Breakout Rooms voor wetenschappers en voor ouders en verzorgers. De gesprekken hadden uren kunnen duren en we kijken ernaar uit om meer van dit soort discussies te hosten.

In de tussentijd zullen we updates hier op dit blog en op onze FOXG1 Research Facebook-pagina delen.

Ten slotte zou geen van dit werk om een ​​remedie te vinden mogelijk zijn zonder donaties. 80% van ons werk is gefinancierd door persoonlijke donaties en bijna 100% van de donaties gaat naar onderzoek. 

 Klik hier om te doneren om behandeling voor het FOXG1-syndroom mogelijk te maken!

- Bonnie Snoek

Uma recapitulação do “FOXG1 Science Symposium 2020”

www.Foxg1research.Buzzcast.com

Nos dias 17 e 18 de agosto, realizamos o “FOXG1 Science Symposium 2020” como um evento virtual, e não na Universidade de Buffalo, conforme planejado originalmente.  Enquanto perdemos a chance de nos reunirmos pessoalmente, o lado positivo foi um público que superou nossas expectativas, com mais de 300 participantes.

Foi um evento verdadeiramente notável, com informações novas e ricas, assim como um consórcio crescente de cientistas, executivos da indústria, cuidadores e mais, todos focados no caminho em direção a terapias para a síndrome FOXG1.

Muito do conteúdo, incluindo sessões de perguntas e respostas, está disponível para assistir aqui. Observe que extraímos a maioria das apresentações devido a informações confidenciais ainda não publicadas.

Dia um: 

Comecei o primeiro dia com uma visão geral do objetivo singular da FOXG1 Research Foundation: encontrar uma cura para a síndrome FOXG1 para todas as crianças afetadas em todo o mundo. Percorremos um longo caminho desde que começamos em setembro de 2017!

Clique no meu Bem-vindo para ver uma visão geral de nossa estratégia e pesquisa.

Temos orgulho de aprender com os melhores líderes de grupos de doenças raras.  Clique na palestra do primeiro dia para assistir à apresentação do Dr. Art Beaudet sobre o caminho percorrido para encontrar a cura para a síndrome de Angelmans.

Nosso primeiro painel, Fenótipos clínicos da síndrome FOXG1, compartilhou dados pré-publicados do Registro de Pacientes FOXG1 que tem como objetivo compreender o espectro de fenótipos (sintomas) FOXG1 que as crianças experimentam.  Vemos sintomas ligeiramente diferentes dependendo da mutação genética específica do FOXG1 (deleção, missense, etc).  Os pais neste painel falaram sobre sintomas clínicos, alterações de desenvolvimento e problemas comportamentais que seus filhos estão enfrentando.  Enviamos um artigo com essas informações para publicação em periódicos científicos intitulado “Expandindo as correlações genótipo-fenótipo na síndrome FOXG1 resultante de um registro de pacientes”.

Os seguintes clínicos e cientistas líderes contribuíram para este estudo:

 Elise Brimble, MS

 Kathryn G. Reyes, BS

 Orrin Devinsky, MD

 Maura Ruzhnikov, MD

 Xilma Ortiz-Gonzalez, MD

 Ingrid Scheffer, MBBS, PhD

 Nadia Bahi-Buisson, MD, PhD

Heather Olsen, MD, MSNext, ouvimos do Dr. Soo-Kyung Lee, Dr. John Mason, Dr. Michael C. Yu e Dr. Priya Banerjee no painel Biologia Básica FOXG1.  Ouvimos que existe a expressão do gene FOXG1 em diferentes tipos de células no cérebro, e que o mesmo é presente na maioria dos animais (a maioria deles têm uma sequência do gene FOXG1 semelhante à dos humanos), portanto sabemos que podemos usar modelos animais como uma plataforma para estudar a biologia do FOXG1.

Os palestrantes discutiram a separação de fases de proteína arginina e líquido-líquido como novas maneiras de entender a biologia do gene FOXG1 a fim de desenvolver tratamentos.  Esses tratamentos podem ajudar a controlar a função da proteína produzida pelo FOXG1.

Em seguida, mergulhamos no painel sobre Modelagem Celular FOXG1 e ouvimos o Dr. Robin Kleiman, Dr. Flora Vaccarino, Dr. Alysson Muotri e Dr. Aparna Bhaduri.  Houve três conclusões principais deste painel:

1. O nível da dose de FOXG1 é fundamental, com evidências claras de que diferentes genes são regulados em diferentes doses. Isso pode ajudar a compreender melhor o desfecho fenotípico variável entre os pacientes.

2. O modelo  organóide de paciente está em andamento e promete revelar insights interessantes sobre a biologia específica de cada paciente e permitir a triagem de drogas.

3. Embora os organóides sejam um grande recurso para modelar o cérebro humano, é importante avaliar cuidadosamente a saúde e o status de diferenciação dos tipos de células de interesse em evolução e garantir que haja uma representação saudável do que estamos tentando modelar.

A Dra. Jessica Mariani substituiu a Dra. Vaccarino na discussão de perguntas e respostas, que você pode assistir aqui.

