A High throughput Organoid Platform for drug discovEry (HOPE) for rare genetic brain disorders: FOXP1 syndrome as a use case

Our project will use FOXP1 syndrome as example to build a drug discovery platform together with Pimbio using novel state of the art Chips and striatal organoids from induced pluripotent stem cells. FOXP1 syndrome has as main features intellectual disability and, speech and language deficits. We will test 3 therapeutic modalities ranging from low to high-throughput. We will initiate clinical trial readiness by selecting patient relevant endpoints to contribute to personalised treatments and novel therapy development for FOXP1S patients.

Approximately 6%–8% of the European population have a rare disease and for very few there is a therapy. There are mostly no animal models available to develop and test novel treatments. Our HOPE platform will be of immediate use for all personalised drug development programs, is adaptable to any genetic brain disorders without the need for animal research.

We will first develop novel chips that allow for standardized high-throughput culturing of FOXP1S striatal organoids. We will validate our previously established FOXP1 phenotype and extend this with in-Chip functional and morphological measurements such as neuronal network analysis and 3D structural analysis. We will use this system to test 3 therapeutic modalities ranging from low throughput (1 novel drug with a known molecular target) to medium throughput (5 drugs currently in use for FOXP1S) to high-throughput (library containing 665 drugs approved for children). By linking the outcomes from our HOPE FOXP1S organoid chip to initiation of clinical trial readiness by selecting patient relevant endpoints, we aim to contribute to personalised treatments and novel therapy development for FOXP1S patients.

We have outlined the following deliverables for this project:.

• The development of Proof-of-concept devices for a novel HOPE platform for culturing and screening striatal organoids. The platform must be adapted to academic and industrial needs such as: 1) high reproducibility; 2) automation; 3) scalable to desired throughput level; and 4) transferability to existing manufacturing, workflow and lab equipment.
• Using our previously established striatal organoid model of FOXP1S and to test various different drugs for their ability to reverse the FOXP1S disease phenotype.
• Preparing for a multiple n-of-1 clinical trial in individuals with FOXP1S by selecting outcome measures for the most clinically-relevant symptoms of FOXP1S.