On August 17th and 18th we held the FOXG1 Science Symposium 2020 as a virtual event rather than at the University at Buffalo as originally planned. While we missed the chance to gather together in person, the silver lining was an audience that far surpassed our expectations with more than 300 attendees. 

It was a truly remarkable event, with new and rich data and a growing consortium of scientists, industry executives, caregivers, and more all focused on the path to disease-modifying therapies for FOXG1 syndrome.

Much of the content, including Q&A sessions, is available to watch here. Please note that we’ve extracted most of the presentations due to sensitive unpublished data. 

I kicked off Day One with an overview of The FOXG1 Research Foundation’s singular goal: to find a cure for FOXG1 syndrome for all affected-children globally. We have come a long way since we started in September 2017!

Click on my Welcome to watch an overview of our strategy and research and our new machine-learning Natural History Study.

We pride ourselves from learning from the best rare disease group leaders. Click on the Day One Keynote to watch the presentation by Dr. Art Beaudet on the road taken to find a cure for Angelmans’ Syndrome. 

Our first panel, Clinical FOXG1 Syndrome Phenotypes, shared prepublished data from the FOXG1 Patient Registry that focuses on understanding the spectrum of FOXG1 phenotypes (symptoms) that children experience. We see slightly different symptoms depending on the specific genetic FOXG1 mutation (deletion, missense, etc). Parents on this panel spoke about medical symptoms, developmental symptoms, and behavioral issues that their children are facing. We have submitted a paper with this information for publication in scientific journals titled “Expanding genotype-phenotype correlations in FOXG1 syndrome resulting from a patient registry.”

The following leading clinicians and scientists have contributed to this study: Elise Brimble, MS, Kathryn G Reyes, BS, Orrin Devinsky, MD, Maura Ruzhnikov, MD, Xilma Ortiz-Gonzalez, MD, Ingrid Scheffer, MBBS, PhD, Nadia Bahi-Buisson, MD, PhD, Heather Olsen, MD, MS

We also heard from three different incredible FOXG1 parents whose children represent a spectrum of FOXG1 phenotypes. Greg Wells, Laura Patterson, and Stefani Miles each shared a presentation welcoming us into the lives of thier children. There is truly no greater resource to understand this syndrome than the children themselves. We were all so moved to get to know Ali, Emma, Bo, and Caleb.

Next, we heard from Dr. Soo-Kyung Lee, Dr. John Mason, Dr. Michael C. Yu and Dr. Priya Banerjee on the panel Basic FOXG1 Biology. We heard that the FOXG1 gene is expressed in different cell types in the brain, and the gene is conserved in most animals (most animals have a similar FOXG1 gene sequence to humans), thus we know we can use animal models as a platform to study FOXG1 biology.

Speakers discussed Protein Arginine Methylation and Liquid-Liquid Phase Separation as novel ways to understand FOXG1 gene biology in order to develop treatments. These treatments can help to control FOXG1 protein function. 

We then dove into the panel on FOXG1 Cellular Modeling and heard from Dr. Robin Kleiman, Dr. Flora Vaccarino, Dr. Alysson Muotri and Dr. Aparna Bhaduri.  

There were three main takeaways from this panel: 

1. The level of FOXG1 dosage is critical with clear evidence for different genes being regulated at different doses. This may help in better understanding the variable phenotypic outcome in patients. 

2. Patient organoid modeling is underway and promises to reveal exciting insights into patient-specific biology and enable drug screening. 

3. While organoids are a great resource for modeling the human brain, it’s important to carefully assess the health and differentiation status of the cell types of interest going forward and to make sure there is a healthy representation of what we are trying to model

Dr. Jessica Mariani replaced Dr. Vaccarino for the Q&A discussion, which you can watch here.

Our last panel of Day One defines a true “global conference” with scientists from Tokyo to Texas!  FOXG1 Animal Modeling featured Dr. Rodney Samaco, Dr. Jae Lee, Dr. Goichi Miyoshi and Dr. Corinne Houart.

Early data was shared from the six heterozygous mouse models being developed and our heterozygous zebrafish models. The most important takeaway was early data establishing a clear phenotype (symptoms) from these models versus the control. This is important as it shows these animals will be excellent models for drug testing. This is the first step in drug testing, without a correct model we will not be able to screen anything. We also learned that we can target both the FOXG1 gene directly, as well as factors like excitatory/inhibitory neuronal imbalance. This is important as it gives multiple ways to rescue symptoms for our children. 

