FOXG1 Research Foundation 2024 Q2 Research & Development Update

The FOXG1 Research Foundation is pleased to share our 2024 Q2 update on FOXG1 Research and Development from our Chief Scientific Officer, Dr. Soo-Kyung Lee and our Chief Drug Development Officer, Dr. Gai Ayalon.

FOXG1 Research:

• FOXG1 Syndrome Epidemiology manuscripts under review 

• FOXG1 mouse model manuscript is under review

• Three abstracts submitted for the ASGCT meeting in May, which will be attended by member of the FOXG1 Research Foundation Scientific, Clinical, and Executive team

• Important preclinical study initiated to further support the choice of the AAV9 drug candidate to progress to the next stage of toxicology studies and manufacturing work

• Initiation of preclinical studies aimed at the characterization of function of FOXG1 in brains of juvenile, young adult, and adult animals

• Investigation of FOXG1 syndrome pathogenesis in human neurons derived from patient cells (thank you to the families that provided patient cells)

• Refined the ASO and small molecule drug repurposing efforts with focus on enhancing the screening platforms

• Continue to support and collaborate with external academic labs with focus on projects with high translational potential

FOXG1 Translation and Development:

• Secured IRB approval for the expanded FOXG1 Coriell Biobank, in final steps of contracting and initiation of the new repository

• Completion of enrollment and sample collection for the Combined Brain biomarker initiative (thank you to the families that participated)

• FOXG1 Disease Concept Model project to inform future trial design and regulatory interactions is in progress (thank you to the families that are participating)

• Launched the development core team which is developing in detail the toxicology, manufacturing and regulatory plans for the AAV9 gene therapy program

• Preparing the data package and meeting request submission for our first interaction with FDA on the AAV9 gene therapy program, the first of several FDA engagements that are planned for 2024 to advance the program through IND-enabling studies

• Initiated a collaboration with other Patient Advocacy Groups (PAGs) to evaluate digital biomarker devices for use in future clinical trials

• In the designing phase of a clinical research study to characterize mosaicism in FS, which could help inform the design of future clinical trials

• Planning the 2024 FOXG1 Research Foundation private science symposium with a focus on translational programs and clinical trial readiness

• FOXG1 Research Foundation Australia is preparing for clinical trial readiness with the Sydney Childrens Hospital Network and the Rare Care Centre in Perth, Western Australia

FOXG1 Research Foundation Chief Scientific Officer, Dr. Soo-Kyung Lee and Chief Drug Development Officer, Dr. Gai Ayalon at the FOXG1 Research Center at the University at Buffalo/

Dr. Soo-Kyung Lee Named FOXG1 Research Foundation Chief Scientific Officer

Dr. Soo-Kyung Lee and the Lee Lab at the FOXG1 Center of Excellence University at Buffalo

Buffalo, New York August 10, 2023: The FOXG1 Research Foundation (FRF), a parent-led rare disease patient organization focused on driving therapeutics for FOXG1 syndrome, an Autism-related neurological condition, announced today the appointment of Dr. Soo-Kyung Lee as the new Chief Scientific Officer of the FOXG1 Research Foundation (FRF). Dr. Lee is an Empire Innovation Professor and Om P. Bahl Endowed Professor at University at Buffalo Department of Biological Sciences. 

Since joining the FRF in 2017, Dr. Lee has elevated the FOXG1 research center at the University at Buffalo to a global leader in the field. Her exceptional work has garnered around $3M annually from federal agencies, FRF, UB, and the Simon Foundation Autism Research Initiative (SFARI), notably receiving SFARI's 2022 Genomics of ASD: Pathways to Genetic Therapies award.

Dr. Lee’s dedication to curing FOXG1 syndrome is deeply personal as a mother to Yuna, diagnosed with FOXG1 syndrome in 2009.

Her passion and commitment have inspired everyone fortunate enough to work with her. It's a rare and special circumstance to have FOXG1 parents leading the scientific journey towards effective therapeutics for all FOXG1 children globally.

Watch Dr. Soo-Kyung Lee's incredible story in this New York Times video.

Together with her neuroscientist husband, Dr. Jae Lee, Dr. Soo-Kyung Lee has created a suite of comprehensive models to understand the full spectrum of FOXG1 syndrome. With a team of more than 20 scientists (and growing) dedicated to FOXG1 syndrome, the Lee Lab is spearheading cutting-edge translational therapeutic strategies, notably the AAV9-dependent viral gene therapy. As parents gearing up to apply this gene therapy to their own daughter, they uphold unparalleled safety, efficacy, and urgency standards.

In her new role as Chief Scientific Officer, Dr. Lee will be responsible for leading the  scientific initiatives of the FOXG1 Research Foundation, which includes the FOXG1 Scientific Consortium of labs along our roadmap to successful therapeutics. With Dr. Lee at the helm, and in collaboration with the global partners, the FRF will operate with the agility and focus of a world-class organization, maintaining their mission-driven ethos to advance multiple therapies into clinical trials as soon as possible.

