CareTalk Podcast: Why Rare Disease Research is SO Important

Rare Disease Research and Its Potential To Unlock Medical Mysteries

We now live in an age where we are closer to being able to decipher the greatest medical mysteries than ever before. Rare diseases, which were once thought of as untreatable cases, could be at the forefront of unlocking some remarkable discoveries with their unique characteristics and symptoms.

With so many possibilities available for medical professionals looking into rare disease research and treatments, it is becoming increasingly important for healthcare workers and business alike to understand just how powerful this form of research can be. Not only will exploring this topic enables us to further dedicate resources towards pioneering treatments that may have previously been overlooked—but also provide a brighter outlook on potential cures for those affected by these and other conditions.

In an episode of the healthcare podcast, CareTalk: Healthcare. Unfiltered., titled “Why Rare Disease Research is So Important” co-host, David Williams is joined by Nasha Fitter, CEO of FOXG1 Research Foundation, which is dedicated to finding a cure for FoxG1 Syndrome and Vice President of RWE and Ciitizen Platform at Invitae, to shed light on the importance of rare disease research, the challenges it faces, and the promising developments in this field.

Understanding Rare Diseases: What They Are and Why They Matter

A rare disease is a medical condition that affects only a small number of people compared to the general population. The exact definition of a rare disease varies depending on the country and the organization providing the classification. In the United States, a rare disease is defined as one that affects fewer than 200,000 people, while in Europe, a disease is considered rare if it affects fewer than 1 in 2,000 people. Although each rare disease affects a small number of people, there are thousands of different rare diseases, and as many as 300 million people worldwide are living with a rare disease.

Genetic mutations or environmental factors can give rise to these conditions, with many having no cure or treatment. Despite their significance, rare diseases are often overlooked and lack funding, leaving those affected and their families to grapple with the consequences. Those living with rare diseases frequently face challenges in obtaining an accurate and timely diagnosis, and their families may have limited resources for treatment and support. Progress in research and treatment is essential to enhance quality healthcare for patients with rare diseases and their loved ones.

“Rare diseases are not that rare. When you add up all the, all the conditions and you know, now we're actually up closer to 10,000. But the truth is, the majority of rare diseases are actually defined as ultra-rare, where you have less than 2000 patients in the United States, and that is the big chunk of the problem”. – Nasha (CareTalk)

Rare Disease Research: The Path to Discovering Treatments and Cures

Rare disease research is a complex and intricate field that requires substantial expertise and resources. Scientists, physicians, and patient advocates pool their knowledge and expertise to identify and study rare diseases. Through a combination of laboratory experiments, clinical studies, and patient surveys, these experts aim to shed light on the underlying causes of rare diseases, as well as potential treatments.

“Only about 5% of the 7,000 or so known rare diseases have treatments, so that makes it a real challenge for families, foundations, pharma companies, anybody trying to do something about it. But there is hope, including the Orphan Drug Act, FDA, programs to speed development, advances in genomics, and the digitization and interconnectivity of patient data”. – David (CareTalk)

Struggles and Limitations of Rare Disease Research

Rare disease research faces a myriad of challenges that hinder progress towards finding effective treatments for those affected. One of the primary issues is the lack of funding available for research, as these diseases do not affect a large population. This leads to a lack of resources, expertise, and technology needed to conduct thorough research. The vast diversity in rare diseases makes it challenging to conduct clinical trials with large enough sample sizes to provide reliable data.

Further complicating matters, diagnostic tools may not exist, making it difficult to properly identify the disease in question. Additionally, there is a lack of interest amongst pharmaceutical companies, as marketing drugs for rare or orphan diseases may not be as profitable. These limitations necessitate a collective effort to raise awareness and shift priorities, as finding cures for rare diseases is crucial for both the affected individuals and the advancement of medicine as a whole.

“I think there's a lot more we can do to innovate and make this experience better and mainly just have clinical trials that are more effective. Even with everything we're doing, the majority of clinical trials fail. So we need better ways to track endpoints to make sure that, you know, these drugs actually have a therapeutic effect on patients track that effect”. - Nasha (CareTalk)

Promising Benefits and Advancements in Rare Disease Research

Advancements in rare disease research hold great promise for patients and families affected by these conditions. With the development of technologies like genome editing and CRISPR-Cas9, scientists now have unprecedented insights into the underlying genetic causes of rare diseases. This knowledge is driving the development of targeted therapies that can address these causes at their source, offering hope for improved outcomes and quality of life.

