New publication shows groundbreaking results in FOXG1 AAV9 gene therapy studies; rescuing structural brain abnormalities

PRESS RELEASE

Groundbreaking Study Shows Promise in AAV9 Gene Therapy for FOXG1 Syndrome; Rescue of Brain Structure Abnormalities and Deficits.

[Buffalo, New York June 10, 2024] – A landmark study led by Dr. Soo-Kyung Lee, Chief Scientific Officer at the FOXG1 Research Foundation and Empire Innovation Professor and Om P. Bahl Endowed Professor in the Department of Biological Sciences at University at Buffalo, and Dr. Jae Lee, Professor in the Department of Biological Sciences at University at Buffalo, in collaboration with Dr. Kathrin Meyer (responsible for the SMA gene therapy), has been published in Molecular Therapy Methods & Clinical Development.

The paper, titled "The postnatal injection of AAV9-FOXG1 rescues corpus callosum agenesis and other brain deficits in the mouse model of FOXG1 syndrome," presents novel findings that have significant implications for treating FOXG1 syndrome, a severe neurodevelopmental disorder characterized by profound brain structure abnormalities.

The study explores the therapeutic potential of adeno-associated virus 9 (AAV9) mediated delivery of the FOXG1 gene. Remarkably, intracerebroventricular injection of AAV9-FOXG1 in a Foxg1 heterozygous mouse model ‘postnatally’ demonstrated the rescue of a wide range of brain pathologies including the amelioration of corpus callosum deficiencies, restoration of dentate gyrus morphology in the hippocampus, normalization of oligodendrocyte lineage cell numbers, and rectification of myelination anomalies.

"Our findings highlight the efficacy of AAV9-based gene therapy as a viable treatment strategy for FOXG1 syndrome and potentially other neurodevelopmental disorders with similar brain malformations," said Dr. Jae Lee. "This research asserts the therapeutic relevance of our approach in postnatal stages, which is a critical time frame for intervention."

Dr. Soo-Kyung Lee commented, 'We are thrilled by the full rescue of brain structure abnormalities observed in our mouse model through this study. It marks a significant step forward in our research. With these promising results, we are eager to advance this AAV9 gene therapy towards human clinical trials, hopeful that we can extend these breakthroughs to benefit children with FOXG1 syndrome.

This pioneering work provides a solid foundation for advancing this gene therapy towards human clinical trials, aiming to offer a transformative impact on the lives of patients with FOXG1 syndrome.

The FOXG1 Research Foundation continues to lead the way in innovative research for rare neurodevelopmental disorders, emphasizing the urgency and potential of cutting-edge treatments to alter the course of these conditions fundamentally.

Find the Molecular Therapy Methods & Clinical Development FOXG1 Paper HERE

Find FOXG1 Key Papers HERE

Contact: [email protected]

FOXG1 AAV9- Gene Therapy Data from FOXG1 Research Center at UB | Graphic Abstract

Learn more about The FOXG1 Research Center at the University at Buffalo

FRF Appoints Chief Drug Development Officer, Dr. Gai Ayalon

We’re thrilled to announce the appointment of Dr. Gai Ayalon as the Chief Drug Development Officer of the FOXG1 Research Foundation (FRF).

Dr. Ayalon is a distinguished neuroscientist and drug developer, who over many years led teams and spearheaded drug development programs for neurological diseases including rare neurodevelopmental disorders, spanning the discovery, translation and clinical phases. He joins our foundation at a critical and pivotal juncture as we enter Phase Four on our Path to a Cure, taking programs through safety studies and clinical trials. 

We have successfully accomplished Phase One through Three on our Path to a Cure: building disease models, studying these models, and testing gene therapies, ASO's, CRISPRa and saRNA therapies on our models. These early experiments have shown that we can upregulate FOXG1 gene and protein levels, we can do so safely, and we can rescue key symptoms in animals such as motor function, cognition and corpus callosum degeneration. Dr. Ayalon will now lead this next phase by taking our therapeutic programs, one by one, to clinical trials. In order to do this we will be performing activities such as vector optimization, exploratory toxicology, GLP manufacturing and toxicology, and completing regulatory filings. 

Dr. Ayalon previously worked at Ultragenyx Pharmaceutical, where he was the Project Team Leader of programs for pediatric neurodevelopmental disorders such as Angelman syndrome. Prior to Ultragenyx, Dr. Ayalon was a scientist at Genentech, in the neuroscience department. At Genentech he led drug discovery programs and teams focused on immunotherapeutic approaches to neurodegenerative diseases. 

Most recently, Dr. Ayalon was Vice President, Head of the Portfolio and Program Management group at Neumora Therapeutics, where he also led clinical stage programs for neuropsychiatric disorders. Dr. Ayalon received his Ph.D. from the Hebrew University Medical School in Jerusalem, Israel, and conducted his postdoctoral research at the Howard Hughes Medical Institute at the Duke University Medical Center.  

In his new role as Chief Drug Development Officer, Dr. Ayalon will navigate the FOXG1 Research Foundation through clinical drug development, working closely with Dr. Soo-Kyung Lee’s lab at the University at Buffalo, as well as the FOXG1 Scientific Consortium of labs, and our global biopharma and clinical partners.  

