Determining Genetic Bases of Differential Response to Antipsychotics Using Patient-Derived Neurons

Project Information

MapGen

Grant agreement ID: 101065629

DOI

10.3030/101065629

Project terminated on 16 June 2025

EC signature date 7 December 2022

Start date 1 January 2023

End date 31 December 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 307 939,68

Coordinated by

HELSE BERGEN HF
Norway

Periodic Reporting for period 2 - MapGen (Determining Genetic Bases of Differential Response to Antipsychotics Using Patient-Derived Neurons)

Reporting period: 2025-01-01 to 2025-12-31

Summary of the context and overall objectives of the project

Schizophrenia (SCZ) remains a major public health concern, partly due to the variable efficacy of current antipsychotic treatments. Not all individuals experience relief from standard medications, resulting in prolonged illness and considerable social and economic burdens. Motivated by these challenges, our project seeks to uncover the genetic factors and cellular mechanisms that drive this differential treatment response. By focusing on rare genetic variants linked to non-responsiveness, we aim to devise precision medicine approaches that could revolutionize therapeutic strategies for SCZ.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

1. Establishment of Human Cortical Organoids: We successfully generated 3D human cortical organoids from induced pluripotent stem cells (iPSCs), creating a physiologically relevant model for studying the cellular basis of schizophrenia (SCZ).
2. Implementation of a Pooled CRISPR Screening Approach: Guided by large-scale genomic studies, we introduced rare de novo variants into our organoid model, targeting genes strongly associated with treatment-resistant SCZ. A pooled CRISPR library was designed to systematically knock out these candidate genes, providing a comprehensive view of their effects on neuronal maturation and function.
3. Optimization of Antipsychotic Treatment Conditions: Using multi-electrode array (MEA) recordings, we determined the optimal concentrations of clozapine and its active metabolite (N-Desmethylclozapine) that induce measurable electrophysiological changes in the glutamatergic neurons.
4. Long-Term Culture and Sample Collection for Single-Cell Analysis: Organoids were cultured to 180 days to achieve enhanced cellular maturity, closely approximating mid-fetal human brain development. This workflow sets the stage for single-cell RNA sequencing (scRNAseq) to dissect cell-type-specific transcriptomic changes.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Refined Disease Model and Expanded Knowledge Base: By integrating a pooled CRISPR screening approach into long-term human cortical organoid cultures, we have established a high-fidelity disease model that captures the cellular diversity and complexity of the developing human brain. Preliminary analyzes indicate that treatment of glutamatergic neurons with clozapine results in measurable alterations in neuronal firing patterns, shedding light on the molecular and electrophysiological underpinnings of treatment resistance.
Advancement Toward Personalized Therapies: The identification of gene-specific effects on drug responsiveness enables the development of more targeted antipsychotic therapies. This work has the potential to reduce the trial-and-error process currently experienced by patients and clinicians, fostering improved patient outcomes and cost savings in healthcare systems.
Further Direction: Continued functional assays—including single-cell transcriptomics—will be essential for pinpointing the exact mechanisms of action for each genetic variant.