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FOXG1 Research Foundation July Newsletter
FOXG1 Research Foundation July Newsletter 2023!
As we've reached the midway point of 2023, we want to take a moment to provide you with an update on our progress, share some exciting news, and express our heartfelt gratitude for your support in our mission to cure FOXG1 syndrome and related neurological disorders.
First and foremost, we are immensely proud to report that we are well on track to achieve our goals for the year. This progress would not have been possible without the continued dedication and encouragement from supporters like you.
On the research front, we have made significant strides in our gene therapy and antisense programs. Encouragingly, both of these initiatives have yielded promising results in our preclinical models. Additionally, we have identified key pathways that can be targeted by FDA-approved drugs, offering potential avenues to alleviate major symptoms. The screening of several hundred FDA-approved drugs on our zebrafish models has opened up new possibilities for future treatments.
A major breakthrough in our efforts is a new publication from our FOXG1 Patient Registry, which is the most comprehensive data on FOXG1 syndrome in patients to date. This invaluable information is instrumental in ensuring our preparedness for clinical trials, bringing us closer to the day when effective treatments can be made accessible to those in need.
As we continue our relentless work with utmost efficiency and diligence, we cannot ignore the heartache we have experienced in losing too many FOXG1 children this year and over the years. Their memory drives us forward, reinforcing the critical nature of our mission to make a difference in the lives of those affected by this devastating condition.
It is with the deepest conviction that we firmly believe, together, we can provide every FOXG1 child in the world with a life free from suffering. Your support has been an integral part of this collective effort, and for that, we extend our heartfelt gratitude.
Thank you for standing with us on this challenging, but immensely rewarding journey. We are confident that brighter days lie ahead for all those affected by FOXG1 syndrome.
Congratulations and thank you to our Director of Clinical Research, Elli Brimble and our esteemed team of Key Opinion Leaders. This publication marks a major milestone in the work to deeply understand the phenotypes of patients with FOXG1 syndrome so that we can target the most effective therapies.
A special thank you to every FOXG1 parent and caregiver who registered their child and who lives this challenging life every day.
Read FOXG1 KEY PAPERS HERE | Register Your FOXG1 Child HERE
After learning about the success of the new anti-epilepsy drug, Fintepla in other rare disease epilepsy clinical trials, we began working with NYU and Zogenix (Now UCB) to launch a clinical trial for FOXG1 patients. It was important for us to make this an open trial with a remote option so that FOXG1 patients do not have to travel to NYC to participate.
This will be the first of many clinical trials designed to help all of our children live easier, healthier lives.
Learn More HERE.
Our lead scientists and parents to Yuna, Dr. Soo-Kyung Lee and Dr. Jae Lee, who run the The FOXG1 Center of Excellence at UB have been awarded $1.5 million from The Simons Foundation Autism Research Initiative for our FOXG1 gene therapy work!
Did you know that FOXG1 is an autism-related gene and the work we're doing has a great potential to help solve autism?
We are extremely lucky to have the Lee's working nonstop to find a cure for FOXG1 syndrome. The combination of being brilliant scientists as well as FOXG1 parents make their determination and devotion to finding a cure unparalleled in the field.
This grant is a great help towards our $20M fundraising goal for our promising FOXG1 gene therapy program.
Continue reading the July newsletter HERE
2022 Impact Report
2022 Research Highlights (see details below)
Breakthrough gene therapy results showing rescue of FOXG1 brain structure, behavior, memory and cognition symptoms in animal models
Positive results on initial compound drug screens to identify molecules to increase FOXG1 levels; now moving forward to larger screens
Never-before understanding of FOXG1 biology uncovered from six FOXG1 patient human cell lines and mouse models
Successful testing of guide RNAs to increase FOXG1 expression with a CRISPRa Cas-9 system
Discovered ASO sequences (antisense gene therapy) to modulate FOXG1 expression; testing initiated with Creyon Bio
FOXG1 data package presented to several biotech companies with high interest
2022 marked five years of the FOXG1 Research Foundation.
Our work brings us closer to successful therapeutics for every child, while supporting families along this difficult journey. We continue to be one of the most innovative foundations in the rare disease space, focused on three equally critical areas: FOXG1 science, FOXG1 patient data, and FOXG1 patients and community. From gene therapy to rescuing a FOXG1 family in the Ukraine, this year marks our biggest breakthroughs in all three areas.
Our greatest purpose is to end the suffering of children with this terrible disease. Our community is mourning the loss of 11 children in 2022/23 alone. We must stop this from happening. We are grateful for this incredible team working collectively to advance this goal, and to our donors who enable this work.