We cannot be more optimistic about joining hands with Dr. Ayalon for this next chapter in our journey to greatly improve the lives of every patient and the families affected by FOXG1 syndrome. 

ONCE UPON A GENE - EPISODE 163 - How Far We've Come - with Nicole Johnson

FOXG1 Research Foundation Co-Founder and rare mom, Nicole Johnson, shares takeaways from the November FOXG1 Syndrome Science Symposium & Parents Conference

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 Foundation

ONCE UPON A GENE - Episode 094 - The 12 Commandments to guide you when you're starting a rare disease patient advocacy group with Nasha Fitter and Mike Graglia

ONCE UPON A GENE - EPISODE 047 - Ciitizen - Take Control of Your Own Medical Records and Advance Research with Nasha Fitter

Ciitizen

Josie's Journey Blog

Pam Skillman

Nikki McIntosh

Dr. Allyson Berent

Race to 100K

FOXG1 Research Foundation YouTube

TUNE INTO THE ONCE UPON A GENE PODCAST

Spotify

Apple Podcasts

Stitcher

Overcast

CONNECT WITH EFFIE PARKS

Website

Twitter

Instagram

Built Ford Tough Facebook Group

The most personalized medicine: Studying your own child’s rare condition

The day Michael Boland’s son was born in July 2018 was blissfully normal. It had been a routine birth, and little Lukas aced the Apgar, a standard health test given to newborns. The next day, Boland made a quick trip home. As he walked back into the hospital room, he saw Lukas move in a sudden, odd way.

“What was that?” he said to his partner, Maja Horn.

“We saw him do that earlier,” Horn said.

A first-time mother, she wondered if the brief, jerky movements were typical of newborns. Or maybe it was hiccups?

Boland suspected otherwise. A cell biologist at the Institute for Genomic Medicine at Columbia University, he studies developmental and epileptic encephalopathies. He knew what seizures looked like in infants. When Lukas moved the same way again an hour later, Boland alerted the doctors. They whisked Lukas to the neonatal intensive care unit and put him on antiseizure medication. Two and a half weeks later, genetic testing revealed a mutation in a gene called STXBP1.

“Oh my God, I was devastated,” Boland says. “I had an idea what we were facing.”

Finding focus: Using stem-cell-derived models, Michael Boland’s team is testing two gene therapies for STXBP1 syndrome. Photograph by Akasha Rabut

He had not studied STXBP1, or syntaxin binding protein 1, but he knew that it plays a critical role in the transmission of electrical signals between neurons. Researchers had identified mutations in STXBP1 that reduce that signaling as a cause of infantile epileptic encephalopathy in 2008. Since then, increases in genetic testing have revealed STXBP1 encephalopathy in about one in 33,000 children. Clinical symptoms vary, but include epilepsy and, often, severe cognitive impairment; about 20 percent of children with the condition exhibit autism traits. Of the most affected children, Boland says, “they’re not going to be potty trained ever, they’re not going to learn to dress themselves.”

A couple of months after Lukas’s birth, Boland sat down with his colleagues at the Institute, David Goldstein and Wayne Frankel, and told them what was going on with Lukas.

“Wayne was like, ‘You’ve got to be kidding me!’” Boland remembers. “David’s jaw hit the table.”

“When do we start working on STXBP1?” Boland asked them.

“Immediately,” they responded.

With that, Boland became one of a handful of scientists in an unenviable but potentially important position: He would turn his heartbreak into hard data and study his own child’s condition. “I’m a scientist. . . This is my son. We have all of the tools here to do this,” he says. “It just feels like that’s what I was trained to do.”

In the world of rare autism-linked genetic syndromes, parents are already playing a central role, pushing to raise funds and advance investigations into their children’s conditions. “Parents are essentially kick-starting, and frankly, de-risking the research,” says Charlene Son Rigby, who in 2017 cofounded the STXBP1 Foundation, which has three parents on its science advisory board, including Boland.

Attracting parents who are also scientists to the cause only turbocharges those efforts. Nasha Fitter, a cofounder of the FOXG1 Research Foundation, a parent-led foundation for research on an autism-linked condition called FOXG1syndrome, could hardly believe it when she stumbled on a 2017 Facebook post by FOXG1 parent Soo-Kyung Lee about a grant she and her husband, Jae Lee, both respected neuroscientists, had secured. “Hold up, you guys are parents and you’re scientists?” she remembers thinking, even before she knew of their expertise and reputation for rigor. The Lees now lead the FOXG1 Center of Excellence at the University at Buffalo in New York State and receive considerable funding from the foundation. FOXG1 families are unfortunate in many ways, Fitter says, “but we’re very fortunate with Soo and Jae.”

Floor time: Cell biologist Boland plays on the floor with his son Lukas. Lukas, nearly 4 years old, doesn’t walk and only recently learned to crawl. Photograph by Akasha Rabut

Experts see little risk in the personalized research of people like Boland and the Lees, noting that ethical review boards and the peer review process help protect against conflicts of interest. Meanwhile, the upside of the urgency and commitment parent-scientists bring may be considerable. “Being extra super smart is great,” says William Dobyns, a pediatric neurologist and medical geneticist at the University of Minnesota in Minneapolis who has helped identify many single-gene brain disorders, “but focus and motivation, that’s one of the difference makers. That gets progress.”

