Charles River Collaborates with Patient Advocacy Group, FOXG1 Research Foundation to Advance Rare Disease Gene Therapy Development

Clinical trials for AAV9 gene therapy bolstered with plasmid and viral vector CDMO expertise

WILMINGTON, Mass.--(BUSINESS WIRE)--Jul. 30, 2024-- Charles River Laboratories International, Inc. (NYSE: CRL) announced today a collaboration with the FOXG1 Research Foundation (FRF) highlighting the patient advocacy group’s model to independently drive drug development through the clinical phase. The parent-led global organization driving the research to cure FOXG1 syndrome and related neurological disorders will collaborate with Charles River in a comprehensive gene therapy contract development and manufacturing organization (CDMO) agreement.

“Charles River is proud to work with the FOXG1 Research Foundation to advance its gene-therapy through clinical trials,” said Kerstin Dolph, Corporate Senior Vice President, Global Manufacturing, Charles River. “The FOXG1 patient population has an incredible unmet need, and we are looking forward to lending our expertise to FRF as they continue to trailblaze a path toward providing rare disease treatments.”

Through the collaboration, Charles River will provide FRF with access to extensive cell and gene therapy expertise and generate materials for FRF’s Phase I-II adeno-associated viral (AAV) vector-based gene therapy clinical trials at its plasmid DNA and viral vector CDMO centers of excellence (CoE). The established CDMO will supply phase-appropriate High Quality (HQ) plasmid starting materials manufactured at its Alderley Park CoE in addition to good manufacturing practice (GMP) AAV9 viral vector manufactured at its Rockville CoE, leveraging an integrated manufacturing and biologics testing portfolio to streamline their path to the clinic.

“Given the limited investment for rare disease groups like ours, our foundation has created a model that allows us and other patient advocacy groups to operate like a virtual biotech company and independently and efficiently drive drug development,” said Nasha Fitter, FOXG1 Parent, Co-founder and Chief Executive Officer, FOXG1 Research Foundation.

A New Approach to Drive Rare Disease Drug Development

Founded in 2017 and propelled by innovation and an urgency to accelerate the road to therapeutics for FOXG1 syndrome, FRF has created a replicable model for rare disease patient advocacy groups to take control and drive the development of treatments when no options exist. This includes pioneering novel AI platforms for patient data and streamlining preclinical work.

“The success of FRF’s model is not only focused on operating as a highly efficient team, but also partnering with organizations that are equally passionate about bringing treatments to children with the highest unmet need and severe burden of disease. Selecting the right partner is critical and Charles River has demonstrated a deep understanding of our model and commitment to working on our therapies,” continued Fitter.

FOXG1 syndrome is a severe rare neurological genetic disorder that greatly impacts early brain development and typically causes epilepsy and a host of medical complexities and disabilities. There are approximately 1,000 patients diagnosed with FOXG1 syndrome worldwide, with the diagnosis rate climbing steadily year-over-year and no approved treatments. Most children with FOXG1 syndrome cannot walk or talk or take care of their basic needs.

Cell and Gene Therapy CDMO Solutions

In recent years, Charles River has significantly broadened its cell and gene therapy portfolio with several acquisition integrations and expansions to simplify complex supply chains and meet growing demand for plasmid DNA, viral vector, and cell therapy services. Combined with the Company’s legacy testing capabilities, Charles River offers an industry-leading “concept to cure” advanced therapies solution.

Presented live at the Charles River Cell and Gene Therapy Summit, March 19, 2024, in San Francisco, watch Nasha Fitter’s FOXG1 Research Foundation Patient Story session on-demand, and explore the Summit resource hub: https://bit.ly/4bb2uDu

Also, listen to "A Mom’s Mission", a Vital Science Podcast, broadcast July 16, 2024, where Nasha discusses the origins of FOXG1 Research Foundation, how daughter Amara’s life has been shaped by her diagnosis, and how collaboration has helped advance their mission: https://bit.ly /3LuCpog

About Charles River

Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts. Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit www.criver.com.