Additionally, advances in diagnostics and data sharing are enabling more accurate and rapid identification of rare diseases, reducing the time to diagnosis and improving access to appropriate care. Despite its many challenges, the benefits of this research are immeasurable. By understanding the underlying biological mechanisms of rare diseases, researchers can shed light on basic biological processes, leading to the development of new diagnostic tools and therapeutic options for patients with rare and common diseases alike.

Furthermore, rare disease research has the potential to uncover novel drug targets and biological pathways, ultimately contributing to a deeper understanding of human health and disease. As the field of rare disease research continues to grow and evolve, we can expect to see even more promising developments on the horizon.

“There’re ways that we need to think about innovative trial design. The good news is that there are a lot of companies innovating in the space. A lot of organizations looking for better endpoints, better biomarkers and the FDA is open to listen and so, and I think the F D A basically needs to be convinced”. - Nasha (CareTalk)

How Can Improvements in Rare Disease Research Help Unlock Cures and Treatments for Other Diseases?

Looking ahead, proactive research into rare diseases holds great potential for medical advancement. While it is impossible to predict the exact outcome of such work, the promising results call for greater investment and collaboration across institutions. As breakthroughs in rare disease treatment hold potential implications far beyond their specific clinical application, there is tremendous potential to unlock cures that may be applicable to a broad range of unexplainable illnesses.

By taking the time to further invest in research on these rare diseases and collaborating with multiple resources and experts, we can help find ways to ease suffering for many and better understand why certain treatments work or don’t work. It is our hope that increased access to research opportunities will bring about great advances in medicine that make these mysteries a thing of the past.

FOXG1 Research Foundation Co-Founder, CEO Nasha Fitter joins CareTalk Podcast to shed light on the importance of rare disease research, the challenges it faces, and the promising developments in this field.

Listen to this episode on Spotify Here

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CareTalk is the only healthcare podcast that tells it like it is. Join hosts John Driscoll (President U.S. Healthcare and EVP, Walgreens Boots Alliance) and David Williams (President, Health Business Group) as they provide an incisive, no B.S. view of the US healthcare industry.

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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

Dallas Morning News: Where is Former American Airline CEO Tom Horton? Raising Awareness for a Rare Genetic Condition.

Horton jumped into the campaign to raise awareness for the rare FOXG1 syndrome after his infant granddaughter was diagnosed in 2020.

By Kyle Arnold – The Dallas Morning News

Former American Airlines chief Tom Horton watched from his second home in New York in March 2020 as the aviation world ground to a near-halt when the emerging coronavirus spread from Asia to the United States and across the globe.

Among Horton’s guests were his son Zach, Zach’s wife Courtney and their newborn daughter, Gianna. But as the pandemic wore on and the aviation industry struggled to find its footing, the Hortons were distracted by Gianna’s early-life progress.

“It was evident to all of us that she was just sort of missing critical milestones,” said Horton, whose primary residence is in North Texas. “She doesn’t scoot around and crawl, and she’s nonverbal but very happy and engaged with everyone that she’s around.” 

It was those early pandemic months, isolated from much of the world, that would eventually put Horton and his tiny granddaughter front and center in an emerging mysterious genetic condition known as FOXG1 syndrome that may have key links to other issues such as autism, schizophrenia and Alzheimer’s.

At the time of her diagnosis, Horton’s granddaughter was only the 800th person in the world verified to have the disorder, and only about 50 more have been added to that list since. FOXG1 is actually a gene present in all humans that helps direct early development brain function and motor skills. Children with FOXG1 syndrome display some common complications, such as developmental delays, along with difficulties eating, speaking and walking. Only now, after 19 months, can Gianna sit up without assistance, a milestone most children hit around 6 or 7 months of age.

In fact, the disorder is so new and so rare that there is little research into FOXG1 syndrome or the potential drugs that could be used to treat people with the disorder.

Tom Horton, now 60, is familiar with tough battles. In 2011, after a 25-year career at American Airlines in finance, he was named CEO and then the next morning had to place the historic Fort Worth-based air carrier with 100,000 employees into bankruptcy. It was a situation that ultimately ended in Horton’s departure as CEO two years later when the airline merged with US Airways.

In the seven years after stepping back from American Airlines, Tom Horton has kept a mostly low profile, working in consulting and sitting on three corporate boards, including Qualcomm, General Electric and Walmart. Most recently, he has taken a position with a private equity firm in New York called Global Infrastructure Partners that has ownership in airports and other aviation-related businesses.

 Then, in May 2021, Horton and his bubbly redheaded granddaughter appeared in a YouTube video for the FOXG1 Research Foundation, trying to raise money to get existing pharmaceuticals into testing for treatment of people with the genetic disorder. Horton put up $1 million of his own money and started reaching out to his contacts in the business world to do more.