STXBP1 and FOXG1 represent two of an ever-growing list of genes implicated in autism-related neurodevelopmental conditions over the past 15 years. Where once children might have been diagnosed with autism, severe intellectual disability, epilepsy or some combination of the three, genetic testing now pinpoints a causative mutation in about 40 percent of cases, according to Dobyns. (For autism without co-occurring conditions requiring high support, that number is far lower, in the low single digits, he says.) The more profound a person’s traits, the more likely it is that an explanation can be found in their DNA. Having a genetic diagnosis fine-tunes the prognosis for a child and reveals whether other family members are at risk. It also allows hope.

“Once we recognize a specific genetically defined disorder, then the possibility of developing targeted therapy is here,” Dobyns says.

Soo Lee understood that better than most. When her daughter Yuna was born in 2010, Lee was a rising star in the world of neurodevelopmental biology. Her research focused on the role of transcription factors, which regulate genes, during brain development. The demands of her career were intense — so much so that when her infant daughter showed signs of profound developmental delays, she worried it was somehow her fault for working too much. Yuna missed every milestone, had enormous trouble feeding and sleeping and had seizures beginning soon after birth. Magnetic resonance imaging (MRI) revealed microcephaly, a small brain, but genetic testing did not initially turn up any mutations. Yuna was diagnosed with congenital Rett syndrome, a catchall for children who have clinical similarities to the autism-linked condition.

The Lees pressed to keep searching for a genetic culprit. Soo Lee took to carrying Yuna’s MRI results wherever she went, including a multiday meeting for the National Institutes of Health held in San Francisco, California. There, she talked about her then 2-year-old daughter’s condition with a researcher who offered to consult a radiologist colleague who had deep experience reading pediatric neurological MRI results. A few days later, that radiologist reported that the abnormalities in Yuna’s brain structure might be tied to FOXG1, a gene so critical to brain development that mice lacking both copies do not develop a functional brain and die shortly after birth. (The same is true of STXBP1.)

The idea that her own daughter might have a condition related to a neurodevelopmental gene, encoding a transcription factor no less — the very thing Lee studied — seemed almost too coincidental to be believed. Although FOXG1 was well known, the syndrome related to FOXG1 mutations had only been named in 2011 and wasn’t yet widely recognized. When the Lees had Yuna tested for it specifically, the radiologist was proved right. Soo Lee reviewed the raw sequencing data herself to be sure. She estimates that Yuna was the 20th child in the world to be identified with FOXG1 syndrome. There are still fewer than 1,000 known cases, although there are likely to be many more who have not been identified.

The hallmarks of the syndrome include microcephaly, cortical atrophy and weak or missing connections between brain hemispheres, as well as seizures, cognitive disabilities, absence of language, movement disorders and, sometimes, autism. Children who have a completely inactivated copy of the gene, like Yuna, have more disabling traits than those with a more mildly affected version that produces faulty FOXG1 protein.

Yuna’s diagnosis prompted Soo Lee to make FOXG1 a centerpiece of her research. “I thought, this is what I have to do,” she says. Jae Lee, who had done important work on gene regulation of metabolism, joined her. “I was more than glad to drop everything else,” he says.

Expressing interest: Biologist Soo-Kyung Lee with her daughter Yuna and her son Joon. Yuna cannot walk or speak, but she likes stuffed animals and toys that light up or play music. Photograph by Eric Tronolone

Much of the Lees’ home on a quiet cul-de-sac near the university is organized with Yuna in mind. The house features wide-open spaces and hardwood floors that can be readily navigated with a wheelchair. Construction on a small indoor swimming pool is underway, because Yuna enjoyed the hotel swimming pools they frequented when they drove across the country from Oregon to Buffalo to start their center in 2019.

Small and thin for a 12-year-old, Yuna usually wears soft clothing such as sweatpants and a fleece top, with her hair pulled into a ponytail atop her head with a fuzzy scrunchie. (Her dad has gotten very good at doing her hair in the morning.) She cannot walk or speak, but her family know what she likes — including stuffed animals and toys that light up or play music. After she gets home from her specialized school, she spends a lot of time in a play area they’ve created for her in an alcove off the kitchen. Her poor motor control means that she is constantly moving, but when her caregiver puts a sticker on the couch and encourages Yuna to go get it, the girl rocks and reaches her way to the couch. The Lees credit years of therapy and hard work. Her movement has become “more purposeful because she has better control,” Jae Lee says.

They take heart from other small, hard-won changes. Yuna never used to make eye contact with her parents. Recently she began glancing out the school bus window at them as they waved goodbye in the morning. One day when Jae did not join Soo in the driveway, Yuna looked far longer than normal. Soo says she believes Yuna was searching for her father. The next day Jae was back in position and Yuna, presumably satisfied, resumed her usual glance. “She’s doing much better than what I thought [was possible] 5 years ago,” Soo Lee says. “It’s a very subtle thing. Nowadays, I can tell what she likes, that she’s happy. It’s just so much easier to know who Yuna is.”

