November 2020 Research Update : Creyon Bio Takes on FOXG1 for ASOs!

We are so excited to deliver this Research Update during FOXG1 Awareness Month! 

1. Two Biotechs are investing in FOXG1 syndrome!  

2. We’re moving into Phase Two and Phase Three of our Path to a Cure!

1. We have Multiple Biotech Investments in FOXG1!

When we launched The FOXG1 Research Foundation in 2017, our goal was to develop the science needed for biotech companies to take us on. As a result of our investments made in developing patient-derived stem cell models, animal models, developing rich patient data, and having amazing community support, we were able to attract the world class talents of Taysha Gene Therapies and Creyon Bio to work on FOXG1 syndrome!

Taysha Gene Therapies: We’re thrilled to announce that Taysha Gene Therapies is developing TSHA-117 for FOXG1 Syndrome. Because the condition requires replacement of dose-sensitive genes, one investigational approach the company plans to explore is using its novel miRNA target panel, which is designed to enable the product candidate to maintain safe transgene expression levels in the brain.

Taysha is focused on developing AAV-based gene therapies specifically for monogenic CNS diseases. Dr. Sarah Sinnett at UT Southwestern leads the FOXG1 syndrome pre-clinical program. In addition, Dr. Sinnett and Dr. Steven Gray, also at UT Southwestern, are working on developing novel approaches for Rett syndrome. Read the announcement here.

Creyon Bio for ASO therapy: ASOs or “antisense oligonucleotides” are an exciting disease-modifying therapeutic approach showing real results in the Angelman and Batten Disease communities.
We are honored and excited to announce a partnership with Creyon Bio to explore and hopefully advance new oligonucleotide based therapeutics for the treatment of FOXG1 syndrome. Creyon Bio is focused on making new gene-centric medicines affordable and rapidly available to patients globally.  Creyon Bio is adopting advances in computational chemistry, biophysics and ML/AI to build a scalable platform that will transform the way oligonucleotide-based medicines (OBMs) are created. The Creyon team brings decades of experience in quantitative biology, genomics and OBM development and is excited to forge a strong collaboration with the FRF Science Team, including Dr. Alysson Muotri, Dr. Soo-Kyung Lee and others. 

NOTE: The collaboration described herein is subject to the negotiation and execution of definitive legal documentation by FOXG1 Research and Creyon.

2. We’re right on trajectory along the Path to a Cure!

Thanks to all of your help, we were able to create the necessary models to understand FOXG1 syndrome as planned. We have successfully:

• funded and developed FOXG1-specific mouse models 

• created a biobank of FOXG1 patient skin and blood samples, which we were able to turn into Induced Pluripotent Stem Cells and Mini Brain Organoids.

This took a long time, and we have all been patiently (sort of) waiting to get to the fun part. 

Now, we start Phase 2 and 3: Studying and Screening Drugs and Therapies on these models. 

What are we studying?

• How FOXG1 mutations affect brain circuits, different brain cells and human biology. What can we target to cure our children?

• What downstream genes are affected by FOXG1; are any of them fixable?

• What biomarkers can we find to test drugs against? Can we connect these biomarkers to clinical endpoints in our children? 

• When we screen drugs, how do they affect protein expression, functional assays and downstream targets?

What are we screening? 

• Small molecule drugs. Here’s a success story in a similar disease.

• Antisense therapies. Here’s a success story in a similar disease. 

• Gene therapies. Here’s a success story in a similar disease. 

We are also converting Astrocytes to Neurons:

In this breakthrough discovery, scientists at UCSD found a fairly simple way to convert astrocytes into neurons. These scientists were further stunned to see that when this treatment was given to Parkinson’s mice, movement disorder symptoms reversed and did not come back for the entire life of these mice. We know that FOXG1 syndrome leads to neuronal death and thus increasing the amount of neurons could reverse major symptoms. Dr Alysson Muotri, whose lab is luckily at UCSD, will be collaborating with these scientists to conduct similar experiments on FOXG1 astrocytes and brain organoids. 

Our goal in 2021 is to find both short-term drugs we can give our children today, as well as longer term solutions like ASO’s, gene therapies and other novel and emerging therapies. 

We’ve assembled a top tier FOXG1 Science Team to collaborate to achieve these goals:

High Throughput Screening

1. Houart Lab, King's College  - High throughput screening of small molecules on zebrafish 

2. Stemonix - A contract research organization conducting high throughput screening of small molecules, vitamins and herbs on neurospheres

3. Bedwell lab, University of Alabama - Screening ~200 primary, validated, non-cytotoxic hits to suppress nonsense mutations in cell lines

Targeted Screening (low-throughput)

1. Muotri Lab, UCSD - Screening of small molecules, antisense therapies, RNA therapies and gene therapies on neurospheres, IPS lines and organoids. Also characterizing/phenotyping these models

2. Lee lab, University at Buffalo - Screening of small molecules, antisense therapies, RNA therapies and gene therapies on mouse models. Also characterizing/phenotyping these models

3. Malamaci lab, SISSA - Developing RNA therapies for screening on IPS lines and mouse models 

1. Creyon Bio - Developing targeted antisense therapies to screen on organoids and mouse models

2. Meyer lab, Nationwide Childrens - Developing gene therapy approaches and new in vitro model systems; screening small molecules and looking at the mechanisms (protein expression, downstream targets) on IPS lines and mouse models

The collaboration within this esteemed team of scientists and labs will enable us to find a basket of solutions to cure FOXG1 syndrome.

WE NEED ALL HANDS ON DECK TO FUND THIS SCIENCE NOW!

We’re often told that we have accomplished more in these last three years than most organizations do in ten. As a community, we all pulled together and raised nearly $2 million to launch the critical Phase One projects. We couldn’t have done this without everyone’s fundraising support. 
Now, it’s time for our next push - we need to raise another $1.5 million in the next six months to screen and test potential therapies. We need all hands on deck to come together and move mountains for our children. Here are a few things you can do:

• Please donate here. 

• Ask your friends and family to help us reach this important goal

  • We’ve added the option to Donate Stock

• Buy your holiday presents at our store (more items coming very soon!).

• Create a Facebook fundraiser. Let followers know we need all hands on deck to get to clinical trials! 

  • If you can, offer to MATCH donations up to an amount.  

• Buy toys and all special needs items for children through our Amazon Affiliate program on our website.

• Go to smile.amazon.com every time you make any purchases on Amazon and set FOXG1 Research Foundation. Tell your friends and family to do this too! 

Thank you for supporting us on this journey.

And stay tuned as we have more exciting announcements coming this month!!

With much gratitude,

The FOXG1 Research Foundation Team

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

The FOXG1 Science Symposium 2020 - Recap

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