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
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.
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.
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.