Play time: Lee helps Yuna peel stickers. Photograph by Eric Tronolone

The research that Boland and the Lees have conducted so far differs in the specifics but offers a basic science primer on how to tackle monogenetic conditions. First, establish viable models, beginning with mice, and use those models to investigate what exactly the genes of interest do in the brain. Because these conditions are developmental, address the pivotal question of whether the work of the gene is complete at birth or whether it continues and offers an opportunity to intervene. Finally, ask the ultimate question: Is it possible to reverse the damage and rescue what has been lost—in humans, not just in mice?

The Lees have focused their efforts on mouse models. The first one they analyzed lacked one copy of the FOXG1 gene and showed altered brain structure and behavior that mimicked the movement, learning and memory deficits seen in children with FOXG1 syndrome. The Lees have since made multiple mouse models that mimic various mutations found in people. And they have shown that FOXG1 helps establish the brain’s cortical layers and create the corpus callosum, which connects the left and right brain hemispheres.

Boland, too, is working with a mouse model of STXBP1, with help from Frankel, who has decades of experience in the field. But Boland also grows human pluripotent stem cells, which he coaxes into two different models: two-dimensional neuronal networks that look like lacy latticework, and three-dimensional brain organoids, which look like chickpeas yet faithfully recapitulate the early cell growth in developing brains. He has even created models using Lukas’s cells and his own. “[That’s] a 3D model of my son’s brain in a dish,” he says during a tour of the lab. The three models — neuronal networks, organoids and mice — trade biological complexity for granularity and together, Boland says, allow more nuanced comparisons of how typical and STXBP1 neurons communicate.

Personalized medicine: Boland grows 3D organoid models of his son’s brain in a culture dish. Photograph by Akasha Rabut

Fortunately, FOXG1’s work appears to be incomplete at birth, the Lees have found, and STXBP1 is critical to how neurons communicate throughout life. That leaves open the possibility of drug treatments or gene therapies. Boland and Frankel are focusing on testing two gene therapies for STXBP1: a traditional replacement therapy that adds back a functional copy of STXBP1 and an adaptation of CRISPR technology that upregulates the gene’s expression. (That work is supported by a grant from The Simons Foundation, Spectrum’s parent organization, and Boland is a part-time consultant for the Foundation.) Unpublished work in other labs has successfully stopped seizures and rescued learning and memory deficits in mice, Boland says.

The Lees are using their mice as platforms for drug screening. One therapy they tried in an unpublished experiment reversed some of the traits in FOXG1 model mice. “We wanted to confirm whether FOXG1 syndrome can be fixed,” Jae says. “The answer seems to be yes. We were just completely stunned.”

Despite the promise, treatment is not imminent for either of these conditions. At home, these scientists focus on being parents, not researchers. Half of Boland and Horn’s Manhattan living room is given over to a colorful rug with toys stacked around its edges. At first glance Lukas, at nearly 4 years old, looks like any child his age, with a cherubic round face. He sits tall on the rug (therapists compliment his posture) and gazes at his parents. But it’s soon evident that his behavior is more like that of a 1-year-old. His feeding issues mean everything he eats must be pureed. He doesn’t talk. He only recently learned to crawl. He might be able to walk by age 6 or so, though it won’t be coordinated walking, Boland says.

Each new skill — head control, sitting up, pulling up, crawling — was the work of many months or even years. Boland and Horn call them “inchstones” not milestones. Nonetheless, they say, Lukas is easygoing and engaged. He loves spinning tops, musical toys and board books. Lying on the floor with an Elmo book, he dips his head to the page and touches it with his lips, giving Elmo a kiss. Such social behavior feels like a gift, Boland says, while mashing up sweet potatoes, spinach and quinoa for Lukas’s dinner. “When he can give you those big beautiful brown eyes that stare into your soul, it makes it easier.”

Small steps: Lukas doesn’t speak but is learning to express his needs through a communication device. Photograph by Akasha Rabut

During her pregnancy, Horn, who was over 40 and at increased risk for having a child with a disability, worried a little bit about that possibility. “Will you do everything you can?” she asked Boland. He said he would. But that was a hypothetical conversation, and the reality of Lukas’s condition was a shock. Over time, however, says Horn, a professor of Spanish literature at Barnard College in New York City, she has come to fully accept Lukas for who he is, and the experience of raising him has changed her “in every imaginable way.” She, too, has shifted her academic interests to think about perceptions of ability and disability. She is glad Boland is studying STXBP1 — that he is, in fact, doing everything he can. But she is not willing to try anything too risky on her child. Her focus is on cherishing Lukas as he is, “a child that’s so lovely and happy,” and facing the immediate future. “My hope is that he will be able to express his needs and wants on his [communication] device. . .to be able to say I’m hungry, I’m thirsty,” she says. “I think that’s totally within reach.”

Boland and the Lees have been changed as well, for better and for worse.

One Sunday afternoon, when Yuna was 5 years old, Soo Lee collapsed in the living room. She had developed vestibular neuritis, a destabilizing condition caused by inflammation, which Soo attributes to stress. Seven years later, she manages her condition with medication but must limit work hours, screen time and some daily activities like driving. When her 9-year-old son, Joon, “wants to show me a YouTube video, he says, ‘Wait, wait, let me lower the brightness,’” she says with a laugh.