“The last three years have really been focused on the basic science to understand from a biological level how this syndrome presents in children,” said Nicole Johnson, executive director of the FOXG1 Research Foundation, whose daughter was one of the earliest diagnosed cases of FOXG1 syndrome. “And now we’re moving into translational science where we can actually start testing potential therapies in models and see if we have any potential treatments.”

Johnson said it’s an exciting time for research into genetic diseases. A team of scientists won the 2020 Nobel Prize in Chemistry for research into CRISPR gene-editing technology. Global teams of scientists were able to develop a handful of COVID-19 vaccines in less than a year in response to the global coronavirus pandemic.

Those kinds of technologies could help develop treatments for FOXG1 syndrome, but only if there is money and attention to do so, Johnson said.

“I think we’re at an amazing moment in history, and I really think there’s an opportunity for meaningful change,” Horton said.

As for the airline industry and his former employer, Horton said he keeps close tabs, especially during the turmoil of the last year.

“It’s extraordinary what they’ve been through,” he said. “I think it really speaks to the resilience of the people that work at these companies and lead them that they’re recovering the way they are.”

FOXG1 Research Foundation to Pioneer a Machine Learning Approach to Accelerate Rare Disease Research with Support From the Chan Zuckerberg Initiative

FOXG1 RESEARCH FOUNDATION is the latest CZI ‘Rare As One’ Partner.

READ NEWS HERE

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The First FOXG1 Scientists Symposium - A Recap.

The first FOXG1 symposium was a tremendous success in bringing together scientists from around the world who are interested in research around FOXG1 to collaborate with one another to find a cure. Scientists from Japan, Australia, Italy, the UK, the US, and more, presented and held deep-diving sessions to discuss what we know and what we need to know to drive research for FOXG1 syndrome.
We strategically chose to register this symposium with the Society of Neuroscience Conference, which attracts 30,000 delegates from around the world in San Diego, California. SfN and San Diego proved to be the perfect choice for this fortuitous event!

One of the most exciting things we learned is that FOXG1 is expressed also after birth and well into adult lives. This means that finding a therapy has potential to stop or improve certain symptoms.

We opened the symposium with a video from some FOXG1 kids and their parents saying thank you to the scientists for dedicating their work to finding answers about FOXG1.

The symposium kicked off with Dr. John Mason from University of Edinburgh and co-author of Building Brains - giving a short history of FOXG1, and it’s previous name - Brain Factor 1. He discussed the current mechanistic understanding of FOXG1 gene action and ideas around biomarkers that could be identified for FOXG1 syndrome.

John Mason PhD Univ. of Edinburgh

Dr Soo-Kyung Lee shared her work that two copies of the FOXG1 gene within the brain’s neurons are critical for the proper development and mapping of the brain in utero. She also showed that missing one copy of FOXG1 in neurons made the corpus callosum thinner and shorter than that of a typical brain. These findings were recently published in Neuron. This cover is a fantastic representation of her work.

Dr. Lee is in a very unique position being a lead scientist for FOXG1 Research and also being a mom of a child (daughter Yuna) with FOXG1 syndrome.

Dr. Soo Kyung-Lee OHSU

Dr. Lee is experimenting on various available FOXG1 mouse models to answer questions around which symptoms can be relieved if the FOXG1 gene mutation is fixed at various time points. She spoke about early results of FOXG1’s role in cell death. Dr. Lee additionally discussed a collaboration to use AAV9 gene therapy to normalize the FOXG1 gene dosage with scientists Dr. Guangping Gao and Dr. Dominic Gessler.

Dr. Guangping Gao and Dr. Dominc Gessler

Dr. Dominic Gessler - Univ. of Massachusettes

Dr. Gessler spoke to the audience on the work they have done to cure Canavan Disease. We were so inspired to learn that by using AAV9-mediated gene therapy, they found that all mouse symptoms were reversed. One family asked Dr. Gao to admit their child into a single-child clinical trial using FDA’s Compassionate Care Use Case guidelines at the University of Massachusetts. In 2017 the trial started. After about 2 weeks they started seeing symptoms begin to reverse! The success of this early trial enabled their work to be licensed by BridgeBio Pharma.

Turning our attention to industry, Michael Pettigrew, Director of Asset Acquisition from BridgeBio Pharma spoke to attendees on the data needed before a biotechnology company makes an investment to take a disease therapy forward into clinical trials. Understanding downstream effects, strong genotype-phenotype correlation, basic biology of the disease, time periods when disease can be cured is all necessary information.