About FOXG1 Research Foundation

The FOXG1 Research Foundation (FRF) is the global, parent-led rare disease patient organization dedicated to advancing treatments for FOXG1 syndrome and related disorders, while advocating for and supporting patients and families worldwide. FOXG1 syndrome is a rare neurological developmental disorder linked to Autism Spectrum Disorder, epilepsy, and developmental disabilities. Founded in 2017, FRF has rapidly emerged as a leader and innovator in the rare disease patient advocacy space, developing novel platforms and an efficient blueprint to accelerate drug development for rare diseases. As a Chan Zuckerberg Initiative partner and recognized through its CEO’s presentation at the inaugural White House Rare Disease Forum, FRF is committed to radically improving the landscape for the 300 million patients affected by rare diseases worldwide.

www.foxg1research.org

View source version on businesswire.com: https://www.businesswire.com/news/home/20240730710706/en/

Charles River Investor Contact:

Todd Spencer
Corporate Vice President, Investor Relations 781.222.6455 [email protected]

Charles River Media Contact:

Amy Cianciaruso
Corporate Vice President, Chief Communications Officer 781.222.6168 [email protected]

FOXG1 Research Foundation Media Contact:

Nicole Johnson
Co-Founder and Executive Director [email protected]

Source: Charles River Laboratories International, Inc.

2023 Impact Report

2023 marked six years of the FOXG1 Research Foundation. We are a parent-driven, global foundation with the mission to help improve the lives of every person affected by FOXG1 syndrome worldwide. We are immensely proud of the organization we have built and the resources we have made available to our community since 2017.

We are known in the industry as innovators focused on three equally critical areas: FOXG1 science, FOXG1 patient data, and FOXG1 patients and community. From advancing our gene therapy program, to building our own bioinformatics platform, to helping guide parents through the rare disease medical caregiver journey, this year has been a year of upward progress in all three areas.

Our community is mourning the loss of 8 children in 2023 alone. We must stop this from happening. We are grateful for this incredible team working collectively to advance this goal, and most importantly, to our donors who enable this work.

Here are some of the FOXG1 Research Foundation highlights from 2023:

• Raised >$1.5M ($7.5M to date)

• Concluded our gene therapy preclinical work to upregulate the FOXG1 gene, rescue symptoms, and pass preliminary safety measures 

• Finalized characterization of key FOXG1 animal models, which are critical for drug screening

• Hired Chief Drug Development Officer, Dr. Gai Ayalon from Neumora Therapeutics to lead us successfully to a gene therapy clinical trial with the FDA and other international regulatory agencies

• Named Dr. Soo-Kyung Lee our Chief Scientific Officer, a FOXG1 mother and esteemed neuroscientist  who leads the FOXG1 Research Center of Excellence at the University at Buffalo with a team of >20 members focused solely on FOXG1 syndrome

• Built FOXG1 bioinformatics platform where all raw scientific, genetic and clinical data is normalized and cleansed enabling drug discovery and data for accelerated drug development from novel AI tools 

• Published paper on FOXG1 syndrome from our FOXG1 patient registry; 3 more publications underway

• Submitted paper to Journal of Neurology on epidemiology of FOXG1 syndrome meta-analysis results 

• Joined pharmaceutical-funded Biomarker studies with CombinedBrain

• Implemented FOXG1 Parent Support Team with monthly support zooms and resourceful webinars

• Connect newly diagnosed families to resources, medical professionals, and other families

• Announced the first FOXG1 patient to our advisory board, bringing a FOXG1 patient’s voice to our community

• Remain sought-after thought leaders/ speaker on podcasts and conferences

Here are some of the things the FOXG1 Research Foundation is working on in 2024:

• Moving our gene therapy program from preclinical to clinical stages with a focus on GMP manufacturing of product and toxicology studies 

• The 2024 FOXG1 Science Symposium and Parents Conference in November in Florida, USA

• Continue preclinical projects around small molecule, RNA and antisense oligonucleotide (ASO) drug screenings while continue studying the FOXG1 gene’s impact on the brain 

• Undertaking a large body of pre-work for clinical trials: deciding clinical trial endpoints, publishing a Disease Concept Model, meetings with clinical trial sites, meetings with the FDA and international agencies 

• Collaborations with biopharma companies as potential partners for our drug development programs 

• Exciting new resources for families to help assist managing their medical journeys, which includes new parent support webinars, virtual support meetings, and more

• Publication on FOXG1 Natural History Study data and FOXG1 Epidemiology papers in peer-reviewed medical journals  

• FOXG1 Research Center of Excellence at the University at Buffalo official ribbon cutting

• Growing FOXG1 clinicians network towards Standard of Care Guide for FOXG1 syndrome

• Establishment of expanded biobank with Coriell

• Continuing to expand our toolkit of assets to evaluate current and future therapeutic approaches
  

2023 FOXG1 Research Foundation Media 

*CARETALK Podcast: Why Rare Disease Research is SO Important with FOXG1 Research Foundation CEO, Nasha Fitter: Rare Disease Research and Its Potential To Unlock Medical Mysteries

*Ranked #9 Top Podcast Episode on Apple Health!