Nosso último painel do primeiro dia, Modelagem Animal FOXG1, apresentou o Dr. Rodney Samaco, Dr. Jae Lee, Dr. Goichi Miyoshi e Dr. Corinne Houart.  Dados iniciais foram compartilhados dos seis modelos de camundongos heterozigotos em desenvolvimento e de nossos modelos de peixe-zebra heterozigotos.  A conclusão mais importante foi o estabelecimento inicial de um fenótipo claro (sintomas) desses modelos em comparação com o controle. Isso é pertinente porque mostra que esses animais serão excelentes modelos para testes de drogas. Esta é a primeira etapa do teste com drogas, sem um modelo correto não seremos capazes de rastrear nada.  Também aprendemos que podemos ter como alvo tanto o gene FOXG1 diretamente, quanto fatores como desequilíbrio neuronal excitatório/inibitório.  Isso é importante porque oferece várias maneiras de resgatar os sintomas de nossos filhos.

 Dia dois:

Quando iniciamos a FOXG1 Research Foundation, não havia nenhum esforço concentrado para investir em pesquisa translacional para a síndrome FOXG1.  Todas as pesquisas até então se concentraram no papel do gene FOXG1 no desenvolvimento geral do cérebro.  Como uma fundação, é muito importante permanecermos colaborativos. O Dr. Soo Kyung-Lee e a Dra. Jae Lee fazem parte da nossa família FOXG1 e somos abençoados por eles continuarem a se envolver profundamente com todos os cientistas e compartilhar seus trabalhos pré-publicados.

Hoje, estamos nos aproximando de uma cura.  Nos próximos dois anos, estaremos testando drogas, terapias genéticas, terapias antisense e muito mais.  Algo que se tornou evidente é quão complexo é o gene FOXG1, mesmo sendo um gene tão pequeno, e quão importante é entender a biologia do FOXG1 em nível molecular e celular.

Essa compreensão da biologia FOXG1 levará a invenções e ideias.

Nossa presidente e cofundadora Nicole Johnson deu início ao segundo dia com uma história pessoal sobre sua filha Josie e, em seguida, definiu o foco do dia na ciência translacional.

Nossa sessão plenária de abertura foi centrada no processo de desenvolvimento de medicamentos para doenças raras.  Queremos evitar o “vale da morte”, onde as ideias acadêmicas ficam presas e nunca chegam ao mercado.  Felizmente, a Lei das Doenças Órfãs americana continua a apoiar o desenvolvimento de medicamentos para doenças raras.  Estamos entusiasmados com o apoio do FDA ao nosso trabalho.

Assista às apresentações plenárias sobre Como levar medicamentos órfãos ao mercado do Dr. Lewis Fermaglich do FDA e da Dra. Diana Wetmore do Harrington Discovery Institute.

Nosso primeiro painel sobre terapias potenciais para a síndrome FOXG1 apresentou o Dr. Yael Weiss, o Dr. Antonello Mallamaci, o Dr. Soo Lee e o Dr. Sylvain Lengacher.  Os principais pontos são:

1. Em todo o espectro de mutações FOXG1, estamos vendo diferentes impactos no nível de proteína, astrogênese e outras atividades no cérebro.  Isso não precisa levar a diferentes tipos de terapia por mutação, mas pode levar a diferentes níveis de dosagem e abordagens combinatórias.

2. A terapia ideal seria a edição genética dos defeitos de mutação, mas, uma vez que os efeitos fora do alvo ainda são uma grande preocupação (nossas crianças desenvolvendo câncer no cérebro por um tratamento, por exemplo), os microRNAs poderiam ser uma forma de modular a proteína FOXG1 e  outros níveis no cérebro.  Estamos vendo sucesso em experimentos em que os microRNAs estão aumentando os níveis da proteína FOXG1.

3. Também vemos que a superexpressão de FOXG1 pode causar um fenótipo de síndrome FOXG1 e isso está sendo estudado para nos ajudar a compreender a dosagem.

4. As células da glia e o metabolismo cerebral são alvos inovadores para a síndrome FOXG1.  Dados pré-clínicos mostram que a regulação inibitória mediada por siRNA do FOXG1 em astrócitos afeta dramaticamente o metabolismo energético do cérebro, e a pequena molécula GP-57 pode ser a droga que usamos para fazer isso.

5. Para não hiper ativar os níveis da proteína FOXG1 e causar mais danos, uma abordagem combinatória pode ser muito importante.  Podemos precisar estimular neurônios e astrócitos, mas ao estimular um tipo de célula poderíamos ter um impacto sobre outra que precisaria ser neutralizado.

O Dr. Soo-Kyung Lee, o Dr. David Bedwell e o Dr. Chris Ahern falaram em nosso último painel, Terapias Potenciais para Mutações Nonsense.  30% de nossos filhos têm mutações nonsense e é extremamente emocionante que tenhamos duas terapias com forte potencial no horizonte.

1. A primeira são compostos de leitura contínua que aumentam a frequência de supressão do códon nonsense.  Atualmente, estamos testando esta biblioteca em células repórter FOXG1 HEK293 (células renais) e SH-SY5Y (células de neuroblastoma).  Achados bem sucedidos serão testados em células-tronco nonsense derivadas de pacientes em modelos de camundongos.  Um aspecto importante desta pesquisa é a porcentagem de supressão que podemos obter por mutação.  Para isso, precisamos saber quanta proteína FOXG1 é suficiente.  Esta é uma questão em que nossos pesquisadores de ciência básica estão trabalhando.

2. A segunda terapia potencial envolve o reparo de códons de parada usando terapia gênica de tRNA.  Aqui, mudaríamos a sequência de tRNA para suprimir os códons de parada.  O que aprendemos é que, se o reparo for robusto, 40-80% da expressão do tipo selvagem pode ser obtida, o que é muito maior do que um composto de leitura poderia atingir. Embora isso seja emocionante, ainda precisamos testar todos os aspectos, como entender se o tRNA causa outros efeitos indesejados.