Dr. Antonello Mallamaci - PhD SISSA Italy

These questions Michael Pettigrew discussed, that are critical for biotech investment, were discussed at length by Dr. Antonello Mallamaci, who runs The Laboratory of Cerebral Cortex Development in SISSA, Italy.

For example, Dr Mallamaci’s experiments show that various FOXG1 missense mutations are showing a gain-of-function response. This means these mutations could require different therapies than those showing a loss-of-function like gene deletion, nonsense or various truncation mutations. Dr. Mallamaci shared data on his learnings around the role of FOXG1 in diverse cellular contexts in forebrain development, including astrocytes, and inhibitory and excitatory neurons.

Similarly, Dr. Flora Vaccarino from Yale Medical School discussed how her work, looking at brain organoids, is showing that overproduction of inhibitory neurons is caused by FOXG1 over-expression.

FOXG1 may directly or indirectly regulate its own levels through a negative feedback mechanism. Dr. Vaccarino is also researching if FOXG1 syndrome differs in females versus males and what downstream genes are affected by the FOXG1 gene.

Dr. Flora Vaccarino - MD Yale School fo Medicine

Dr. Fabien Delerue who came from Australia spoke about his work to introduce FOXG1 mutations in mouse models. Dr. Tanja Vogel from Germany spoke about a novel mechanism of FOXG1 action involving RNA-binding proteins.

Dr. Alessandra Renieri from University of Siena in Italy discussed early experiments around using CRISPR to fix FOXG1 mutations in patient derived stem cells.

Dr Fabien Delerue -PhD Macquaire Univ.

De Tanja Vogel - PhD Univ. of Frieberg

Dr. Alessandra Renieri - MD, PhD Univ. Sienna, Italy

Dr. Corrine Houart - PhD King’s College London

We also learned that FOXG1 syndrome can be modeled in Zebrafish. Dr. Corrine Huoart from King’s College London shared her work on the previously unknown relationship between ASPM and FOXG1 genes.

She found that FOXG1 is downregulated when ASPM is affected. FOXG1 requires ASPM - they form a complex together. She shared ideas around modeling FOXG1 syndrome in Zebrafish and to use Zebrafish as a high throughput platform to screen small molecule drugs and learn about FOXG1 at a cellular level.

Dr. Goichi Miyoshi - PhD Tokyo Women’s Medical Univ.

We heard from Dr. Goichi Miyoshi who came from Japan on FOXG1’s role in Autism.

Various mouse experiments showed that FOXG1 deletion in specific neurons in mice tended to make these mice avoid social interactions. His experiments will help create a behavioral guide that other scientists can use when phenotyping FOXG1 syndrome in animal models.

Dr. Roberta Cilio - MD, PhD Univ. of Louvain

Dr. Roberta Cilio joined us all the way from University of Louvain in Brussels and spoke about the importance of identifying clinical endpoints that really measure a patient's improvement in symptoms. Dr. Cilio stressed the importance of this information long before even designing a clinical trial and pushed scientists to think about clinical endpoints when devising experiments in animals.

The first FOXG1 Symposium brought together an array of basic scientists, gene therapists, and clinicians focused on FOXG1 syndrome.

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Zach Horn, Rockefeller University Hourinaz Behesti , PhD
Developmental Neurobiologist, Rockefeller University, Nasha Fitter, Co-Founder FOXG1 Research Foundation, Alyson Mourti UCSD Associate Professor of Cellular & Molecular Medicine,

The symposium also brought together parents of FOXG1 affected children from all over the world. Over the course of three days in San Diego, we were able to share our experiences and build a plan to work together to raise awareness, help more parents, and fundraise for projects along our Path to a Cure.

FOXG1 Research Worldwide Team and Scientists

We held a special Parents and Scientists meeting / Q&A

The most special guest visit came from these amazing local San Diego FOXG1 sisters and parents!

Emma & Ali Wells!

And while the symposium was the main event, our team held back-to-back deep diving sessions with scientists for three days.

UCSD

This was just the first FOXG1 symposium for scientists to collaborate. We are looking forward to the progress we will see when we meet again next, and to the new scientists who will join us next time. The phrase we kept talking about is “beyond measure” - as it goes with research, the work we are doing will benefit the blueprint of human life beyond measure.

Everything we learn, every layer we peel away, will help us get closer and closer to the core of our goal - to cure every child today and in the future who is born with FOXG1 syndrome, and potentially help many other disorders. The potential is simply beyond measure.

FOXG1 Research Foundation Co-founders Nasha Fitter and Nicole Johnson