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HEIndividual fellowship2023–2025

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

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-01-01 → 2025-12-31
EU contribution
€307,940
Participants
2
Scheme
HORIZON-TMA-MSCA-PF-GF

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Results in brief

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

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.

Data: CORDIS, © European Union

Project objective

Schizophrenia (SCZ) affects 20 million people worldwide and antipsychotics remain the only effective pharmacological intervention. However, one-third of people with SCZ do not respond to first-line antipsychotic drugs. In the absence of clinical biomarkers to stratify SCZ subtypes, all individuals receive the same initial intervention, and it takes >4 years on average before people with resistant forms of the condition receive suitable treatment.My overall aim is to unravel the pre-symptomatic cell-type-specific genetic circuits contributing to differential treatment response in SCZ. To achieve my aim I will use an interdisciplinary approach that improves my technical and soft skills and further extends my international network through a two-year stay at Yale University, and three months secondment at Harvard Medical School. During the return phase, I will establish myself as an independent researcher and a suitable candidate for leadership of a to-be-established stem cell lab at the host institute.Objectives are (O1) to identify cell-type-specific neuronal pathways associated with distinct neurotransmission imbalances in each SCZ subgroup using a human-based neurodevelopmental model. (O2) To determine the functional link between SCZ-associated risk variants and response to antipsychotics.Method: I will couple advanced stem cell models (region-specific brain organoids) with single-cell RNA sequencing to generate cell-type-specific transcriptomic profiles of patient-derived brain organoids from treatment-responsive and treatment-resistant forms of SCZ. I will integrate the potential risk variants from SCZ-GWAS and use published functional genomics data to determine the genetic pathways and associated regulators implicated in the etiopathophysiology of differential response to antipsychotics.Impact: identify distinct genetic makeup for each SCZ subgroup to serve as potential predictive biomarkers and points of therapeutic intervention.

Original text from CORDIS.

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Data: CORDIS, © European Union