San Francisco Business Times: How two mothers are finding hope in searching for their children’s cures

Video Recap: The 2022 FOXG1 Science Symposium and Parents Conference

SFARI News: 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 

Cafe Mom: 'Power of Moms': This Mom Quit Her Job To Find a Cure for Her Daughter’s Rare Disease

Press Release: New Children's Book "Joyfully Josie" Aims to Spark Conversations Around Disabilities, Rare Diseases, and Inclusion

Enable Magazine: Disability Pride Month: Educating the next generation to create an inclusive future

FRF Appoints Chief Drug Development Officer, Dr. Gai Ayalon

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

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

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

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

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

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

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

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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COMBINEDBrain Biorepository enrolling FOXG1 participants at conferences across the USA

Principal investigator: FOXG1 Research Foundation in partnership with COMBINEDBrain

About the study:

COMBINEDBrain is a non-profit consortium of over 60 patient advocacy groups for rare, genetic neurodevelopmental disorders. They recognize the need to collect patient samples for researchers to identify biomarkers to be used to treat /develop treatments for our children. They are on a mission to collect ~500 samples from our member organizations over the next 6-8 months and the FOXG1 Research Foundation is one of them. Samples collected from our community will be stored and available to researchers across the world.

Are you or one of your family members interested in participating in this exciting project for FOXG1-related disorders ?

Here are the basics:

Who can participate?

Any participant diagnosed with FOXG1 syndrome and unaffected sibling.

What does participation involve?
COMBINEDBrain will be collecting urine samples and blood samples (processed for plasma and a finger stick) to be stored in the COMBINEDBrain Biorepository and available for select biomarker projects as well as other interested researchers. They will also collect several online surveys to be completed by caregivers.

Where can you participate?
COMBINEDBrain is collecting samples all across the United States this year. Please see the list below of locations to find the closest biorepository collection to you. You may attend ANY of these meetings

Sample size: The goal is to collect 20 samples from each patient group

How to enroll
Please contact [email protected] to determine the best way and location to participate.

Use of Clinical Research ID (CRID)

This study uses a CRID, or Clinical Research ID. This is a unique identification number generated and known only to the participant. This ID number allows researchers to merge data across research projects without any personally identifying information from the participant.

Please obtain a CRID prior to enrolling in this study, which is a simple online process that takes 2-3 minutes.

Then, please add your CRID to your FOXG1 Patient Registry Profile HERE

Biorepository collection locations:

COMBINEDBrain, August 6th, 9am-5pm (Courtyard by Marriott New York Queens/Fresh Meadows

183-15 Horace Harding Expy, Queens, NY 11365)

GLUT1 Deficiency, August 26th, 9am-5pm (Embassy Suites, 13700 Conference Center Drive South, Noblesville, IN 46060)

I

RF2BPL Foundation, Sept 22nd-23rd 2023 (Home 2 Suites by Hilton, 7145 Liberty Centre Drive, Liberty Township, OH 45069, 513-644-2207)

KCNQ2 Cure Alliance Conference, Sept 29th-30th 2023 (Hilton Hotel Chicago 300 E Ohio St, Chicago, IL 60611)

NARS1 Conference, October 1st, 9am-5pm (13550 Commerce Blvd Rogers, MN 55374)

Prader-Willi Syndrome/USP7 Foundation, October 5-7 (1672 Lawrence St, Denver, CO 80202) 

TBRS Community, Oct 12th-14th 2023 (Morgan’s Wonderland, 5223 David Edwards Dr, San Antonio, TX 78233)

COMBINEDBrain Meeting, Oct 15th-16th 2023 (Washington DC)

FAM177A1, Oct 29th 2023, 9am-5pm (2737 77th Ave Se Suite 101 Mercer Island, WA 98040)

