Funded Research Projects
Research Projects Funded by the
International FOXP1 Foundation in 2024
Joseph Buxbaum, Seaver Autism Institute, Mt. Sinai Hospital
Three-dimensional Organoid Model of FOXP1 Syndrome ($50,000)
The ultimate goal of this project is to develop an in vitro medium-to-high throughput
assay for screening of compound libraries. The “hits” from such a screen will be defined as compounds that “normalize” the FOXP1 organoid phenotype in a dose-dependent manner. While there is no obvious mechanistic or functional link between the organoid phenotype and the clinical presentations, it is reasonable to assume that changes in organoid development reflect changes in brain development and that utilizing organoid phenotypes validated in patient-derived cell lines carrying clinically-relevant mutations will ensure identification of potential drug candidates. This approach is in line with the current industry standards for development of the high-throughput screening assays. These drug candidates (hits) will be further validated in a number of in vitro and in vivo assays to validate preclinical efficacy and provide more mechanistic insight.
Genevieve Konopka and Jay Gibson
Functional restoration of FOXP1 haploinsufficiency using AAV-mediated gene rescue in the brain ($73,274)
Understanding FOXP1 function in the mouse brain is crucial to develop effective therapeutics for FOXP1 syndrome in humans. In this project, we will use a mouse model that mimics the genetic basis of many forms of FOXP1 syndrome, where only one out of the two functional copies of FOXP1 gene is present. We will perform intracerebroventricular (ICV) injections of a unique adeno associated virus (AAV) called AAV9 and/or its modified and improvised version (AAV-PHP.eB) at an early developmental stage to restore FOXP1 expression in the brains of these mice. In this strategy, FOXP1 will be re-expressed under the control of the human synapsin 1 promoter, ensuring neuron specific expression. We will then examine whether FOXP1 gene replacement can correct behavioral deficits in the mice. If successful, we will extend the gene restoration to later developmental time points to determine a potential critical window of gene replacement therapy in this mouse model. Results from this project should provide fundamental knowledge about the feasibility of FOXP1 gene therapy in humans and form the basis for future clinical trials.
Paige Siper, Seaver Autism Institute, Mt. Sinai Hospital
FOXP1 Qualitative Assessment and Clinical Global Impression Scale Development ($69,772)
Clinical trial readiness is a key priority for families affected by FOXP1 syndrome.
Clinical Global Impression (CGI) scales are one of the most commonly used clinical trial endpoints, and syndrome-specific versions have been developed in other neurogenetic disorders. To date, there are no existing tools to effectively measure
treatment response in individuals with FOXP1 syndrome. The Seaver Autism Center will carry out a comprehensive research study, funded by the International FOXP1 Foundation, to quantify key parental concerns at different ages. This information will then be used to create a FOXP1 syndrome CGI for use in future clinical trials.
Henning Fröhlich, Gudrun Rappold, and Julia Ladewig, University of Heidelberg
Testing a potential treatment for FOXP1 syndrome in striatal organoids derived from individuals with pathogenic FOXP1 variants ($62,400)
Dr. Fröhlich and Prof. Rappold at the Institute of Human Genetics in Heidelberg, Germany have discovered that murine Foxp1 haploinsufficiency leads to mitochondrial dysfunction in the striatum and altered expression of striatum-specific phosphodiesterase 10A (PDE10a), an enzyme that plays a crucial role in the regulation of basal ganglia circuits. Specific inhibition of PDE10a with MP-10 significantly improved the existing behavioral deficits in these animals. Working with organoids has significant implications for a safe and humane testing of new drugs, particularly when organoids are grown from a patient's own cells. In the planned project, iPSC lines derived from FOXP1 patient and control cells will be used and differentiated into striatal organoids to investigate whether mitochondrial dysfunction and PDE10A dysregulation can also be found in human cells. In addition, it will be analyzed how the administration of MP-10 affects gene expression and signaling pathways in striatal medium spiny neurons and whether the drug improves mitochondrial function.