3. O objetivo pode ser novamente combinacional - usando tRNA e camadas de compostos nonsense para a abordagem mais eficaz para nossas crianças com mutações nonsense.

Não perdemos tempo discutindo os esforços da terapia genética e da terapia antisense para a síndrome FOXG1. Esses estão nas fases preliminares e não há dados suficientes para compartilhar.  Em nossa próxima conferência em 2021, esperamos ter um painel robusto sobre essas abordagens terapêuticas.

O segundo dia terminou com duas horas de sala de discussão envolventes para cientistas, pais e responsáveis.  As conversas poderiam ter durado muitas horas e estamos ansiosos para proporcionar mais desse tipo de discussão.

Enquanto isso, estaremos compartilhando atualizações aqui neste blog e em nossa página FOXG1 Research no Facebook.

Por último, nenhum trabalho deste tipo para encontrar a cura seria possível sem doações. 80% do nosso trabalho foi financiado por doações pessoais e quase 100% das doações vão para pesquisa. Clique aqui para doar e encontrar a cura para a síndrome FOXG1!

- Letícia Piccoli Tergolina

El Simposio de ciencia FOXG1 2020

www.FOXG1research.buzzcast.com

El 17 y 18 de agosto celebramos el Simposio de ciencia FOXG1 2020 como un evento virtual en lugar de en la Universidad de Buffalo como se planeó originalmente. Si bien perdimos la oportunidad de reunirnos en persona, el lado positivo fue una audiencia que superó con creces nuestras expectativas con más de 300 asistentes.

Fue un evento verdaderamente notable, con datos nuevos y fructíferos y un consorcio creciente de científicos, ejecutivos de la industria, cuidadores y más, todos enfocados en el camino hacia las terapias modificadoras de la enfermedad para el síndrome FOXG1.

Gran parte del contenido, incluidas las sesiones de preguntas y respuestas, está disponible para que lo puedan ver en el sitio de la Fundación FOXG1 Research Foundation (en idioma inglés). Tenga en cuenta que extrajimos la mayoría de las presentaciones debido a datos confidenciales no publicados.

PRIMER DIA

Comencé el primer día con una descripción general del objetivo singular de la Fundación FOXG1 Research Foundation: encontrar una cura para el síndrome FOXG1 para todos los niños afectados a nivel mundial. ¡Hemos recorrido un largo camino desde que comenzamos en septiembre de 2017!

Haga clic en mi bienvenida para ver una descripción general de nuestra estrategia e investigación y nuestro nuevo estudio de historia natural de aprendizaje automático. (Disponible en el sitio de la Fundación FOXG1 Research Foundation - en idioma inglés)

Nos enorgullecemos de aprender de los mejores líderes de grupos de enfermedades raras. Haga clic en el Keynote del primer día para ver la presentación del Dr. Art Beaudet sobre el camino que se tomó para encontrar una cura para el síndrome de Angelmans. (Disponible en el sitio de la Fundación FOXG1 Research Foundation - en idioma inglés)

Nuestro primer panel, Fenotipos clínicos del síndrome FOXG1, compartió datos pre publicados del Registro de pacientes de FOXG1 que se centra en comprender el espectro de fenotipos (síntomas) de FOXG1 que experimentan los niños. Vemos síntomas ligeramente diferentes según la mutación genética específica de FOXG1 (deleción, sentido erróneo, etc.). Los padres de este panel hablaron sobre los síntomas médicos, los síntomas del desarrollo y los problemas de comportamiento que enfrentan sus hijos. Hemos enviado un artículo con esta información para su publicación en revistas científicas titulado "Expandiendo las correlaciones genotipo-fenotipo en el síndrome FOXG1 como resultado de un registro de pacientes".

Los siguientes médicos y científicos destacados han contribuido a este estudio: Elise Brimble, MS, Kathryn G Reyes, BS, Orrin Devinsky, MD, Maura Ruzhnikov, MD, Xilma Ortiz-Gonzalez, MD, Ingrid Scheffer, MBBS, PhD, Nadia Bahi- Buisson, MD, PhD, Heather Olsen, MD, MS

También escuchamos a tres padres diferentes de FOXG1 increíbles cuyos hijos representan un espectro de fenotipos de FOXG1. Greg Wells, Laura Patterson y Stefani Miles compartieron cada uno una presentación dándonos la bienvenida a la vida de sus hijos. Realmente no hay mayor recurso para comprender este síndrome que los propios niños. Todos estábamos muy emocionados de conocer a Ali, Emma, Bo y Caleb.

A continuación, escuchamos al Dr. Soo-Kyung Lee, el Dr. John Mason, el Dr. Michael C. Yu y la Dra. Priya Banerjee en el panel de Biología Básica de FOXG1. Escuchamos que el gen FOXG1 se expresa en diferentes tipos de células en el cerebro y que el gen se conserva en la mayoría de los animales (la mayoría de los animales tienen una secuencia del gen FOXG1 similar a la de los humanos), por lo que sabemos que podemos usar modelos animales como plataforma para estudiar Biología FOXG1.

Los oradores discutieron la metilación de proteínas y arginina y la separación de fases líquido-líquido como formas novedosas de comprender la biología del gen FOXG1 para desarrollar tratamientos. Estos tratamientos pueden ayudar a controlar la función de la proteína FOXG1.