2022 Research Highlights (see details below)
Breakthrough gene therapy results showing rescue of FOXG1 brain structure, behavior, memory and cognition symptoms in animal models
Positive results on initial compound drug screens to identify molecules to increase FOXG1 levels; now moving forward to larger screens
Never-before understanding of FOXG1 biology uncovered from six FOXG1 patient human cell lines and mouse models
Successful testing of guide RNAs to increase FOXG1 expression with a CRISPRa Cas-9 system
Discovered ASO sequences (antisense gene therapy) to modulate FOXG1 expression; testing initiated with Creyon Bio
FOXG1 data package presented to several biotech companies with high interest
2022 Foundation Highlights
Hosted first-ever FOXG1 Syndrome Parents Conference (in-person and virtual) with parents, families, clinicians, scientists from all over the world
Hosted third FOXG1 Syndrome Science Symposium (in-person and virtual) with a consortium of global scientists collaborating on the path to a cure
Publishing first 100 patient natural history study of FOXG1 syndrome patients
Launched successful rescue operation of FOXG1 family trapped in the Ukraine; created fundraising campaign to help rebuild their lives in Poland
Asked to speak on multiple podcasts and industry events, continued to be called “innovators” and “leaders,” assisting many other rare disease foundations
Launched FOXG1 Research Foundation España
Raised over $1,000,000 globally in 2022 ($6M to-date)
2022 Funding and Research Details (View Research Projects)
Gene Therapy:
Breakthrough AAV9 gene therapy preclinical trial results with two promoters that successfully rescue FOXG1 brain structure, behavior, memory and cognition symptoms in animal models. Next step is toxicology studies as we begin an IND application. If successful, we will be in clinical trials within two years
Further testing of additional promoters at the Lee Lab - FOXG1 Center of Excellence that may more-effectively drive FOXG1 in specific cells
Funding Dr. Goichi Miyoshi at Gunma University Graduate School of Medicine to identify cells and circuits responsible for the manifestation of FOXG1 Syndrome in the brain and test a specialized rescue strategy
Initiated the development of a “rescue” mouse model to be used to determine the cell types and timelines that are key to restoration of FOXG1 symptoms
RNA Therapies
RNAi/a therapies - Identified multiple sequences and conducted experiments that both upregulate and downregulate FOXG1 gene expression via RNAa and RNA mechanisms in human neurons. Now stabilizing sequences and testing for efficacy and toxicity in additional patient derived human stem cells and animal models. If successful, we are within 3 years of clinical trials
ASO therapies - Identified a group of ASO molecules that upregulate FOXG1 gene expression. Using a proprietary platform, we are testing these ASO’s to find the most optimal ones. If successful, we could be in clinical trials in 2024
Drug Repurposing and Label Expansion
Screening of 4,000 compounds to increase FOXG1 expression led to 40 FDA-approved drug candidates found through Rarebase neuroscience platform
Screened ~150 small molecules on our zebrafish platform
Created neuronal assets and investigated several neuronal platforms, screens to start within next few months
Initiating c-elegans genetic screen in FOXG1 worm models to identify pathways that can compensate for the loss of FOXG1
CRISPRa Therapy
Identified a number of lead sgRNA and dCas9-effector combinations for upregulating FOXG1 expression in HEK293 cells, healthy NSC, and in patient iPSC-derived NSC
Next steps are to check for potential off-target effects and ability to rescue neuronal phenotypes before embarking on toxicity studies to assess if this is an effective modality for FOXG1
Genetic Model Characterization Work
Analyzed brain structure and behavioral deficits in three mouse models, developed insight into impact of DNA binding affinity; continuing to research additional models and publication underway
Confirmed the presence of FOXG1 mutations and otherwise normal chromosomal composition in six patient iPSC lines; seeing protein expression changes
Funded Dr. Jeanne Paz at Gladstone Institute to characterize the electrophysiology and seizures in our mouse models. This will identify where in the brain seizures are forming as well as identify any unique brain signatures
Confirmed the formation of smaller brain organoids from two patient lines compared to healthy controls
FOXG1 Patient Data
Enrolled >100 children and adults with FOXG1 syndrome into our natural history study, hosted on the Ciitizen platform, the most comprehensive and innovative natural history study for FOXG1 syndrome patients
Longitudinal medical record collection for all participants, averaging ~1200 pages of data from ~5 institutions, per participant - this totals 618 years of data reviewed
Uncovered information on demographics, comorbidities, common medications, exam findings, therapeutic procedures, developmental milestones; data will assist in identifying primary and secondary endpoints in clinical trials