When we started the FOXG1 Research Foundation there was no concerted effort to invest in translational research for FOXG1 syndrome. The research, at that point, had been focused on the FOXG1 genes’ role in overall brain development. As a foundation, it is so important that we stay collaborative. Dr. Soo Kyung-Lee and Dr. Jae Lee are part of our FOXG1 family and we are blessed that they continue to engage deeply with all scientists and share their pre-published work. 

Today, we are getting closer to a cure. Over the next two years we will be screening drugs, gene therapies, antisense therapies, and more. One thing that has been made obvious is how complex the FOXG1 gene is, even though it is such a small gene, and how important it is to understand the biology of FOXG1 at a molecular and cellular level. 

This understanding of FOXG1 biology will lead to inventions and ideas. 

Our President, and co-founder Nicole Johnson kicked off Day Two with a personal story about her daughter, Josie and then set up the day’s focus on translational science.

The Day Two opening plenary session was centered on the drug development process for rare diseases. We want to avoid the “valley of death,” where academic ideas get stuck and never make it to market. Luckily the Orphan Disease Act continues to support the development of rare disease drugs. We are thrilled the FDA is so supportive of our work.

Watch the presentations on Getting Orphan Drugs to Market from Dr. Lewis Fermaglich of the FDA and Dr. Diana Wetmore from the Harrington Discovery Institute.

Our first panel on Potential Therapies for FOXG1 Syndrome featured Dr. Yael Weiss, Dr. Antonello Mallamaci, Dr. Soo Lee and Dr. Sylvain Lengacher. Key takeaways are:

1. Across the spectrum of FOXG1 mutations, we are seeing different impacts on protein level, astrogenesis and other activities in the brain. This doesn’t need to lead to different therapies per mutation, but it could lead to different dosage levels and combinatorial approaches.

2. The ideal therapy would be to gene edit mutation defects, but, since off-target effects are still too high of a concern (our children developing brain cancer from a treatment, for example), micro RNA’s could be a way to modulate FOXG1 protein and other levels in the brain. We are seeing success in experiments that microRNAs are increasing FOXG1 protein levels. 

3. We also see that FOXG1 overexpression can cause a FOXG1 syndrome phenotype and this is being studied to assist us in understanding dosage. 

4. Glial cells and brain metabolism are innovative targets for FOXG1 syndrome. Preclinical data shows that  siRNA-mediated down-regulation of FOXG1 in astrocytes dramatically affects brain energy metabolism and small molecule GP-57 could be a drug we use to accomplish this. 

5. In order not to over-activate FOXG1 protein levels and cause more damage, a combinatorial approach can be very important. We may need to stimulate neurons and astrocytes, but by stimulating one cell type we could have an impact on another that would need to be countered. 

As noted, we removed the presentations from the videos, but the panel discussions and Q&A with attendees is available to watch here.

Dr. Soo-Kyung Lee stayed online to moderate the final panel of the symposium with Dr. David Bedwell and Dr. Chris Ahern titled: Potential Therapies for Nonsense Mutations. 30% of our children have nonsense mutations and it is extremely exciting that we have two strong potential therapies on the horizon.

1. The first are readthrough compounds increasing frequency of nonsense codon suppression. We are currently screening this library on FOXG1 HEK293 (kidney cells) and SH-SY5Y (neuroblastoma cells) reporter cells. Successful hits will be further tested in patient derived nonsense stem cells and mouse models. One important aspect of this research is the percentage of suppression we can get by mutation. For this, we need information on how much FOXG1 protein is enough? This is a question our basic science researchers are working on. 

2. The second potential therapy involves repairing stop codons using tRNA gene therapy. Here, we would change the tRNA sequence to suppress stop codons. What we’ve learned is that if repair is robust, 40-80% of wildtype expression can be gained, which is much higher than what a readthrough compound could achieve. While this is exciting, we still need to test all aspects such as understanding if tRNA’s cause other unwanted effects. 

3. The goal may again be combinational - using both tRNA and layering on nonsense compounds for the most effective approach for our children with nonsense mutations

We did not spend time discussing gene therapy and antisense therapy efforts for FOXG1 syndrome. Those are in the preliminary phases and not enough data is present to share. At our next conference in 2021, we plan to have a robust panel on these therapeutic approaches. 

Day Two included two hours of engaging Breakout Rooms for scientists and for parents and caregivers. The conversations could have gone on for hours and we’re looking forward to hosting more of these types of discussions.  

In the meantime we will be sharing updates here on this blog and on our FOXG1 Research Facebook page

Last, none of this work to find a cure would be possible without donations. 80% of our work has been funded by personal donations, and nearly 100% of donations go towards research. Please click here to donate to find a cure for FOXG1 syndrome! We are all on this excting path to a cure together.

Written by Nasha Fitter, FOXG1 Research Foundation CEO, co-founder, and mom to Amara