“The FOXG1 community is privileged to have Dr. Lee spearheading our therapeutic efforts for FOXG1 syndrome. Her unparalleled dedication, acumen, and urgency have consistently shone through her work, with biopharma leaders, the NIH and other global agencies tapping her knowledge in the field of FOXG1 research. We eagerly anticipate the continued groundbreaking accomplishments her leadership will usher, and therapies for all children suffering from FOXG1 syndrome,”expressed FOXG1 Research Foundation CEO and co-founder, Nasha Fitter.

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Dr. Soo-Kyung Lee, FOXG1 Research Foundation Scientist, Earns Grant from Simon Foundation Autism Research Initiative (SFARI) for Genomics of ASD: Pathways to Genetic Therapies

FOXG1 Research Foundation CSO Named The Simons Foundation Autism Research Initiative (SFARI) Grantee 2022 Genomics of ASD: Pathways to Genetic Therapies

2022 Genomics of ASD: Pathways to Genetic Therapies awardees announced

The Simons Foundation Autism Research Initiative (SFARI) is pleased to announce that it intends to fund 15 grants in response to the 2022 Genomics of ASD: Pathways to Genetic Therapies request for applications (RFA).

Grants funded through this RFA are intended to advance our understanding of the genetic basis of ASD and the molecular and cellular consequences of genetic risk, and to provide a foundation for the development of treatments for select genetically defined forms of the condition.

Applications in response to this RFA were sought in three broad areas: (1) integrative analyses of multi-omic ASD data, (2) functional analysis of variants associated with ASD risk genes and (3) gene-targeted therapies. Proposals that span the different focus areas were encouraged, as were collaborations between academic and industry partners. Furthermore, SFARI encouraged proposals that focused on a subset of 50 genes from the SPARK gene list; these genes were selected, for a variety of different reasons, as strong candidates for the development of translational programs.

“SFARI is honored to support this group of awardees, whose research promises to not only elucidate the neurobiological pathways that are regulated by autism genes, but to also identify new therapeutic targets and strategies,” says SFARI executive vice president Kelsey Martin.

SFARI intends to provide approximately $15.7 million in funding over the next three years to 27 investigators as part of this program.

“SFARI is pleased to fund these projects under the 2023 Genomics RFA,” says SFARI senior scientist Julia Sommer. “We hope that the combination of additional insights into the genetic basis of ASDs and a better understanding of the molecular and cellular changes brought about by genetic risk factors will create a fertile ground for the development of genetically informed therapies.”

The projects that were selected for funding focus on several different risk genes and conditions, including GRIN disorders, Rett syndrome and SLC6A1-related autism disorder. A variety of different approaches and methods will be used, including high-throughput screens to ascertain the functional effects of autism variants, and the development of antisense oligonucleotide and adenoviral vector-based gene therapies.

The projects that SFARI intends to fund are:

Marta Biagioli, Ph.D. (University of Trento)
SINEUP RNAs: a new platform for treating haploinsufficiency in autism spectrum disorders (ASD)

Fikri Birey, Ph.D. (Emory University)
Uncovering phenotypic convergence across high-risk autism genes using forebrain assembloids

Arjun Krishnan, Ph.D. (University of Colorado, Denver) and Julia Ganz, Ph.D.(Michigan State University)
An integrative framework to unravel the genes, gene networks, cell types, and developmental states underlying ASD-associated GI dysfunction

Soo-Kyung Lee, Ph.D. (University at Buffalo)
Development of therapeutics for FOXG1 syndrome using patient-specific human iPSC and mouse models

Jingjing Li, Ph.D. (University of California, Berkeley), Arnold Kriegstein, M.D., Ph.D. (University of California, San Francisco), Michael Snyder, Ph.D. (Stanford University) and Mohan Babu, Ph.D. (University of Regina)
High-resolution proteome mapping in the developing human cerebral cortex to uncover mutationally convergent pathways in autism spectrum disorders

Matthew MacDonald, Ph.D. (University of Pittsburgh) and Bernie Devlin, Ph.D.(University of Pittsburgh)
Putting genes associated with autism in their neurobiological context by transcriptomic and proteomic analyses

Randall Platt, Ph.D. (Swiss Federal Institute of Technology in Switzerland)
High-throughput precision gene editing and multi-omics profiling of patient-specific CHD8 variants in human-derived stem cells and induced neurons

Elise Robinson, Sc.D. (Massachusetts General Hospital), Luke O’Connor, Ph.D.(Broad Institute of MIT and Harvard), Michael Talkowski, Ph.D. (Massachusetts General Hospital) and Kaitlin Samocha, Ph.D. (Massachusetts General Hospital)
Identifying functionally convergent genetic factors associated with autism