Two years of FDA validated surveys completed by the first 50 participants, evaluating developmental milestones, behavior, and sleep
Three breakthrough manuscripts in preparation that include clinical data about FOXG1 syndrome
Continued to build global FOXG1 Patient Registry encompassing ~500 unique patient mutations
FOXG1 Research Models / Assets Created
6 human stem cell lines and 16 patient fibroblasts containing unique mutations available in FOXG1 Coriell global repository
Five CRISPR corrected patient stem cells stored in FOXG1 In-House Cellular lab
Inducible rescue mouse line underway at Lee Lab - FOXG1 Center of Excellence
5+ patient mouse models being characterized and stored at Lee Lab - FOXG1 Center of Excellence; publication underway
Accessible raw patient survey and natural history data available at FOXG1 Data Center and Ciitizen
2023 Goal: Drive the science to clinical drug development
Continue progress towards clinical trials for gene therapies
Accelerate each project by funding additional post-docs; continue funding scientific team
Fund further understanding of FOXG1 symptoms, such as electrophysiology characterization in mouse models
Compile arsenal of repurposed drugs that can be prescribed by individual physicians
Continue to expand upon patient registry and natural history study work
Raise reserves for clinical drug development
Partner with biopharma to include FOXG1 syndrome in their pipelines
Host continued parent and science conferences
Be there for our community through resources, encouragement and love
Funding:
FOXG1 Research Foundation 2022 Source of Funds
Media
The Lee Lab in Spectrum News | Global Genes Rare Leader Interview | I AM BIO Podcast | Port Washington Living | Rare Mama Rising Podcast | Female Founders Paving the Way for Innovation - BIO International Convention | Women’s Entrepreneur Day (WEDO) Conference at the UN |
THANK YOU
This work to improve countless lives is truly a global collective and collaborative effort. We can not thank every person who is a part of this journey with us enough. On behalf of the worldwide FOXG1 community, thank you for believing is us, guiding, and supporting us.
ONCE UPON A GENE - EPISODE 163 - How Far We've Come - with Nicole Johnson
Effie Parks talks to the co-founder of the FOXG1 Research Foundation, Nicole Johnson in this episode of Once Upon a Gene. Nicole shares the FOXG1 Research Foundation journey marking five years, and shares tips on how to throw a successful conference for scientists, clinicians and parents from all over the world
EPISODE HIGHLIGHTS
Can you tell us about your daughter Josie and about starting the FOXG1 Foundation?
Josie is 11 years old and she is the cutest little girl. She's amazing in that she has FOXG1 syndrome and can't do much, and yet she's the happiest, most joyful little girl and I feel blessed to have her in my world. My mission is to give Josie and every child with FOXG1 syndrome the healthy life they deserve. On the diagnostic journey, I was blogging and that's how I met Nasha Fitter after her daughter was diagnosed. We teamed up with other FOXG1 parents across the world and formed the FOXG1 Research Foundation in 2017.
What were your top highlights and takeaways from the FOXG1 Syndrome Science Symposium & Parents Conference?
We hosted two conferences in one and the first was a science symposium where scientists from all over the world met privately in Florida to present their data. I couldn't believe how much science was underway. Seeing how far we've come on the science-front was really incredible, as was the promising data that was uncovered. It was clear that this isn't a job for the scientists involved-- they are invested in helping all children with FOXG1 to live a life without suffering. The parent's conference was a blend of clinicians, scientists and FOXG1 parents that all came together to learn from each other-- to connect, learn and inspire. There was a lot of information and a lot of inspiration.
What advice do you have for patient advocacy leaders in motivating their caregiver and patient population to better understand their disease, get involved and participate in fundraising?
There's a lot we want to say to parents to communicate the work that's being done to improve their children's lives, but it's a challenge because people see things quickly and go on about their day. My best advice is to let the work speak for you. For anyone starting or running a patient organization, it is hard to reach your whole community and convince your whole community to get involved, but the more work you do, the more parents will see the work that's being done.
What advice do you have for advocacy leaders who want to hold a conference?
If you're thinking about doing it, absolutely do it. We were able to get sponsors which allowed us to do a travel scholarship and that helped parents to come, removing the burden of cost. When we were deciding on a venue, we looked at where the majority of the families lived and chose a place that doubled as a vacation. I recommend choosing a vacation-type location that adds an extra level of enjoyment.