Luego nos sumergimos en el panel sobre el modelado celular FOXG1 y escuchamos al Dr. Robin Kleiman, la Dra. Flora Vaccarino, la Dra. Alysson Muotri y la Dra. Aparna Bhaduri.

Hubo tres conclusiones principales de este panel:

1. El nivel de dosificación de FOXG1 es crítico con una clara evidencia de que diferentes genes están regulados a diferentes dosis. Esto puede ayudar a comprender mejor el resultado fenotípico variable en los pacientes.

2. El modelado de organoides de pacientes está en marcha y promete revelar conocimientos interesantes sobre la biología específica del paciente y permitir la detección de fármacos.

3. Si bien los organoides son un gran recurso para modelar el cerebro humano, es importante evaluar cuidadosamente el estado de salud y diferenciación de los tipos de células de interés en el futuro y asegurarse de que haya una representación saludable de lo que estamos tratando de modelar.

La Dra. Jessica Mariani reemplazó a la Dra. Vaccarino para la discusión de preguntas y respuestas (Disponible en el sitio de la Fundación FOXG1 Research Foundation - en idioma inglés)

¡Nuestro último panel del Día Uno define una verdadera “conferencia global” con científicos desde Tokio hasta Texas! El modelado de animales FOXG1 contó con el Dr. Rodney Samaco, el Dr. Jae Lee, el Dr. Goichi Miyoshi y la Dra. Corinne Houart.

Se compartieron los primeros datos de los seis modelos de ratones heterocigotos que se están desarrollando y nuestros modelos de pez cebra heterocigotos. La conclusión más importante fueron los datos iniciales que establecían un fenotipo (síntomas) claro de estos modelos frente al control. Esto es importante ya que muestra que estos animales serán

excelentes modelos para las pruebas de drogas. Este es el primer paso en las pruebas de drogas, sin un modelo correcto no podremos detectar nada. También aprendimos que podemos apuntar tanto al gen FOXG1 directamente como a factores como el desequilibrio neuronal excitador / inhibitorio. Esto es importante ya que brinda múltiples formas de rescatar los síntomas de nuestros hijos.

Cuando comenzamos la Fundación de Investigación FOXG1, no había ningún esfuerzo concertado para invertir en investigación traslacional para el síndrome FOXG1. En ese momento, la investigación se había centrado en el papel de los genes FOXG1 en el desarrollo general del cerebro. Como fundación, es muy importante que sigamos colaborando. El Dr. Soo Kyung-Lee y el Dr. Jae Lee son parte de nuestra familia FOXG1 y tenemos la bendición de que continúen comprometiéndose profundamente con todos los científicos y compartan su trabajo previamente publicado.

Hoy nos acercamos a una cura. Durante los próximos dos años analizaremos medicamentos, terapias genéticas, terapias antisentido y más. Una cosa que se ha hecho evidente es cuán complejo es el gen FOXG1, a pesar de que es un gen tan pequeño, y cuán importante es comprender la biología de FOXG1 a nivel molecular y celular.

Esta comprensión de la biología FOXG1 conducirá a inventos e ideas.

SEGUNDO DIA

Nuestra presidenta y cofundadora Nicole Johnson inició el segundo día con una historia personal sobre su hija, Josie, y luego estableció el enfoque del día en la ciencia traslacional.

La sesión plenaria de apertura del segundo día se centró en el proceso de desarrollo de fármacos para enfermedades raras. Queremos evitar el “valle de la muerte”, donde las ideas académicas se atascan y nunca llegan al mercado. Afortunadamente, la Ley de Enfermedades Huérfanas sigue apoyando el desarrollo de medicamentos para enfermedades raras. Estamos encantados de que la FDA apoye tanto nuestro trabajo.

Vea las presentaciones sobre cómo llevar medicamentos huérfanos al mercado del Dr. Lewis Fermaglich de la FDA y la Dra. Diana Wetmore del Harrington Discovery Institute. (Disponible en el sitio de la Fundación FOXG1 Research Foundation - en idioma inglés)

Nuestro primer panel sobre terapias potenciales para el síndrome FOXG1 contó con el Dr. Yael Weiss, el Dr. Antonello Mallamaci, el Dr. Soo Lee y el Dr. Sylvain Lengacher. Los puntos clave son:

1. En todo el espectro de mutaciones FOXG1, estamos viendo diferentes impactos en el nivel de proteínas, astrogénesis y otras actividades en el cerebro. No es necesario que esto conduzca a diferentes terapias por mutación, pero podría conducir a diferentes niveles de dosificación y enfoques combinatorios.

2. La terapia ideal sería editar los defectos de mutación de genes, pero, dado que los efectos fuera del objetivo siguen siendo una preocupación demasiado alta (nuestros hijos desarrollan cáncer de cerebro a partir de un tratamiento, por ejemplo), los micro ARN podrían ser una forma de modular FOXG1 proteínas y otros niveles en el cerebro. Estamos viendo éxitos en los experimentos de que los microARN están aumentando los niveles de proteína FOXG1.

3. También vemos que la sobreexpresión de FOXG1 puede causar un fenotipo de síndrome FOXG1 y esto se está estudiando para ayudarnos a comprender la dosis.

4. Las células gliales y el metabolismo cerebral son objetivos innovadores para el síndrome FOXG1. Los datos preclínicos muestran que la regulación negativa de FOXG1 mediada por ARNip en los astrocitos afecta drásticamente el metabolismo energético del cerebro y la GP-57 de molécula pequeña podría ser un fármaco que utilizamos para lograr esto.

