Using patient-derived human induced pluripotent stem cells (hiPSCs) to interrogate disease mechanisms and treatment in spinocerebellar ataxias

Informazioni relative al progetto

PEDIATAX

ID dell’accordo di sovvenzione: 101023312

DOI

10.3030/101023312

Progetto chiuso

Data della firma CE 16 Marzo 2021

Data di avvio 1 Novembre 2021

Data di completamento 30 Aprile 2023

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 168 700,32

Contributo UE

€ 168 700,32

Coordinato da

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 1 - PEDIATAX (Using patient-derived human induced pluripotent stem cells (hiPSCs) to interrogate disease mechanisms and treatment in spinocerebellar ataxias)

Periodo di rendicontazione: 2021-11-01 al 2023-04-30

Sintesi del contesto e degli obiettivi generali del progetto

Spinocerebellar ataxias (SCAs) constitute a group of rare disorders that lead to progressive loss of motor coordination and movement as well as issues with speech and cognition. Determining their genetic aetiology is challenging due to the large number of genes involved. Furthermore, SCAs are predominantly incurable, and the development of novel treatment options has been hindered by a lack of appropriate disease models. The EU-funded PEDIATAX project proposes to generate human induced pluripotent stem cells (hiPSC) from SCA patients as well as isogenic hiPSC lines using CRISPR/Cas9-mediated genome editing, as a model for studying a SCA that affects children, spinocerebellar ataxia type 29 (SCA29). This early-onset genetic ataxia is associated with a significantly delayed development of motor skills and speech and causes cognitive deficits ranging from learning difficulties to intellectual disability. The pluripotent stem cells are differentiated into three-dimensional models, organoids, of the developing cerebellum to study disease mechanisms involved in SCA29. The research will focus on key factors implicated in the development of Purkinje cells known to play a role in the pathophysiology of SCA. The results will help determine SCA disease mechanisms and pave the way for the discovery of novel treatment targets in SCA29 and several other disorders that involve the mGluR1/IP3R1/TRPC3 calcium signalling pathway.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

In total, the PEDIATAX project has generated 14 human iPSC lines and up to 10,000 cerebellar organoids establishing the first cerebellar organoid-derived disease model of SCA29. Final data analyses are currently being performed so that the dataset is predicted to be published as a peer-reviewed scientific article in 2024. In addition, the project has characterised two clinical patient cohorts: the PEDIATAX cohort of approximately 110 patients with confirmed or suspected cerebellar disorders who have been cared for at the Oulu University Hospital in Northern Finland, and a large international cohort of patients with SCA29 which has helped to standardise the missense variant nomenclature for SCA29 and identify important principles in genotype-phenotype associations within the SCA29 disorder. Finally, the project has produced content for social media including five videos for Youtube, three workshops with different target audiences, and a book chapter on the cerebellar organoid protocol. The output from this action, especially the disease model of SCA29, has paved the way for the development of new treatment options in SCA29 and other related disorders.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

The PEDIATAX project has helped to produce several impacts for the scientific and clinical communities, as well as make the human iPSC and brain organoid technologies more approachable for different audiences with non-scientific backgrounds. The impacts include the first cerebellar organoid-based disease model of SCA29 with an advanced calcium imaging assay which will enable the screening of potential treatment options in SCA29; a better understanding of genotype-phenotype associations in SCA29 which helps clinicians diagnose patients, predict symptom development, and support family planning; a wealth of information on the genetic landscape of cerebellar diseases affecting children in Northern Finland; a book chapter on the cerebellar organoid protocol helping other laboratories to adopt this methodology in their work; and, finally, a platform for individuals with genetic cerebellar diseases and their families to discuss participation in research, and what the scientific community could do to support this participation.

SCA29 is caused by mutations (red dots) in the IP3R1 protein (Protein Data Bank: 7LHF).