Science is famously competitive and ego-driven; there is only so much money and recognition to go around. For Boland and the Lees, however, ego has less to do with it these days. Regardless of funding or support, Jae Lee says, “this is what we would be doing.” Interactions with other scientists are different, too. It used to be “like holding a poker hand,” Boland says. No more. “As a parent, I’m less of the poker player. I’m more like, these are my cards. If you can learn from me, then maybe that’ll help you develop a therapy faster than mine.”

BY LYDIA DENWORTH

FOXG1 Symposium Advances Science, Gives Hope to Families Battling Rare Disease

UB biological sciences faculty member Soo-Kyung Lee, left, and UB biological sciences researcher Younjung Park work in the lab. Photo: Douglas Levere

By CHARLOTTE HSU

Published August 20, 2020

UB biologists Soo-Kyung Lee and Jae Lee have devoted their careers to studying FOXG1 syndrome, a neurological disorder that affects their daughter, Yuna.

This month, as part of that work, the couple took part in the FOXG1 Science Symposium 2020, which brought researchers, industry executives and families together for two days of presentations and conversation about the latest scientific advancements tied to the disease.

The disorder, caused by mutations in a gene called FOXG1, can lead to severe abnormalities in brain development. When Yuna was younger, she suffered from many seizures and had trouble swallowing milk. Now, at 10 years old, the seizures have subsided and she is a joyful child, but she still cannot eat, walk or get dressed on her own.

“It is exciting to see how the FOXG1 community has grown worldwide and is coming together to support each other and FOXG1 research,” says Soo-Kyung, Empire Innovation Professor and Om P. Bahl Endowed Professor of Biological Sciences, College of Arts and Sciences.

UB biologists Soo-Kyung Lee (left) and Jae Lee are researching the FOXG1 gene. Their daughter, Yuna, has a mutation in the gene, which has severely impacted her development. Photo: Douglas Levere / University at Buffalo.

“This is our second FOXG1 science symposium. Our first symposium two years ago was really about basic science. This year, we’re really focused on answering the question of what we know about FOXG1 syndrome, and what the path forward is toward potential therapies,” says Nicole Johnson, president and co-founder of the FOXG1 Research Foundation, which organized the event and has funded the research of the Lees and other scientists. Johnson’s daughter, Josie, has FOXG1 syndrome.

The symposium — originally scheduled to take place at UB — was hosted virtually instead from Aug. 17-18. About 300 people attended.

Soo-Kyung and Jae, professor of biological sciences, presented on and moderated a number of panels on topics such as the biology of FOXG1 and efforts to develop animal models for the disease. Other UB presenters included Michael Yu, associate professor of biological sciences, and Priya Banerjee, assistant professor of biological sciences.

Yuna flashes a big smile as she plays with her father, Jae Lee, and mother, Soo-Kyung Lee (right), who both are biology researchers at UB. Photo: Douglas Levere

A growing FOXG1 community, and advancements in science

Johnson notes that while FOXG1 syndrome is a rare disease, the number of diagnosed cases is rising as genetic sequencing becomes more accessible, as FOXG1 has been added to several diagnosis panels, and as awareness of the disorder grows. Globally, the number of known patients has topped 700, according to the FOXG1 Research Foundation, which tracks cases through means such as a private social media group for families of children with FOXG1 mutations.

The growth of this community has given caregivers a support network. Soo-Kyung recalls that earlier this year, she and Jae received a message from a family in China with a baby girl who has FOXG1 syndrome, saying that they had enjoyed reading about the Lees’ research and Yuna’s progress.

“It is so heartwarming to know that someone out there finds comfort in our research efforts and is cheering for us,” Soo-Kyung says.

Prior to Yuna’s birth, Soo-Kyung’s lab focused on understanding the development of the central nervous system, with much of that work centering on transcription factors that regulate gene expression. Jae is also an expert on gene transcription. So when Yuna was diagnosed with FOXG1 syndrome, her parents were perfectly positioned to pivot and make FOXG1 the focal point of their work (FOXG1 is a transcription factor that plays a crucial role in development of the human brain.)

Together, the Lees are making discoveries about the functions of FOXG1, and breeding mice with FOXG1 mutations that mirror those found in human patients. The ultimate goal of their work is to develop a treatment: Though problems in early brain development cannot be reversed, a therapy could alleviate some symptoms.

“The symposium gave FOXG1 scientists around the world the chance to get together to share their work, with the potential to build collaborations,” Jae says.

For families who attended, “It’s very hopeful for parents to see so much work being done, and see different scientists really investing their entire work in FOXG1,” Johnson says. “It gives hope.”

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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.
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

Infinitesimal Odds: A Scientist Finds Her Child’s Rare Illness Stems From the Gene She Studies - NYT Video

PORTLAND, Ore. — By the time her mother received the doctor’s email, Yuna Lee was already 2 years old, a child with a frightening medical mystery. Plagued with body-rattling seizures and inconsolable crying, she could not speak, walk or stand.

“Why is she suffering so much?” her mother, Soo-Kyung Lee, anguished. Brain scans, genetic tests and neurological exams yielded no answers. But when an email popped up suggesting that Yuna might have a mutation on a gene called FOXG1, Soo-Kyung froze.