LINKS & RESOURCES MENTIONED
FOXG1 Research Foundation YouTube
TUNE INTO THE ONCE UPON A GENE PODCAST
CONNECT WITH EFFIE PARKS
Global Genes Podcast: Empowering Rare Disease patients With Their Own Health Recods
Global Gene’s RareCast Podcast interviews our CEO and Co-founder about our innovative Ciitizen Natural History Study and how health records empower parents and caregivers to make sure researchers really understand our children’s condition.
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.
FOXG1 Research Foundation to Pioneer a Machine Learning Approach to Accelerate Rare Disease Research with Support From the Chan Zuckerberg Initiative
The parent-led FOXG1 Research Foundation (FRF) announced today a nearly $500k grant from the Chan Zuckerberg Initiative (CZI) to revolutionize the ability for patient-led advocacy groups to use machine learning to help accelerate rare disease drug development.
FOXG1 RESEARCH FOUNDATION is the latest CZI ‘Rare As One’ Partner.
READ NEWS HERE
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The First FOXG1 Scientists Symposium - A Recap.
The first FOXG1 symposium was a tremendous success in bringing together scientists from around the world who are interested in research around FOXG1 to collaborate with one another to find a cure. Scientists from Japan, Australia, Italy, the UK, the US, and more, presented and held deep-diving sessions to discuss what we know and what we need to know to drive research for FOXG1 syndrome.
The first FOXG1 symposium was a tremendous success in bringing together scientists from around the world who are interested in research around FOXG1 to collaborate with one another to find a cure. Scientists from Japan, Australia, Italy, the UK, the US, and more, presented and held deep-diving sessions to discuss what we know and what we need to know to drive research for FOXG1 syndrome.
We strategically chose to register this symposium with the Society of Neuroscience Conference, which attracts 30,000 delegates from around the world in San Diego, California. SfN and San Diego proved to be the perfect choice for this fortuitous event!
One of the most exciting things we learned is that FOXG1 is expressed also after birth and well into adult lives. This means that finding a therapy has potential to stop or improve certain symptoms.
We opened the symposium with a video from some FOXG1 kids and their parents saying thank you to the scientists for dedicating their work to finding answers about FOXG1.
The symposium kicked off with Dr. John Mason from University of Edinburgh and co-author of Building Brains - giving a short history of FOXG1, and it’s previous name - Brain Factor 1. He discussed the current mechanistic understanding of FOXG1 gene action and ideas around biomarkers that could be identified for FOXG1 syndrome.
John Mason PhD Univ. of Edinburgh
Dr Soo-Kyung Lee shared her work that two copies of the FOXG1 gene within the brain’s neurons are critical for the proper development and mapping of the brain in utero. She also showed that missing one copy of FOXG1 in neurons made the corpus callosum thinner and shorter than that of a typical brain. These findings were recently published in Neuron. This cover is a fantastic representation of her work.
Dr. Lee is in a very unique position being a lead scientist for FOXG1 Research and also being a mom of a child (daughter Yuna) with FOXG1 syndrome.
Dr. Soo Kyung-Lee OHSU
Dr. Lee is experimenting on various available FOXG1 mouse models to answer questions around which symptoms can be relieved if the FOXG1 gene mutation is fixed at various time points. She spoke about early results of FOXG1’s role in cell death. Dr. Lee additionally discussed a collaboration to use AAV9 gene therapy to normalize the FOXG1 gene dosage with scientists Dr. Guangping Gao and Dr. Dominic Gessler.
Dr. Guangping Gao and Dr. Dominc Gessler
Dr. Dominic Gessler - Univ. of Massachusettes
Dr. Gessler spoke to the audience on the work they have done to cure Canavan Disease. We were so inspired to learn that by using AAV9-mediated gene therapy, they found that all mouse symptoms were reversed. One family asked Dr. Gao to admit their child into a single-child clinical trial using FDA’s Compassionate Care Use Case guidelines at the University of Massachusetts. In 2017 the trial started. After about 2 weeks they started seeing symptoms begin to reverse! The success of this early trial enabled their work to be licensed by BridgeBio Pharma.
Turning our attention to industry, Michael Pettigrew, Director of Asset Acquisition from BridgeBio Pharma spoke to attendees on the data needed before a biotechnology company makes an investment to take a disease therapy forward into clinical trials. Understanding downstream effects, strong genotype-phenotype correlation, basic biology of the disease, time periods when disease can be cured is all necessary information.