5. Para no sobreactivar los niveles de proteína FOXG1 y causar más daño, un enfoque combinatorio puede ser muy importante. Es posible que necesitemos estimular neuronas y astrocitos, pero al estimular un tipo de célula podríamos tener un impacto en otro que tendría que ser contrarrestado.

Como se señaló, eliminamos las presentaciones de los videos, pero las discusiones del panel y las preguntas y respuestas con los asistentes están disponibles para ver en el sitio de la Fundación FOXG1 Research Foundation - en idioma inglés.

El Dr. Soo-Kyung Lee permaneció en línea para moderar el panel final del simposio con el Dr. David Bedwell y el Dr. Chris Ahern titulado: Terapias potenciales para mutaciones sin sentido. El 30% de nuestros niños tienen mutaciones sin sentido y es extremadamente emocionante que tengamos dos terapias potenciales fuertes en el horizonte.

1. Los primeros son compuestos de lectura continua que aumentan la frecuencia de supresión de codones sin sentido. Actualmente estamos analizando esta biblioteca en células informadoras FOXG1 HEK293 (células renales) y SH-SY5Y (células de neuroblastoma). Los hallazgos exitosos se probarán más a fondo en modelos de ratones y células madre sin sentido derivadas de pacientes. Un aspecto importante de esta investigación es el porcentaje de supresión que podemos obtener por mutación. Para ello, necesitamos información sobre cuánta proteína FOXG1 es suficiente. Esta es una cuestión en la que están trabajando nuestros investigadores de ciencias básicas.

2. La segunda terapia potencial implica la reparación de codones de terminación utilizando terapia génica de ARNt. Aquí, cambiaríamos la secuencia de tRNA para suprimir los codones de parada. Lo que hemos aprendido es que si la reparación es sólida, se puede obtener del 40% al 80% de la expresión de tipo salvaje, que es mucho más alta de lo que podría lograr un compuesto de lectura completa. Si bien esto es emocionante, aún necesitamos probar todos los aspectos, como comprender si el ARNt causa otros efectos no deseados.

3. El objetivo puede volver a ser combinacional: usar ARNt y capas de compuestos sin sentido para lograr el enfoque más eficaz para nuestros niños con mutaciones sin sentido.

No dedicamos tiempo a discutir la terapia génica y los esfuerzos de la terapia antisentido para el síndrome FOXG1. Se encuentran en las fases preliminares y no hay suficientes datos para compartir. En nuestra próxima conferencia en 2021, planeamos tener un panel sólido sobre estos enfoques terapéuticos.

El segundo día incluyó dos horas de atractivas salas de reuniones para científicos, padres y cuidadores. Las conversaciones podrían haber durado horas y esperamos poder albergar más de este tipo de discusiones.

Mientras tanto, compartiremos actualizaciones aquí en este blog y en nuestra página de Facebook de FOXG1 Research

Por último, nada de este trabajo para encontrar una cura sería posible sin donaciones. El 80% de nuestro trabajo ha sido financiado por donaciones personales y casi el 100% de las donaciones se destinan a la investigación.

En el sitio de la Fundación FOXG1 Research Foundation encontrarán el link para poder hacer donaciones y así contribuir a encontrar una cura para el síndrome FOXG1! Todos estamos juntos en este camino emocionante hacia una cura.

Escrito por Nasha Fitter, directora ejecutiva, cofundadora y madre de Amara de la Fundación de Investigación FOXG1

- MAGDALENA LABBE

Un récapitulatif du Symposium scientifique FOXG1 2020

Symposium scientifique FOXG1 2020 - www.FOXG1Research.buzzcast.com

Les 17 et 18 août, nous avons organisé le Symposium scientifique FOXG1 2020 en tant qu'événement virtuel plutôt qu'à l'Université de Buffalo comme initialement prévu. La déception de ne pas pouvoir nous rencontrer en personne fut de courte durée lorsqu’on a constaté que le public dépassait de loin nos attentes avec plus de 300 participants.

Ce fut un événement vraiment remarquable, avec des données nouvelles et riches et un consortium croissant de scientifiques, de dirigeants de l'industrie, de soignants, et autres.

Nous étions tous focalisés sur les thérapies à développer pour les personnes affectées par le syndrome FOXG1.

Une grande partie du contenu, y compris les séances de questions-réponses, est disponible en ligne (en anglais). Veuillez prendre note que nous avons extrait la plupart des présentations des scientifiques en raison de données sensibles non publiées.

J'ai démarré la première journée avec un aperçu de l'objectif de la Fondation FOXG1 Research: soit celui de trouver un remède pour le syndrome FOXG1 pour tous les enfants affectés dans le monde. Nous avons parcouru un long chemin depuis nos débuts en septembre 2017.

Nous sommes fiers de pouvoir beaucoup apprendre des leaders mondiaux spécialisés dans les maladies rares et le Dr Art Beaudet est intervenu en tout début de conférence pour parler du chemin parcouru pour trouver un remède au syndrome d'Angelmans.

Notre premier panel, dédié aux Phénotypes Cliniques du Syndrome FOXG1, a partagé des données prépubliées du registre des patients FOXG1 qui se concentrent sur la compréhension du spectre des phénotypes FOXG1 (symptômes) que les enfants ressentent. Nous constatons des symptômes légèrement différents selon la mutation génétique spécifique FOXG1 (délétion, faux-sens, etc.). Les parents de ce panel ont parlé des symptômes médicaux, des symptômes liés au développement et des problèmes de comportement auxquels leurs enfants sont confrontés. Nous avons soumis un article contenant ces informations pour publication dans des revues scientifiques intitulé «Expansion des corrélations génotype-phénotype dans le syndrome FOXG1 résultant d'un registre de patients».

