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

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/

University at Buffalo launches center to find treatments for FOXG1 syndrome

Research will be led by biologists Soo-Kyung and Jae Lee, whose daughter has the rare neurological disorder, FOXG1 syndrome

FOXG1 Research Center at the University at Buffalo is led by Biologists and FOXG1 parents Dr. Soo-Kyung lee and Dr. Jae Lee

By Tom Dinki

Release Date: January 17, 2024

BUFFALO, N.Y. — University at Buffalo biologists Soo-Kyung and Jae Lee were already studying genetics and brain development when their daughter, Yuna, was born with a rare neurological disorder caused by a mutation of the FOXG1 gene.

So the Lees are well positioned — and motivated — to lead a research center dedicated to FOXG1.

UB’s new FOXG1 Research Center (FRC), set to launch in the coming months, aims to translate new discoveries from the lab to clinical trials and, ultimately, develop a cure for FOXG1 syndrome, as well as related autism spectrum disorder.

The FRC will be supported by the FOXG1 Research Foundation (FRF), as well as UB's College of Arts and Sciences and Office of the Vice President for Research and Economic Development. 

“This center will make UB the home of the world’s premier research center devoted to the studies of FOXG1 syndrome, as well as provide our campus with a new neurodevelopmental biology training program and numerous research funding opportunities,” says Soo-Kyung Lee, PhD, Empire Innovation Professor and Om P. Bahl Endowed Professor in the UB Department of Biological Sciences, who is currently FRF’s chief scientific officer and will serve as the FRC’s inaugural director. “The FRC will harness the expertise of our faculty to unravel the remaining mysteries of FOXG1 syndrome and, hopefully, help Yuna and the other children impacted by this disorder.”

The FOXG1 gene is one of the most important genes for early brain development. A master regulator gene, FOXG1 carries the instructions for making a protein called forkhead box G1 that regulates the activity of other genes, many of which are crucial for cellular connectivity and communication. Impairment of FOXG1 causes cognitive and physical disabilities as well as life-threatening seizures. 

There are only about 1,000 known patients diagnosed with FOXG1 syndrome worldwide, according to the FOXG1 Research Foundation. However, the FOXG1 gene has been linked to autism, Alzheimer’s disease and schizophrenia, suggesting that therapy development may be transferable to more common disorders.

There has also been a national push to better study and raise awareness for rare diseases, like FOXG1 syndrome. Last year, the Biden administration established the Advanced Research Projects Agency for Health (ARPA-H) within the National Institutes of Health, whose mission includes treating rare disorders.

The Lees, who joined UB in 2019, have established themselves as leading experts on FOXG1 syndrome since Yuna, now 14, was diagnosed with the disease at the age of 2. Their research has found that the FOXG1 gene and protein remain active in mice after birth, providing hope that some symptoms can be alleviated.

“Although we cannot go back and undo the damage to people who have FOXG1 syndrome, we may be able to modify the effects of the disease and increase their quality of life,” says Jae Lee, PhD, professor of biological sciences. 

They’ve recently had success in this area. Mice who began receiving the Lees’ viral gene therapy a day after their birth saw some functions restored. Soo-Kyung Lee received a $1.5 million grant from the Simons Foundation Autism Research Initiative earlier this year to continue the research.

Planned research topics for the FRC include drug discovery, sensory issues like sleep disturbance and mood changes, and the role of mitochondria in neurodevelopmental disorders.

Joining the Lees at the FRC will be an interdisciplinary team of UB faculty, including expected new hires. Collaborators already in place include:  

• Denise Ferkey, PhD, associate professor and associate chair of the Department of Biological Sciences;

• Michael Yu, PhD, associate professor of biological sciences; 

• Wei Sun, PhD, associate professor and director of undergraduate studies of the Department of Communicative Disorders and Sciences; 

• Priya Banerjee, PhD, associate professor of physics; 

• Yungki Park, PhD, associate professor of biochemistry; 

• Edward Kwon, DDS and PhD, assistant professor of oral biology.  

Graduate students are also expected to conduct research in FRC labs.

“The FRC will harness the expertise of our faculty to unravel the remaining mysteries of FOXG1 syndrome and, hopefully, help Yuna and the other children impacted by this disorder. ”

Soo-Kyung Lee, Empire Innovation Professor and Om P. Bahl Endowed Professor of Biological Sciences

University at Buffalo

Media Contact Information

Tom Dinki
News Content Manager
Physical sciences, economic development
Tel: 716-645-4584
[email protected]

The FOXG1 Research Center at the University at Buffalo led by FOXG1 parents Dr. Soo-Kyung Lee and Dr. Jae Lee, along with FOXG1 Research Foundation, co-founder Nicole Johnson, Chief Drug Development Officer Dr. Gai Ayalon, and FOXG1 grandparents Tom and Janet Horton

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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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.”

For two UB scientists, love means studying their daughter's rare disease

Biologist Soo-Kyung Lee was researching a gene crucial to brain development. Then, her baby, Yuna, was born with a mutation in that gene

By Charlotte Hsu

READ ARTICLE HERE

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.”

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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