Dr. Antonello Mallamaci - PhD SISSA Italy
These questions Michael Pettigrew discussed, that are critical for biotech investment, were discussed at length by Dr. Antonello Mallamaci, who runs The Laboratory of Cerebral Cortex Development in SISSA, Italy.
For example, Dr Mallamaci’s experiments show that various FOXG1 missense mutations are showing a gain-of-function response. This means these mutations could require different therapies than those showing a loss-of-function like gene deletion, nonsense or various truncation mutations. Dr. Mallamaci shared data on his learnings around the role of FOXG1 in diverse cellular contexts in forebrain development, including astrocytes, and inhibitory and excitatory neurons.
Similarly, Dr. Flora Vaccarino from Yale Medical School discussed how her work, looking at brain organoids, is showing that overproduction of inhibitory neurons is caused by FOXG1 over-expression.
FOXG1 may directly or indirectly regulate its own levels through a negative feedback mechanism. Dr. Vaccarino is also researching if FOXG1 syndrome differs in females versus males and what downstream genes are affected by the FOXG1 gene.
Dr. Flora Vaccarino - MD Yale School fo Medicine
Dr. Fabien Delerue who came from Australia spoke about his work to introduce FOXG1 mutations in mouse models. Dr. Tanja Vogel from Germany spoke about a novel mechanism of FOXG1 action involving RNA-binding proteins.
Dr. Alessandra Renieri from University of Siena in Italy discussed early experiments around using CRISPR to fix FOXG1 mutations in patient derived stem cells.
Dr Fabien Delerue -PhD Macquaire Univ.
De Tanja Vogel - PhD Univ. of Frieberg
Dr. Alessandra Renieri - MD, PhD Univ. Sienna, Italy
Dr. Corrine Houart - PhD King’s College London
We also learned that FOXG1 syndrome can be modeled in Zebrafish. Dr. Corrine Huoart from King’s College London shared her work on the previously unknown relationship between ASPM and FOXG1 genes.
She found that FOXG1 is downregulated when ASPM is affected. FOXG1 requires ASPM - they form a complex together. She shared ideas around modeling FOXG1 syndrome in Zebrafish and to use Zebrafish as a high throughput platform to screen small molecule drugs and learn about FOXG1 at a cellular level.
Dr. Goichi Miyoshi - PhD Tokyo Women’s Medical Univ.
We heard from Dr. Goichi Miyoshi who came from Japan on FOXG1’s role in Autism.
Various mouse experiments showed that FOXG1 deletion in specific neurons in mice tended to make these mice avoid social interactions. His experiments will help create a behavioral guide that other scientists can use when phenotyping FOXG1 syndrome in animal models.
Dr. Roberta Cilio - MD, PhD Univ. of Louvain
Dr. Roberta Cilio joined us all the way from University of Louvain in Brussels and spoke about the importance of identifying clinical endpoints that really measure a patient's improvement in symptoms. Dr. Cilio stressed the importance of this information long before even designing a clinical trial and pushed scientists to think about clinical endpoints when devising experiments in animals.
The first FOXG1 Symposium brought together an array of basic scientists, gene therapists, and clinicians focused on FOXG1 syndrome.
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Zach Horn, Rockefeller University Hourinaz Behesti , PhD
Developmental Neurobiologist, Rockefeller University, Nasha Fitter, Co-Founder FOXG1 Research Foundation, Alyson Mourti UCSD Associate Professor of Cellular & Molecular Medicine,
The symposium also brought together parents of FOXG1 affected children from all over the world. Over the course of three days in San Diego, we were able to share our experiences and build a plan to work together to raise awareness, help more parents, and fundraise for projects along our Path to a Cure.
FOXG1 Research Worldwide Team and Scientists
We held a special Parents and Scientists meeting / Q&A
The most special guest visit came from these amazing local San Diego FOXG1 sisters and parents!
Emma & Ali Wells!
And while the symposium was the main event, our team held back-to-back deep diving sessions with scientists for three days.
UCSD
This was just the first FOXG1 symposium for scientists to collaborate. We are looking forward to the progress we will see when we meet again next, and to the new scientists who will join us next time. The phrase we kept talking about is “beyond measure” - as it goes with research, the work we are doing will benefit the blueprint of human life beyond measure.
Everything we learn, every layer we peel away, will help us get closer and closer to the core of our goal - to cure every child today and in the future who is born with FOXG1 syndrome, and potentially help many other disorders. The potential is simply beyond measure.
FOXG1 Research Foundation Co-founders Nasha Fitter and Nicole Johnson