Les principaux cliniciens et scientifiques suivants ont contribué à cette étude:

Elise Brimble, MS

Kathryn G Reyes, BS

Orrin Devinsky, MD

Maura Ruzhnikov, MD

Xilma Ortiz-Gonzalez, MD

Ingrid Scheffer, MBBS, PhD

Nadia Bahi-Buisson, MD, PhD

Heather Olsen, MD, MS

Ensuite, nous avons entendu le Dr Soo-Kyung Lee, le Dr John Mason, le Dr Michael C. Yu et le Dr Priya Banerjee sur le thème de la Biologie de Base FOXG1. Ils ont parlé du fait que le gène FOXG1 est exprimé dans différents types de cellules du cerveau et que le gène est conservé chez la plupart des animaux (la plupart des animaux ont une séquence du gène FOXG1 similaire à celle des humains), nous savons donc que nous pouvons utiliser des modèles animaux comme plate-forme pour étudier la biologie FOXG1.

Les orateurs ont discuté de la méthylation de la protéine arginine ainsi que de la séparation de phase liquide-liquide comme de nouvelles façons de comprendre la biologie du gène FOXG1 afin de développer des traitements. Ces traitements peuvent aider à contrôler la fonction de la protéine FOXG1.

Nous avons ensuite plongé dans le panel sur la modélisation cellulaire FOXG1 et entendu le Dr Robin Kleiman, le Dr Flora Vaccarino, le Dr Alysson Muotri et le Dr Aparna Bhaduri. Il y avait trois principaux points à retenir de ce panel:

1. Le niveau de dosage de FOXG1 est critique avec des preuves claires de la régulation de différents gènes à différentes doses. Cela peut aider à mieux comprendre le résultat phénotypique variable chez les patients.

2. La modélisation des organoïdes des patients est en cours et promet de révéler des informations intéressantes sur la biologie spécifique au patient et de permettre le dépistage des médicaments.

3. Bien que les organoïdes soient une excellente ressource pour modéliser le cerveau humain, il est important d'évaluer soigneusement l'état de santé et de différenciation des types de cellules qui nous intéressent et de s'assurer qu'il existe une représentation saine de ce que nous essayons de modéliser

Le Dr Jessica Mariani a remplacé le Dr Vaccarino pour la discussion de questions-réponses, que vous pouvez regarder ici.

Notre dernier panel du premier jour, La Modélisation FOXG1 sur les Animaux, comprenait le Dr Rodney Samaco, le Dr Jae Lee, le Dr Goichi Miyoshi et le Dr Corinne Houart. Ils ont évoqué les premières données obtenues à partir des six modèles de souris hétérozygotes en cours de développement ainsi que de nos modèles de poissons zèbres hétérozygotes. La chose la plus importante à retenir est la suivante:

• Les premiers résultats démontrent qu’on arrive à obtenir un phénotype clair (soit des symptômes précis) à partir de ces modèles affectés par FOXG1 par rapport au modèle témoin. 

Ceci est important car cela montre que ces animaux seront d'excellents modèles pour le dépistage des drogues. C'est la première étape du dépistage des drogues, sans un modèle correct, nous ne pourrons pas faire de dépistage. Nous avons également appris que nous pouvons cibler à la fois le gène FOXG1 directement, ainsi que d’autres facteurs tels que le déséquilibre neuronal excitateur / inhibiteur. Ceci est important car cela nous offres plusieurs chemins à suivre pour un jour avoir un effet réparateur sur les symptômes de nos enfants.

Deuxième jour :

Lorsque nous avons lancé la Fondation de recherche FOXG1, nous ne nous étion spas penché sur la recherche translationnelle sur  le syndrome FOXG1. Toutes les recherches à ce moment-là se sont concentrées sur le rôle du gène FOXG1 dans le développement global du cerveau. En tant que fondation, il est très important que nous restions collaboratifs. Le Dr Soo Kyung-Lee et le Dr Jae Lee font partie de notre famille FOXG1 et nous sommes heureux qu'ils continuent à s'engager profondément avec tous les scientifiques et à partager leurs travaux pré-publiés.

Aujourd'hui, nous nous rapprochons d'un traitement. Au cours des deux prochaines années, nous examinerons des médicaments, des thérapies géniques, des thérapies antisens et plus encore. Une chose qui a été rendue évidente est la complexité du gène FOXG1, même s'il s'agit d'un gène tout petit, et à quel point il est important de comprendre la biologie de FOXG1 au niveau moléculaire et cellulaire.

Cette compréhension de la biologie FOXG1 conduira à des inventions et des idées.

Notre présidente et cofondatrice, Nicole Johnson, a lancé la deuxième journée avec une histoire personnelle sur sa fille Josie, puis a mis l'accent sur la science translationnelle.

Notre séance plénière d'ouverture était centrée sur le processus de développement de médicaments pour les maladies rares. Nous voulons éviter la «vallée de la mort», où les idées académiques restent bloquées et ne parviennent jamais sur le marché. Heureusement, la loi sur les maladies orphelines continue de soutenir le développement de médicaments contre les maladies rares. Nous sommes ravis que la FDA  soutienne notre travail.

Regardez les présentations en plénière Getting Orphan Drugs to Market du Dr Lewis Fermaglich de la FDA et du Dr Diana Wetmore du Harrington Discovery Institute.