“I knew,” she said, “what that gene was.”

Almost no one else in the world would have had any idea. But Soo-Kyung is a specialist in the genetics of the brain—“a star,” said Robert Riddle, a program director in neurogenetics at the National Institute of Neurological Disorders and Stroke. For years, Soo-Kyung, a developmental biologist at Oregon Health and Science University, had worked with the FOX family of genes.

“I knew how critical FOXG1 is for brain development,” she said.

She also knew harmful FOXG1 mutations are exceedingly rare and usually not inherited — the gene mutates spontaneously during pregnancy. Only about 300 people worldwide are known to have FOXG1 syndrome, a condition designated a separate disorder relatively recently. The odds her own daughter would have it were infinitesimal.

“It is an astounding story,” Dr. Riddle said. “A basic researcher working on something that might help humanity, and it turns out it directly affects her child.”

Suddenly, Soo-Kyung, 42, and her husband Jae Lee, 57, another genetics specialist at O.H.S.U., had to transform from dispassionate scientists into parents of a patient, desperate for answers.

Soo-Kyung and Yuna on a FaceTime call with Soo-Kyung’s parents in Korea.CreditRuth Fremson/The New York Times

They were plunged into a fast-moving ocean of newly identified gene mutations, newly named diagnoses, and answers that raise new questions.The newfound capacity to sequence genomes is spurring a genetic gold rush, linking mystifying diseases to specific mutations — often random mutations not passed down from parents.

New research shows that each year, about 400,000 babies born worldwide have neurological disorders caused by random mutations, said Matthew Hurles, head of human genetics at Wellcome Trust Sanger Institute. As sequencing becomes cheaper, more children will receive specific diagnoses like FOXG1 syndrome, doctors say.

This burst of discovery might eventually help doctors treat or prevent some brain damage. “We used to lump them all together under autism or another category,” said Dr. Joseph Gleeson, a neurogeneticist at University of California San Diego. “It’s really changing the way doctors are thinking about disease.”

Balancing the missions of science and motherhood, Soo-Kyung has begun doing what she is uniquely positioned to do: aiming her research squarely at her daughter’s disorder. With Jae’s help, she is studying how the FOXG1 gene works and why mutations like Yuna’s are so devastating.

“Our ultimate goal is to find a better treatment for FOXG1 syndrome patients,” she said. Her day-to-day goal is helping Yuna make slivers of developmental progress.

Yuna is now a sweet-natured 8-year-old still wearing a toddler’s onesie over a diaper. “Cognitively she’s about 18 months,” Jae, her father, said.

A major achievement would be getting Yuna to indicate when her diaper is wet. Or to stand when they prop her against a kitchen corner and remove their hands for a split second. “If Yuna doesn’t fall down right away,” Soo-Kyung said, “we consider that a success.”

“My daughter’s brain is so damaged,” Soo-Kyung said, eyes brimming with tears. “Can we rescue any of her skills?”

Soo-Kyung, left, and Jae, right, work next door to each other; together they are researching FOXG1 syndrome, the rare disorder Yuna has.CreditRuth Fremson/The New York Times

When their daughter was born in Houston in January 2010, southeast Texas experienced a rare snowfall. It inspired the Lees, then professors at Baylor College of Medicine, to name her “Yuna,” meaning “snow girl” in a Korean dialect, with the middle name “Heidi” for its allusion to snowy peaks.

“She was perfectly normal,” Jae said. “We were joking, ‘What will come later?’ Yuna’s mom is a very smart person, so we thought, ‘Well, she will make the world better.’”

But soon, things seemed off. Yuna often failed to respond to sounds. She struggled to swallow milk from breast or bottle. What she did swallow she vomited. “She looked like someone with malnutrition,” Soo-Kyung said.

A doctor said her head circumference was not growing enough. Then Yuna began having seizures , often sending the Lees to the emergency room. She cried so persistently that Soo-Kyung had to assure neighbors Yuna was not being abused.

“What did I do wrong?” Soo-Kyung grilled herself. Had she eaten something while pregnant that infected Yuna? “I was traveling a lot during the pregnancy to attend seminars — was I too stressed?”

Yuna and her mother in a family photo. Born in Texas during a rare snowfall, her name, Yuna, means “snow girl” in a Korean dialect.

Shortly after Yuna’s second birthday, Soo-Kyung traveled to Washington, D.C. to serve on a National Institutes of Health panel reviewing grant proposals from brain development researchers. At dinner, she found herself next to Dr. David Rowitch, a respected neonatologist and neuroscientist she knew only by reputation.

“She started to tell me what’s going on with her daughter,” recalled Dr. Rowitch, professor and head of pediatrics at the University of Cambridge who was then at the University of California San Francisco. He was stumped but offered to send Yuna’s brain scans to “the world’s expert” in neuroradiology: Dr. Jim Barkovich at U.C.S.F.

Dr. Barkovich said Yuna’s scans revealed “a very unusual pattern,” one he had not seen in decades of evaluating brain images sent to him from around the world. Yuna’s cerebral cortex had abnormal white matter, meaning “there were probably cells dying,” he said, and the corpus callosum, the corridor across which cells in the left and right hemispheres communicate, was “way too thin.”