CombinedBrain November 4th, Los Angeles, California

SYNGAP1 Research Fund, Dec 1st-3rd 2023 (8978 International Drive Orlando, FL, 32819)

SLC6A1 Connect, Dec 1st-3rd 2023 (9700 International Dr, Orlando, FL 32819)

New Children's Book and Digital Platform "Joyfully Josie" Aims to Spark Conversations Around Disabilities, Rare Diseases, and Inclusion

NEW YORK, June 7, 2023 /PRNewswire/ -- Nicole Zeitzer Johnson announced today the release of her debut book, "Joyfully Josie." Designed to help parents and families discuss inclusion in the context of disabilities, this captivating children's book series aims to foster understanding of rare diseases and the experiences of medically complex individuals.

As the co-founder of the FOXG1 Research Foundation and mother to Josie, who suffers with FOXG1 syndrome, a rare genetic neurodevelopmental disorder, Zeitzer Johnson brings her personal journey and expertise to the pages of "Joyfully Josie." Through the power of storytelling, she enlightens both parents and children, helping them feel comfortable with those who are different.

"Joyfully Josie" is a heartwarming tale that showcases Josie's unwavering spirit and her ability to spread joy to everyone she encounters, despite her many challenges.

"My goal is to help give parents the tools to introduce disabilities and inclusion to their children at a young age. Children are often afraid when they see Josie because they don't understand disabilities or medical complexities. It's intimidating. I hope "Joyfully Josie" will turn their fear into excitement to meet any child with disabilities." Zeitzer Johnson said.

"Joyfully Josie" extends beyond the pages of the book with an innovative interactive digital platform. Through this platform, children can play Josie's favorite games and become a character in Josie's playground, immersing themselves in her world and joining her mission to find a cure for FOXG1 syndrome and childhood neurological diseases. This unique blend of storytelling and interactivity creates an engaging learning experience that empowers children to make a difference.

Nicole Zeitzer Johnson's dedication to promoting awareness and finding a cure for rare diseases is exemplified by her work with the FOXG1 Research Foundation. As one of the fastest-growing rare disease patient organizations and a Chan Zuckerberg Initiative "Rare As One" partner, the foundation has made significant strides in advancing research, raising awareness, and supporting affected families. Through "Joyfully Josie," Nicole continues to champion the cause, using her platform to create positive change in the lives of countless individuals and families. All profits from book sales go directly to the FOXG1 Research Foundation.

"Joyfully Josie" is available to purchase at www.joyfullyjosie.love and multiple retailers including, Amazon. Retailers contact [email protected] for information.

About Nicole Zeitzer Johnson:
Nicole Zeitzer Johnson is an inspirational leader who co-founded the FOXG1 Research Foundation, known for its innovative approaches in the field of rare diseases. With her personal experience as a mother to Josie, who was born with FOXG1 syndrome, a severe rare neurological disease, Nicole brings a deep understanding and passion to her work. Leveraging nearly three decades of experience in media and entrepreneurship, she leads the foundation in pioneering initiatives that aim to bring successful therapeutics, including gene therapy, to clinical trials in the near future.

In June 2023, Nicole launched "Joyfully Josie," a groundbreaking children's book series and digital platform. This project not only serves as a testament to her dedication to raising awareness about disabilities and rare diseases but also offers parents a valuable tool to teach their children about empathy, understanding, and inclusion from an early age.

About the FOXG1 Research Foundation:
The FOXG1 Research Foundation has gained recognition as one of the fastest growing and innovative global rare disease organizations. Notably, it has been honored as a Chan Zuckerberg Initiative "Rare As One" partner, reflecting the foundation's commitment to making a significant impact in the lives of individuals affected by rare diseases. Through pioneering research, advocacy, and collaborative efforts, the foundation strives to advance treatments and therapies for FOXG1 syndrome and other childhood neurological diseases including Autism. By focusing on cutting-edge solutions and fostering partnerships, the FOXG1 Research Foundation is at the forefront of driving meaningful change within the rare disease community.

www.foxg1research.org | www.joyfullyjosie.love

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

Rarebase launches a neuroscience drug discovery platform collaborating with 15 rare disease patient organization

The Function platform, including the FOXG1 Research Foundation, enables drug and target discovery for rare genetic diseases

PALO ALTO, Calif., Sept. 14, 2021 /PRNewswire/ -- Rarebase, a public benefit biotechnology company, launched a tech-enabled drug discovery platform called Function. Function's 15 patient organization collaborators represent genes that cause epilepsy, autism, developmental delay and neurodegeneration. Learn more about the capabilities of Function here.