Notre premier panel sur les thérapies potentielles pour le syndrome FOXG1 comprenait le Dr Yael Weiss, le Dr Antonello Mallamaci, le Dr Soo Lee et le Dr Sylvain Lengacher. Les principaux points à retenir sont:

1. À travers le spectre des mutations FOXG1, nous constatons différents impacts sur le niveau de protéines, l'astrogenèse et d'autres activités dans le cerveau. Cela n'a pas besoin de conduire à des thérapies différentes par mutation, mais cela pourrait conduire à différents niveaux de dosage et approches combinatoires.

2. La thérapie idéale serait de modifier le gène des défauts de mutation, mais, comme les effets hors cible sont encore trop préoccupants (nos enfants développant un cancer du cerveau à la suite d'un traitement, par exemple), les micro-ARN pourraient être un moyen de moduler la protéine FOXG1 et d'autres niveaux dans le cerveau. Nous constatons un succès dans les expériences selon lesquelles les microARN augmentent les niveaux de protéines FOXG1.

3. Nous voyons également que la surexpression de FOXG1 peut provoquer un phénotype de syndrome FOXG1 et ceci est à l'étude pour nous aider à comprendre le dosage.

4. Les cellules gliales et le métabolisme cérébral sont des cibles innovantes du syndrome FOXG1. Les données précliniques montrent que la régulation à la baisse médiée par l'ARNsi de FOXG1 dans les astrocytes affecte considérablement le métabolisme énergétique du cerveau et la petite molécule GP-57 pourrait être un médicament que nous utilisons pour y parvenir.

5. Afin de ne pas suractiver les niveaux de protéines FOXG1 et de causer plus de dommages, une approche combinatoire peut être très importante. Nous pouvons avoir besoin de stimuler les neurones et les astrocytes, mais en stimulant un type de cellule, nous pourrions avoir un impact sur un autre qui devrait être contré.

Le Dr Soo-Kyung Lee, le Dr David Bedwell et le Dr Chris Ahern ont pris la parole lors de notre dernier panel, Thérapies potentielles pour les mutations non-sens. 30% de nos enfants ont des mutations non-sens et il est extrêmement excitant que nous ayons deux thérapies à fort potentiel à l'horizon.

1. Les premiers sont des composés de lecture qui augmentent la fréquence de suppression des codons non-sens. Nous examinons actuellement cette bibliothèque sur des cellules rapporteurs FOXG1 HEK293 (cellules rénales) et SH-SY5Y (cellules de neuroblastome). Les réussites seront testées en amont dans des cellules souches non-sens dérivées de patients et des modèles de souris. Un aspect important de cette recherche est le pourcentage de suppression que nous pouvons obtenir par mutation. Pour cela, nous avons besoin d'informations sur la quantité de protéine FOXG1 suffisante. C'est une question sur laquelle travaillent nos chercheurs en sciences fondamentales.

2. La deuxième thérapie potentielle consiste à réparer les codons d'arrêt à l'aide de la thérapie génique ARNt. Ici, nous changerions la séquence d'ARNt pour supprimer les codons d'arrêt. Ce que nous avons appris, c'est que si la réparation est robuste, 40 à 80% de l'expression de type sauvage(9) peut être obtenue, ce qui est beaucoup plus élevé que ce qu'un composé de lecture peut réaliser. Bien que ce soit passionnant, nous devons encore tester tous les aspects pour comprendre si l'ARNt provoque d'autres effets indésirables.

3. L'objectif peut à nouveau être combinatoire - en utilisant à la fois l'ARNt et la superposition sur des composés non-sens pour l'approche la plus efficace pour nos enfants avec des mutations non-sens

Nous n'avons pas passé de temps à discuter des efforts de thérapie génique et de thérapie antisens pour le syndrome FOXG1. Celles-ci sont dans les phases préliminaires et il n'y a pas assez de données à partager. Lors de notre prochaine conférence en 2021, nous espérons disposer d'un panel solide sur ces approches thérapeutiques.

La deuxième journée s'est terminée par deux heures de réunion engageantes pour les scientifiques, les parents et les soignants. Les conversations auraient pu durer des heures et nous sommes impatients d’accueillir davantage de ces types de discussions.

En attendant, nous partagerons les mises à jour ici sur ce blog et sur notre page Facebook FOXG1 Research.

Enfin, aucun de ces travaux pour trouver un remède ne serait possible sans dons. 80% de nos travaux ont été financés par des dons personnels, et près de 100% des dons sont destinés à la recherche. Cliquez ici pour faire un don afin de trouver un remède contre le syndrome FOXG1!

- Christine Revkin

The Rare Disease Crusaders

A feature about our FOXG1 Research CEO and Co-founder Nasha Fitter from the Ciitizen Blog…

My daughter was seven months old when she had her first seizure. It scared me to death, and her spells would continue for months until we discovered the reason:

she suffers from a severe and rare neurodevelopmental disorder called FOXG1 syndrome. 

It wasn’t until weeks after her diagnosis that I found the courage to go online and read about the condition: due to a genetic protein deficiency children experience severe intellectual disability, epileptic symptoms, and many never walk or talk for their entire lives.

I vomited immediately after reading that. 

The subsequent months were full of terror and grief, but eventually my sadness evolved into determination and I took action, joining a group of parents like me who were piggybacking on a wave of scientific progress to find cures for their children’s rare disorders. Today, we call ourselves the Rare Disease Crusaders.