Searching scientific literature, he said, “I found a gene that seemed to be expressed in that area and found that when it was mutated it caused a very similar pattern.” That gene was FOXG1.

Left, Soo-Kyung watching a postdoctoral fellow with mouse brains in her lab at OHSU. Right, examining chicken embryos. She has begun aiming her research at understanding Yuna’s brain disorder.CreditRuth Fremson/The New York Times

Yuna exploring her mother’s closet after her bath. Her mother, Soo-Kyung, began sleeping on the mattress after she collapsed from the stress of caring for Yuna; sleeping in the closet helps Soo-Kyung rest without noise or distraction.CreditRuth Fremson/The New York Times

FOXG1 is so crucial that its original name was “Brain Factor 1,” said Dr. William Dobyns, a professor of pediatrics and neurology at University of Washington, who published a 2011 study recommending a separate diagnosis: FOXG1 syndrome. “It’s one of the most important genes in brain development.”

FOXG1 provides blueprints for a protein that helps other genes switch on or off. It helps with three vital fetal brain stages: delineating the top and bottom regions, adjusting the number of nerve cells produced and “setting up the organization of the entire cortex,” Dr. Dobyns said.

So, when Dr. Barkovich’s email said he “would not be surprised if this is a FOXG1 mutation,” Soo-Kyung’s heart shuddered. “That’s unthinkable,” she despaired.

Yuna’s neurologist declined to authorize FOXG1 gene analysis, considering the possibility improbable — and irrelevant because it would not change Yuna’s treatment, Soo-Kyung said. So she decided to sequence the gene herself, preparing to seek university permission since her lab only worked with animals. Then, she became pregnant again. That provided justification for professional analysis of Yuna’s gene to determine if there was a heritable mutation the Lees could have also transmitted to their second child.

When results showed a FOXG1 mutation, Soo-Kyung requested the raw data, hoping the lab had messed up. But scanning the data, Soo-Kyung spotted the problem instantly: Yuna was missing one nucleotide, Number 256 in the 86th amino acid of one copy of FOXG1, which has 489 amino acids.

It was a random mutation, so she felt relief her second child was at little risk. But its location in the DNA sequence had given Yuna a smaller, incompletely functioning brain. A single mutation had disabled the entire gene.

Music seems to calm Yuna, so her father Jae often plays guitar in the evenings. Yuna’s brother, Joon, 5, helps as he can.CreditRuth Fremson/The New York Times

Bridlemile Elementary School’s long hallway is both minefield and laboratory for Yuna. In a wheelchair or special walker, she is guided by a paraprofessional, Audrey Lungershausen, who tries to keep her from grabbing student artwork and coats, while encouraging her to identify balls and faces on a mural.

Soo-Kyung must also navigate a daunting hallway. In June 2016, overcome by stress, she collapsed. Diagnosed with vestibular neuritis, an infection involving nerves linking the ear and brain, she was bedridden for weeks and struggled to stand. She still experiences vertigo and nausea walking the hall to her lab, “like I’m on a ship that’s constantly moving.”

Her disability, glancingly parallel to her daughter’s, helps her understand that “the world that Yuna has to face with her limited ability to control her body — that must be really scary to her,” she said.

While Yuna’s condition gives Soo-Kyung’s work personal importance, her own condition makes it harder. She cannot look at her computer more than 25 minutes straight, reads with a yellow filter often used by children with autism, and does visual exercises using paper images taped to her office wall..

Like Yuna, Soo-Kyung needed physical, occupational and speech therapy. A psychiatrist prescribed an antidepressant. Instead of sleeping in Yuna’s room, Soo-Kyung began blocking out light and sound by sleeping on a mattress on the floor of the master bedroom closet. “They say I may not recover to a normal level.”

Soo-Kyung’s peripheral vision being tested at an occupational therapy session. She suffered a collapse in 2016 from the stress of juggling her scientific career while caring for Yuna, and dealt with the after-effects of vertigo.CreditRuth Fremson/The New York Times

Long before Yuna was born, Soo-Kyung stumbled upon research she found fascinating, showing that mice missing both FOXG1 genes did not form brains. That would apply to humans, too. “There’s nobody who is missing two copies of the gene,” said Dr. Riddle of the National Institute of Neurological Disorders and Stroke. “They don’t survive.”

Soo-Kyung told Jae she wanted to someday study how FOXG1 drives brain development. “Then Yuna arrived,” Jae said.

Now, studying mouse brains, the Lees have identified genes that interact with FOXG1, helping explain why one crippled copy of FOXG1 damages the corpus callosum’s ability to transmit signals between hemispheres.

“We now understand how this gene works and why,” Soo-Kyung said.

Many mysteries remain. Individual FOXG1 mutations affect gene function differently, so one FOXG1 patient’s symptoms can vary from another’s. For example, Charles A. Nelson III, an expert in child development and neurodevelopmental disorders at Boston Children’s Hospital and Harvard Medical School, evaluated two 10-year-old patients with mutations in different locations and markedly distinct levels of impairment.

Since patients like Yuna, with one dysfunctional and one functional FOXG1 gene, produce half the necessary FOXG1 protein, Soo-Kyung wonders if gene therapy could restore some protein or boost protein activity in the good gene.