Mariah Gillaspie, the Founder and CEO of the Lightning and Love Foundation, reads a book to her daughter Emma who is affected by THAP12 epileptic encephalopathy.

Function platform collaborators include: ADNP Kids Research Foundation, SynGAP Research Fund, FOXG1 Research Foundation, STXBP1 Research Foundation, Hereditary Neuropathy Foundation, Hope4Harper, Lightning and Love Foundation, Cure ATRX, Charlotte and Gwenyth Gray Foundation, CureMito Foundation, the SHANK2 Foundation and multiple funds associated with the Rare Village and Rare Crossroads networks. 

"We're thrilled to be actively collaborating with rare disease patient organizations. In our first year, we have built relationships with more than 100 patient organizations who are seeking to find therapies for their loved ones. We see the potential of applying our technology at scale to the discovery of drugs and targets for thousands of diseases that currently have no treatments." said Onno Faber, Co-Founder and CEO of Rarebase.

"Rarebase is pushing the limits of science and innovating a financial structure that allows patient organizations to directly support drug discovery," said Mike Graglia, the Founder and Managing Director of the SynGAP Research Fund. 

"There are many common elements shared between neurological diseases. Instead of each of us working in silos, partnering on specific projects is critical. With Rarebase, we can screen more drugs, we can share costs, and we have more opportunity to learn from one another," said Nasha Fitter, the Co-Founder and CEO of the FOXG1 Research Foundation. 

"There is an urgent, unmet need for effective therapies for STXBP1 and other neurological diseases. We are excited to partner with Rarebase and other patient organizations to accelerate drug discovery across multiple conditions, and to do so through a novel collaborative model," said Charlene Son Rigby, Co-Founder and President of the STXBP1 Foundation.

"Rarebase is stepping outside the traditional drug development pipeline and harnessing new technology and science that patient organizations like ours would never be able to utilize alone," said Sandra Sermone, the Founder and CEO of the ADNP Kids Research Foundation. 

"We want our children to be independent in life and, honestly, just be able to live another day. Function is finally doing justice to how we need to approach finding answers for rare diseases," said Penny Howard, the Founder and CEO of Hope4Harper. 

"A single strand of spider silk can be easily broken. However, add thousands together and they become stronger than steel. The same goes for our rare disease communities; there is undeniable strength in numbers and exponential power in supporting each other towards our common goal," said Allison Moore, the Founder and CEO of the Hereditary Neuropathy Foundation.

Rare diseases represent a major unmet medical need as millions of people globally suffer without treatment options. The number of identified rare diseases is rapidly growing due to advances in genetic testing. Nearly 10,000 rare diseases affect an estimated 400 million people worldwide, but only 5% of them have an FDA approved treatment. 

About Rarebase, PBC
Rarebase is a public benefit biotech led by patients, scientists, advocates and engineers. We leverage innovative technologies to build platforms that help us discover and develop treatments for the millions of people worldwide affected by the long tail of rare genetic disorders. The company is funded by BlueYard Capital.

Media Contact: Lynsey Chediak
[email protected] 

ONCE UPON A GENE - The 12 Commandments to Guide You When You're Starting a Rare Disease Patient Advocacy Group. With Nasha Fitter and Mike Graglia

FOXG1 advocate Nasha Fitter and SYNGAP1 advocate Mike Graglia are leaders in the rare disease community and two of the top parent leaders in the advocacy game. In this episode, they're sharing their knowledge, expertise and experiences in an information-packed masterclass on how to build a rare disease patient advocacy group, get funding and forge a path to a cure. 

EPISODE HIGHLIGHTS

Where do you start to launch a rare disease foundation?

The first thing to do is to build your team. If you've just been diagnosed and realized there isn't a patient group for your disease, build your team of other parents and recruit friends and family to help you. The next step is to build a scientific advisory board to go to for advice and guidance.

How does a rare disease foundation make connections with parents and experts?