Yufeng Shen, Ph.D. (Columbia University Medical Center), Brian O’Roak, Ph.D.(Oregon Health & Science University) and Jacob Michaelson, Ph.D. (University of Iowa)
Triangulation of missense variant impact through multimodal modeling and functional assays

Max Staller, Ph.D. (University of California, Berkeley)
Functionally characterizing genetic variants in the activation domains of ASD-associated transcription factors

Michael Wells, Ph.D. (University of California, Los Angeles)
Cell village-based detection of shared molecular and cellular defects across autism risk factors

Anne West, M.D., Ph.D. (Duke University School of Medicine)
Orchestration of synaptic gene regulation by H3K27me3-dependent modulation of chromatin architecture

Hyejung Won, Ph.D. (University of North Carolina at Chapel Hill), Kristen Brennand, Ph.D. (Yale University) and Nan Yang, Ph.D. (Icahn School of Medicine at Mount Sinai)
Reciprocal impacts of rare and common polygenic risk architecture for autism into biological measures

Timothy Yu, M.D., Ph.D. (Boston Children’s Hospital)
Piloting gene- and mutation- specific ASO therapies for ASD

Zhaolan (Joe) Zhou, Ph.D. (Perelman School of Medicine, University of Pennsylvania)
Understanding the epigenetic contribution to autism

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

A Daughter's Rare Disease Brings Mother-Father Researchers to Buffalo for Answers

Soo-Kyung Lee, Empire Innovation Professor of Biology at the University at Buffalo, has been driven to focus greater attention on FOXG1 syndrome since her daughter, Yuna, was diagnosed with the neurological condition almost nine years ago.

Douglas Levere/University at Buffalo

Maybe Yuna Lee was built to be in Buffalo.

The 11-year-old – whose name means “snow girl” in a Korean dialect – was born during a rare January snowstorm in Houston, where her parents worked as medical researchers at Baylor College of Medicine.

Yuna seemed a typical newborn, but things changed in months that followed. Her head didn’t grow quickly enough. Seizures became common. She missed developmental milestones.

It took two years for doctors and top U.S. neurologists to tease out a diagnosis, which at first seemed unfathomable to her mother, Soo-Kyung Lee, a leading researcher in genetic brain disorders.

Yuna had FOXG1 syndrome, a rare condition caused by a random mutation in a key gene needed during fetal development to set the stage for speech, mobility and thought.

“Yuna was born in the right place, to the right mom. She kind of came to the right family,” said Jae Lee, her father, who for most of his career focused on diabetes and metabolic research.

The Lee parents, both biology professors, spent the bulk of the last decade at Oregon Health and Science University, on the West Coast in Portland, slowly taking more professional time on their daughter’s condition – until they were drawn in summer 2019 to the University at Buffalo by the prospect of creating a center of excellence in FOXG1 research.

Jae Lee, above, and his wife, Soo-Kyung Lee, natives of South Korea, came to Buffalo from Portland, Oregon two years ago with aims to create a center of excellence in FOXG1 research.

Douglas Levere/University at Buffalo

Their lab on the UB North Campus already has yielded greater understanding about how the related syndrome develops, raising hopes that their work could one day help with breakthrough research and treatment, including for related conditions such as autism, Alzheimer’s disease, epilepsy and schizophrenia.

Much work remains, Soo-Kyung Lee said.

The FOXG1 gene, once called “Brain Factor 1,” is a master regulator that is key to establishing cells that build the central nervous system, particularly the forebrain.

Yuna lacked a nucleotide, Number 256 in the 86th amino acid of one of two copies of FOXG1, which has 489 amino acids. Those born with such mutations on both copies cannot survive.

This and similar mutations almost always happen randomly, as was the case with Yuna.

Her mother has long used genes in the FOX family, including FOXG1, in her research.

Roughly 400,000 babies born worldwide have neurological disorders caused by random mutations.

Dr. Joseph Gleeson, a neurogeneticist at University of California San Diego, told the New York Times for a 2018 story on the Lees that doctors used to lump all those conditions together under autism or other categories before genetic sequencing became more common and provided more clarity.

“It’s really changing the way doctors are thinking about disease,” Gleeson told the Times.

Only about 650 people in the world are known to have FOXG1 syndrome, although FOXG1 genes also play a role in several other neurological conditions.

An estimated one in 68 children is diagnosed on the autism spectrum. More than 44 million people have Alzheimer’s or other forms of dementia worldwide. More than 2 million Americans have epilepsy. Roughly the same number have schizophrenia.

Yuna cannot talk, walk or eat on her own. She lacks control of her bowels. For years, she found it hard to sleep. She has learned to sit up and is making other slow, steady progress with help from physical, occupational and speech therapy. She communicates basic needs with her eyes and other facial expressions. She and her family live in Amherst.

