2022 marked five years of the FOXG1 Research Foundation.
Our work brings us closer to successful therapeutics for every child, while supporting families along this difficult journey. We continue to be one of the most innovative foundations in the rare disease space, focused on three equally critical areas: FOXG1 science, FOXG1 patient data, and FOXG1 patients and community. From gene therapy to rescuing a FOXG1 family in the Ukraine, this year marks our biggest breakthroughs in all three areas.
Our greatest purpose is to end the suffering of children with this terrible disease. Our community is mourning the loss of 11 children in 2022/23 alone. We must stop this from happening. We are grateful for this incredible team working collectively to advance this goal, and to our donors who enable this work.
2022 Research Highlights (see details below)
Breakthrough gene therapy results showing rescue of FOXG1 brain structure, behavior, memory and cognition symptoms in animal models
Positive results on initial compound drug screens to identify molecules to increase FOXG1 levels; now moving forward to larger screens
Never-before understanding of FOXG1 biology uncovered from six FOXG1 patient human cell lines and mouse models
Successful testing of guide RNAs to increase FOXG1 expression with a CRISPRa Cas-9 system
Discovered ASO sequences (antisense gene therapy) to modulate FOXG1 expression; testing initiated with Creyon Bio
FOXG1 data package presented to several biotech companies with high interest
2022 Foundation Highlights
Hosted first-ever FOXG1 Syndrome Parents Conference (in-person and virtual) with parents, families, clinicians, scientists from all over the world
Hosted third FOXG1 Syndrome Science Symposium (in-person and virtual) with a consortium of global scientists collaborating on the path to a cure
Publishing first 100 patient natural history study of FOXG1 syndrome patients
Launched successful rescue operation of FOXG1 family trapped in the Ukraine; created fundraising campaign to help rebuild their lives in Poland
Asked to speak on multiple podcasts and industry events, continued to be called “innovators” and “leaders,” assisting many other rare disease foundations
Launched FOXG1 Research Foundation España
Raised over $1,000,000 globally in 2022 ($6M to-date)
2022 Funding and Research Details (View Research Projects)
Gene Therapy:
Breakthrough AAV9 gene therapy preclinical trial results with two promoters that successfully rescue FOXG1 brain structure, behavior, memory and cognition symptoms in animal models. Next step is toxicology studies as we begin an IND application. If successful, we will be in clinical trials within two years
Further testing of additional promoters at the Lee Lab - FOXG1 Center of Excellence that may more-effectively drive FOXG1 in specific cells
Funding Dr. Goichi Miyoshi at Gunma University Graduate School of Medicine to identify cells and circuits responsible for the manifestation of FOXG1 Syndrome in the brain and test a specialized rescue strategy
Initiated the development of a “rescue” mouse model to be used to determine the cell types and timelines that are key to restoration of FOXG1 symptoms
RNA Therapies
RNAi/a therapies - Identified multiple sequences and conducted experiments that both upregulate and downregulate FOXG1 gene expression via RNAa and RNA mechanisms in human neurons. Now stabilizing sequences and testing for efficacy and toxicity in additional patient derived human stem cells and animal models. If successful, we are within 3 years of clinical trials
ASO therapies - Identified a group of ASO molecules that upregulate FOXG1 gene expression. Using a proprietary platform, we are testing these ASO’s to find the most optimal ones. If successful, we could be in clinical trials in 2024
Drug Repurposing and Label Expansion
Screening of 4,000 compounds to increase FOXG1 expression led to 40 FDA-approved drug candidates found through Rarebase neuroscience platform
Screened ~150 small molecules on our zebrafish platform
Created neuronal assets and investigated several neuronal platforms, screens to start within next few months
Initiating c-elegans genetic screen in FOXG1 worm models to identify pathways that can compensate for the loss of FOXG1
CRISPRa Therapy
Identified a number of lead sgRNA and dCas9-effector combinations for upregulating FOXG1 expression in HEK293 cells, healthy NSC, and in patient iPSC-derived NSC
Next steps are to check for potential off-target effects and ability to rescue neuronal phenotypes before embarking on toxicity studies to assess if this is an effective modality for FOXG1
Genetic Model Characterization Work
Analyzed brain structure and behavioral deficits in three mouse models, developed insight into impact of DNA binding affinity; continuing to research additional models and publication underway
Confirmed the presence of FOXG1 mutations and otherwise normal chromosomal composition in six patient iPSC lines; seeing protein expression changes
Funded Dr. Jeanne Paz at Gladstone Institute to characterize the electrophysiology and seizures in our mouse models. This will identify where in the brain seizures are forming as well as identify any unique brain signatures
Confirmed the formation of smaller brain organoids from two patient lines compared to healthy controls
FOXG1 Patient Data
Enrolled >100 children and adults with FOXG1 syndrome into our natural history study, hosted on the Ciitizen platform, the most comprehensive and innovative natural history study for FOXG1 syndrome patients
Longitudinal medical record collection for all participants, averaging ~1200 pages of data from ~5 institutions, per participant - this totals 618 years of data reviewed
Uncovered information on demographics, comorbidities, common medications, exam findings, therapeutic procedures, developmental milestones; data will assist in identifying primary and secondary endpoints in clinical trials
Two years of FDA validated surveys completed by the first 50 participants, evaluating developmental milestones, behavior, and sleep
Three breakthrough manuscripts in preparation that include clinical data about FOXG1 syndrome
Continued to build global FOXG1 Patient Registry encompassing ~500 unique patient mutations
FOXG1 Research Models / Assets Created
6 human stem cell lines and 16 patient fibroblasts containing unique mutations available in FOXG1 Coriell global repository
Five CRISPR corrected patient stem cells stored in FOXG1 In-House Cellular lab
Inducible rescue mouse line underway at Lee Lab - FOXG1 Center of Excellence
5+ patient mouse models being characterized and stored at Lee Lab - FOXG1 Center of Excellence; publication underway
Accessible raw patient survey and natural history data available at FOXG1 Data Center and Ciitizen
2023 Goal: Drive the science to clinical drug development
Continue progress towards clinical trials for gene therapies
Accelerate each project by funding additional post-docs; continue funding scientific team
Fund further understanding of FOXG1 symptoms, such as electrophysiology characterization in mouse models
Compile arsenal of repurposed drugs that can be prescribed by individual physicians
Continue to expand upon patient registry and natural history study work
Raise reserves for clinical drug development
Partner with biopharma to include FOXG1 syndrome in their pipelines
Host continued parent and science conferences
Be there for our community through resources, encouragement and love
Funding:
FOXG1 Research Foundation 2022 Source of Funds