You'll have to do a lot with little knowledge or resources. As you build your team, encourage others to engage with their network and invite others to join the group. Strive to get roles filled for every category- clinician, geneticist, biotech and translational therapy. 

How does a rare disease patient organization you engage parents?

Repeat your message again and again and realize that getting to a cure isn't a race. Act as a lighthouse to get researchers, clinicians, diagnosed and un-diagnosed families to gather around a common goal. Use the tools within reach- podcasts, newsletters and social media as a digital lighthouse, sending signals out to the community. Get on every platform and engage patients.

What is a rare disease registry and how do you build one? 

It's a legal entity that allows you to collect patient information and disease symptom data. The registry platform should be Institutional Review Board (IRB) approved, which means patients and caregivers have consented to information sharing so they can be counted as a patient and share their information with researchers. Once the registry platform is set up, use social media to explain the benefits and invite patients to join.

How do you develop a path to a cure for your rare disease?

Search for publications and contact the authors to discuss the research and inquire about developing a treatment. Understand the biology of the disease. If you don't have assets, think about the assets that mimic the core of the disease, making models of the disease for testing treatments and drugs and ensure finding are on open access. While you wait for biotech companies to test on your assets, you can create proof of concepts that make sense and are along your path to a cure.

How do you fundraise for your rare disease?

It takes money and you'll need to raise money. You'll never know how much you can raise unless you ask. Invigorate the patient community to raise money and think big.

RESOURCES MENTIONED

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

ONCE UPON A GENE - EPISODE 041 - Time is Brain: SYNGAP Research Fund with Mike Graglia

SynGAP10 Podcast

PubMed

Global Genes

COMBINEDBrain

SLC6A1 Connect - Amber Freed

TUNE INTO THE ONCE UPON A GENE PODCAST

Spotify

Apple Podcasts

Stitcher

Overcast

CONNECT WITH EFFIE PARKS

Website

Twitter

Instagram

Built Ford Tough Facebook Group

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 

"Inside Research with Nasha" - Repurposed Drug Screening for FOXG1

We’re kicking off a new series called “Inside Research with Nasha.”

Our FOXG1 Research strategy is to leave no stone unturned. We’re looking at every possible angle in science to find disease-modifying therapies and ultimately a cure for FOXG1 syndrome and we want to keep everyone informed along the way. We’re also taking this opportunity to really explain what so many buzz words in science mean and how they fit into the research projects we are funding.

Today, we’re very excited to talk about our small molecule drug screening projects. Nasha explains some of those buzz words that covid made mainstream, like high-throughput screening, repurposing, small molecules, and more.

You can find more information about our Research Projects, our Path to a Cure and our FOXG1 Science Team on our website.

Please follow us on social @FOXG1Research so you don’t miss any of our Inside Research updates!

Taysha Gene Therapies Takes on FOXG1 Syndrome!

October 21, 2020

Dear FOXG1 Community,

As you may have learned, Taysha Gene Therapies is a new company that launched at the end of April focusing on developing gene therapies for central nervous system disorders.

Our Founder, President and CEO RA Session II became excited about the research program prior to joining Taysha after learning more about the high unmet medical needs associated with the disease. When RA founded Taysha, he recognized how certain technological gene therapy approaches available at our company, specifically those able to regulate re-expression of protein, could enable the team to identify a unique method of treating the cause of this disease in a regulated manner. It is now our pleasure to introduce the FOXG1 Community to Taysha Gene Therapies.

Taysha is a word in the Caddo Native American language meaning “ally” or “friend,” and when translated, also means “Texas.” Between our UT Southwestern collaboration and patient advocacy partnerships, we hope to be an ally to the rare disease community, including the FOXG1 community.

Our focus is gene therapy, which is a highly innovative approach to treating genetic diseases. We are working hand-in-hand with our collaborators at UT Southwestern collaborators, who are well-known gene therapy experts, medical experts in FOXG1 Syndrome, regulatory agencies and, importantly, patient groups every step of the way. We are truly embracing an integrated approach—one that will help get new medicines in the hands of physicians treating children affected by FOXG1 Syndrome in the most efficient, effective way possible.

We have a lot of work ahead of us but are encouraged by the strength of the FOXG1 Research Foundation that has been built to achieve this goal. By working together, our efforts will help bring gene therapy to the FOXG1 Community.

Warm regards,

The Taysha Team