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

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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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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

Boston Children's Heather Olson on the Importance of the FOXG1 Digital Natural History Study

Heather Olson, MD, MS, Neurologist at Boston Children’s and Neurology Instructor at Harvard Medical, discusses FOXG1 Research Foundation’s Ciitizen Digital Natural History Study.

Heather Olson, MD, MS, Neurologist at Boston Children’s and Neurology Instructor at Harvard Medical, discusses FOXG1 Research Foundation’s Natural History Study.

FOXG1 syndrome is a neurological condition characterized by impaired development and structural brain abnormalities. The condition can be caused by mutations within the FOXG1 gene or a deletion of genetic material from the region of the long arm of chromosome 14 where the gene is located. FOXG1 syndrome is considered an autosomal dominant condition. While it is possible for parents to be carriers, most cases result from new mutations.

As Dr. Olson explains, natural history studies like the one supported by Ciitizen and the FOXG1 Research Foundation are critically important, especially for rare diseases. These studies allow researchers to learn about different symptoms, how heterogeneous the patient population is, and to avoid bias when conducting studies. Dr. Olson also explains that this particular natural history study is unique in that it is digital which is beneficial as it puts less strain on families and patients participating in the study.

To learn more about FOXG1 syndrome and rare neurological disorders, visit checkrare.com/diseases/neurology 

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