But because FOXG1 is crucial so early in development, Dr. Rowitch said, “I don’t think you can just go back when the baby’s born and build the brain back up.”

Still, Dr. Dobyns said, “are there parts of FOXG1 syndrome that we might be able to fix once we understand it better? Sure, parts of it.”

Yuna Lee with her speech therapist, Diana Deaibes at Shriners Hospital for Children in Portland, Ore. nearly a year ago. A computer program was used to teach her to communicate with her eyes by staring at something she likes onscreen. The hope is for her to eventually direct her gaze to show that she wants food or a toy.CreditRuth Fremson/The New York Times

When Yuna was 6, Soo-Kyung, half-asleep in bed with her, noticed something extraordinary: Yuna was sitting up. “Am I dreaming?” Soo-Kyung wondered. For years, Yuna failed to learn this skill, usually mastered by six-month-old babies.

Physical therapists had stopped Yuna’s sessions, saying “ ‘What’s the point of doing it when she’s not making any progress?’” Soo-Kyung recalled. She began painstakingly urging Yuna to push up using her elbow, never sure Yuna understood. Then, “suddenly Yuna was sitting up and I didn’t know how it happened.” Probably a fluke, Soo-Kyung thought—but soon Yuna began sitting up regularly.

Experts say too little is understood about newly recognized neurological disorders to know children’s developmental limits. But the Lees believe the sitting-up success shows that if they persevere, Yuna can make incremental progress. Their next goal is for Yuna to communicate when she is hungry, uncomfortable or wants something.

Speech therapists could not get Yuna to intentionally press a button activating a recorded voice saying things like “more.” “I don’t know if she understands what I am telling her,” said Diana Deaibes, a speech-language pathologist at Shriners Hospital for Children.

But the Lees refused to let Shriners pause speech therapy, urging therapists to try teaching Yuna to stare at something she wants. “We insisted,” said Jae, optimistic even though they attempted visual communication before “and it was a complete mess — she wasn’t able to do it at all.”

Ms. Deaibes tried pictures and then computer eye-gaze programs that track Yuna’s eye movements. After months of Ms. Deaibes darkening the room to minimize distractions, buckling Yuna to control her jerky movements, Yuna can now stare for about three seconds, causing barn doors to open in computerized farmyards and other onscreen responses. The Lees hope to train Yuna to choose toys or books with her eyes.

At school, Yuna spends time in a regular second-grade classroom where social exposure helps her and enlightens other students, said Bridlemile’s principal, Brad Pearson. These days, she increasingly responds to her name with eye contact or sound and rarely puts school materials in her mouth anymore, said Jim Steranko, who teaches Yuna in Bridlemile’s learning resource center.

Listening to a teacher read.CreditRuth Fremson/The New York Times

Therapists working with Yuna are uncertain whether she is cognitively able to understand that the label contains her name.CreditRuth Fremson/The New York Times

Ms. Lungershausen assists Yuna with everything, including feeding her and, with another aide’s help, changing her diapers. She recently made colorful shapes for Yuna to grab while the second-graders studied fractions. “We have our bad days,” Ms. Lungershausen said. But she said Yuna increasingly recognizes phrases like “Let’s find the library door,” recently “brought a Kleenex to her nose after being prompted” and “brought my hand to her mouth and ‘kissed’ it, deliberately, first time since I’ve known her.”

—

At 41 pounds, Yuna weighs 10 pounds less than her little brother, Joon, 5, who has begun helping care for his older sister. One day, after Yuna’s state-funded caregiver, Anne Marie Nguyen, bathed her and propped her in a baby play center to dry her, Joon, announcing he had finished “going potty,” brushed Yuna’s hair. Seeing her rip the bathroom thermostat’s cover off, Joon pulled Yuna’s hands from the wall, saying, “Don’t touch that.”

When Soo-Kyung returned home after lab work involving gene manipulation in mouse and chicken brains, she crouched on the playroom carpet, watching Yuna commando crawl and elbow herself to a sitting position. She lifted Yuna into the special walker, called a gait trainer and, waving toys, coaxed her to propel the contraption with her feet.

Then came Yuna’s nightly FaceTime visit with her grandparents in South Korea, who sing and show pictures as Yuna intermittently eyes the screen. Later, Jae played guitar, while Soo-Kyung held Yuna, keeping her rangy arms from tearing into the instrument. Yuna smiled and bobbed.

Soo-Kyung rarely used to mention her daughter to fellow scientists, but recently began thanking Yuna during presentations. “I was afraid every day that she might not be with me the next day,” Soo-Kyung said, voice breaking. “But she’s done amazing things that we wouldn’t dare to dream. So, how can anyone say she will never be able to do this, she will never be able to do that?”

They carried Yuna upstairs to her giant crib, her body arching elastically. Carting her up and down is getting harder, so the Lees expect to move from the three-level, cliff-side house they bought to be closer, for Yuna’s sake, to the hospital and their labs. With breathtaking views of Mount St. Helens, it is an optimist’s house, where it is possible to see beyond the horizon.

As Yuna, in the arms of her caregiver, Anne Marie Nguyen, grows, it gets harder to carry her up and down the house’s several flights of stairs.CreditRuth Fremson/The New York Times