She and her brother, Joon, 8, attended Maple East Elementary School before the pandemic, but have been learning at home because of coronavirus risks for Yuna. An experienced caregiver looks after the children while the Lees work mostly from home.

“It's not ideal,” Jae Lee said. “We look forward to the day that we can send Yuna back to school and back to the clinics, but we've been coping as well as we could have under the circumstances.”

Meanwhile, related research progresses. Those financially supporting the work of the Lees include New York State, the National Institute of Neurological Disorders and Stroke and the FOXG1 Research Foundation.

FOXG1 research could have implications for several neurological diseases, said Soo-Kyung Lee, including autism, Alzheimer’s, epilepsy, and schizophrenia.

Douglas Levere/University at Buffalo

For Yuna: OHSU Scientist Unveils Origins Of Daughter’s Rare Condition: Study Findings Could Lead To New Treatment Options For FOXG1 Syndrome

For more than 20 years, Soo and Jae W. Lee have studied the specialized functions of transcription factors including FOX proteins, a family of 40-plus genes integral to the lifetime development and function of such organs as the brain and heart.

With expertise in neurodevelopment, Soo Lee, Ph.D., a professor of pediatrics in the OHSU School of Medicine and the Papé Family Pediatric Research Institute at OHSU Doernbecher Children’s Hospital, was drawn to FOXG1’s influence on brain growth and function, and the role it plays in rare neurological syndromes that impact human communication, mobility and sleep.

Unbeknownst to Soo, what started as an idea for an interesting scientific experiment would ultimately inspire her life’s work.

YUNA’S BRAIN

In January 2010, the Lees welcomed their first child, a beautiful baby girl with dark hair and eyes. They named her Yuna.

“She was perfect,” said Jae W. Lee, Ph.D., a professor of pediatrics in the OHSU School of Medicine and the Papé Family Pediatric Research Institute at OHSU Doernbecher Children’s Hospital. “We knew that she would be an incredible addition to the world.”

As she grew, Yuna experienced frequent seizures, difficulty sleeping and periods of inconsolable crying. At age 2, she could not sit up, stand, walk or speak.

Following multiple discussions with colleagues within their respective scientific circles, Soo and Jae received the news they suspected and dreaded. While the odds were staggering, genetic testing confirmed that Yuna had a mutation in one copy of her FOXG1 gene.

Approximately 350 people worldwide have been diagnosed with FOXG1 syndrome, or FS. While medications and therapies are available to help manage symptoms, currently no treatment or cure is available.

“As both a scientist and a mother, I needed to better understand how Yuna’s brain works,” said Soo. “I wanted to discover a pathway for treatment to help my daughter.” 

Soo-Kyung Lee, Ph.D., with her daughter Yuna. (Courtesy of the Lee family)

UNDERSTANDING FOXG1

Using a mouse model, Soo and a team of scientists at OHSU and the University of California, Santa Cruz, set out to determine how the corpus callosum, a thick band of nerve fibers that allows communication between the left and right sides of the brain, is constructed during fetal development.

The results, recently published online in the journal Neuron, revealed the corpus callosum missing one copy of FOXG1 appeared thinner and shorter compared with that of a typical brain. This change likely reduced communication across the brain’s hemispheres.

Jae W. Lee (left) keeps a photo of his daughter Yuna on his desk. Soo (right) says their research gives them hope for their daughter. “The ability to better understand my daughter’s condition inspires me to keep moving forward. I am a more optimistic scientist because of her.” (OHSU/Kristyna Wentz-Graff)

Furthermore, while it was previously understood that the presence of FOXG1 within stem cells helps to facilitate proper brain formation, the scientists also demonstrated similar FOXG1 traits within neurons.

“Our findings confirm that two copies of the FOXG1 gene within the brain’s neurons are critical to the proper development and mapping of the brain in utero,” said Soo. “This gives us a better understanding of Yuna’s impaired brain structure, as well as a starting point for future research.”

Although more research is needed, Soo believes these findings will facilitate downstream treatments that may help repair some FS symptoms in human patients.

“It gives me hope for Yuna, as well as the hundreds of others living with FS,” said Soo. “The ability to better understand my daughter’s condition inspires me to keep moving forward. I am a more optimistic scientist because of her.”

This research was supported by the National Institute of Neurological Disorders and Stroke (grants R01NS054941, R56NS054941, R01NS100471, R01NS089777and P30NS061800, the National Institute of Diabetes and Digestive and Kidney Diseases (grants R01DK064678 and R01DK103661) and the National Institute of Mental Health (grant R01MH094589), all components of the National Institutes of Health; the American Heart Association; the Blackswan Foundation; and the FOXG1 Research Foundation.

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