Considering the amount of energy and campaigning required to find answers for our kids, I think “crusader” sums up our struggle quite accurately. We have become de facto pediatricians, neurologists and scientists, as many doctors have never heard of FOXG1. We have developed mouse models, learned how to turn skin cells into neurons and spoken directly with biopharma about gene and antisense therapies. 

Yet, no matter how much we learn about our children, we’re lacking the one informational resource that can actually move the needle in transforming their lives: aggregated clinical data.

Computational data is the key to medical research. Without it, no biotech company will invest the time or the money to find therapies for our children, and we have neither the time nor the capacity to keep educating the medical industry on our own.

Having spent the majority of my career in tech, I am still fairly confused as to why healthcare  operates in the dark when so many other industries have successfully used data to solve major problems. I don’t understand why our neurologist doesn’t have access to a database of medications for FOXG1 patients around the world. I’m terrified by the fact that she is making decisions for my child and prescribing her heavy antipsychotic drugs based on a limited experience from treating two other FOXG1 children.

Research is also failing us. Natural History Studies—when researchers collect clinical information on a group of patients and use that data to inform drug development—are done in a completely archaic manner. If we are lucky enough to find someone who has spent the millions of dollars necessary to sponsor a Natural History Study for our specific disease, we then have to fly or drive our medically fragile children to a few select academic institutions that may or may not be anywhere near our home.

Once there, they ask us the same questions that we answer for our local neurologists every few months. Once we’ve given them our information, neither they, nor our biopharma partners, can access the aggregated data we need to improve research because many of these institutions don’t share.

But given that every patient has a right to their own medical data, there’s a solution right in front of us: we take control of our own medical records and share them to create the database we need.

I joined Ciitizen and initiated our entry into neurological diseases because I am both passionate and desperate to find an answer for my daughter. At Ciitizen, we’re creating a platform where medical records are collected on behalf of each patient, then automatically digitized into the computational data we need. From there, sophisticated machine learning technology is used to extract clinical data in order to create regulatory-grade Natural History Studies that do not require exorbitant amounts of time, energy, or money. Patient reported outcomes can then be added by us parents. 

More importantly, this database of computational data we’re creating will be accessible and open to all patients, parents, caregivers, clinicians, academics, and biopharma researchers. Our goal is to eliminate the slow, manual, and expensive processes that we currently use to collect information and use the best technologies to be quick, cost-effective and more accurate when it comes to developing research.

I am eager for the day I can search this database for “movement disorder” and find exactly what medications other FOXG1 children and children affected by similar neurodevelopmental disorders are using, and which are most effective. I am eager for my fellow Rare Disease Crusaders to tell biopharma there is a platform available where they can easily access Natural History Studies, and clearly see that our diseases are worth investing in. 

At four years old, my daughter is still completely non-verbal. I’m hoping I can one day hear her speak. Only in my dreams does she come up to me and say, “Mama, I love you.” 

Nasha Fitter leads the rare and neurological initiatives for Ciitizen and is the CEO of the FOXG1 Research Foundation (http://foxg1research.org)

The View Along the Path to a Cure for FOXG1 Syndrome | An Overview by Nasha Fitter

When Amara was diagnosed three years ago, I didn’t even know what a gene was. My background was in technology and business and I wasn’t prepared for the world of science. Luckily, my career had prepared me to tackle an impossible problem that no one has solved before. Being strategic and understanding the various pieces that need to be put together to achieve your end goal is critical in rare disease leadership. I have made mistakes over the past three years, and I have had successes. My goal in this blog series is to share those, and to continue sharing our experiences and journey of the FOXG1 Research Foundation as we work to find a cure for our children and everyone with FOXG1 syndrome.

The first step is to create your destination and strategy. Without those, you cannot motivate people to join your cause. 

In our case, the end destination is not just a singular cure for FOXG1 syndrome. It is to find a host of therapies to help our children. This includes gene editing, gene therapy, RNA therapy, ASO therapy, small molecule therapy, naturopathic therapies. It was clear that for the most part, biopharma would be developing these therapies (or for approved small molecule therapies potentially compassionate use-cases with trials conducted at academic centers). But generally, biopharma was our target. 

After spending a considerable amount of time speaking to various biotech representatives, we realized each one of these therapies could take tens of millions of dollars to develop, and we needed to “de-risk” the investment and make our disease area, FOXG1 syndrome, appealing for industry.

Here are the areas we began focusing on:

1. Organizing patients

   1. FOXG1 Patient Registry 

   2. FOXG1 Patient Biobank

   3. FOXG1 syndrome Parents Facebook Group

2. Understanding the clinical side of FOXG1 syndrome

   1. FOXG1 Patient surveys / registry

   2. FOXG1 Natural History Study

3. Building FOXG1 Assets for testing

   1. HEK lines

   2. IPS lines

   3. Rescue mouse models

   4. Patient specific mouse models

   5. Humanized mouse models

   6. Zebrafish screening platform

   7. Investigating higher order animals

4. Understanding the molecular and cellular pathways of FOXG1 and surrounding area

   1. Characterizing IPS lines

   2. Characterizing animal models

   3. Investing in basic science

5. Conducting screens

   1. Screening ASO targets

   2. Screening small molecule drugs

I will be delving into each of these areas in subsequent blog posts. Below is an info-graph showing the FOXG1 syndrome Path to a Cure. Note that all of our research projects can be found on our website HERE.

Thank you for your interest, and support along our journey towards a cure for FOXG1 syndrome and more.

-Nasha Fitter