Transferring autonomous and non autonomous cell degeneration 3D models between EU and USA for development of effective therapies for neurodegenerative diseases (ND)

Project Information

CROSS-NEUROD

Grant agreement ID: 778003

DOI

10.3030/778003

Project closed

EC signature date 8 February 2018

Start date 1 June 2018

End date 31 March 2024

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 693 000,00

EU contribution

€ 594 000,00

Coordinated by

UNIVERSITA DEGLI STUDI DI MILANO
Italy

Periodic Reporting for period 2 - CROSS-NEUROD (Transferring autonomous and non autonomous cell degeneration 3D models between EU and USA for development of effective therapies for neurodegenerative diseases (ND))

Reporting period: 2020-06-01 to 2024-03-31

Summary of the context and overall objectives of the project

Neurodegenerative diseases (NDs), including dementia, Parkinson's, and motor neuron diseases, represent a significant and growing challenge in global healthcare. These conditions are particularly devastating for patients and their families. Despite extensive research, decisive cures remain elusive. This is largely due to the insufficient understanding of the pathogenic mechanisms underlying NDs. Addressing NDs is crucial due to their severe impact on individuals’ quality of life, the increasing prevalence as populations age, and the substantial healthcare burdens they impose. Improved understanding and innovative treatments are urgently needed to alleviate both personal and societal costs. The CROSS-NEUROD program aimed to elucidate common cellular and molecular pathways in NDs, exploring both autonomous and non-autonomous mechanisms. By leveraging advanced three-dimensional (3D) cell culture systems, our project aimed to uncover shared genetic and molecular mechanisms across different NDs. This approach is pivotal in identifying potential targets for therapeutic intervention. Throughout the project, we identified critical pathways and genes that are consistent across various NDs, with a particular focus on post-translational protein modifications such as sumoylation and prenylation, and specific genes like STMN2. These findings are promising due to their potential translational impact on the development of new treatment strategies for ND patients. The elucidation of these shared mechanisms in human-relevant models establishes a foundation for future therapeutic advancements, potentially leading to effective prevention and treatment options for a spectrum of neurodegenerative conditions.

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

Throughout the duration of this project, we successfully generated and characterized cerebral and spinal cord organoids from patient-specific induced pluripotent stem cells (iPSCs). Our team conducted comprehensive analyses using these cellular models to examine common autonomous and non-autonomous cell death mechanisms and disordered processes across ALS, SMA, FTD, and PD, employing both neuropathological and transcriptomic analysis techniques. Particular emphasis was placed on exploring the sumoylation of key pathogenic proteins, investigating the role of the translocator protein 18kDa (TSPO), studying prenylation processes, and assessing the dysregulation of STMN2. In addition to these studies, therapeutic experimental modulation of identified pathways was performed. This modulation was facilitated by viral-mediated targeting using adeno-associated viral vector 9 (AAV9) in both iPSC-derived 3D disease models and in vivo transgenic motor neuron disease models. Training, practice, and dissemination activities were central to our project's implementation. We actively shared our findings by presenting at international meetings and publishing them in high-impact factor, peer-reviewed journals, ensuring the project's insights reached both the scientific community and broader audiences effectively.

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)

The CROSS-NEUROD project has established a community of neuroscience researchers, propelling the field into a new, cutting-edge domain. This initiative has enhanced the 3D-model approach, contributing significant advancements to neuroscience research by facilitating the sharing of knowledge and tools necessary for the field's progression. Key achievements include the development of fully structured brain, spinal cord, and mesencephalic human patient-specific 3D models. These models have allowed for a more precise definition of the molecular mechanisms underlying neurodegenerative diseases (NDs) and have led to the identification of novel therapeutic targets. Notably, the project has highlighted the roles of sumoylation, the translocator protein 18kDa (TSPO), prenylation, and STMN2 dysregulation as promising target mechanisms across NDs. The collaborative spirit among the project partners has not only supported the development of the CROSS-NEUROD project but has also fostered the generation of new knowledge. This cooperation lays the groundwork for future research initiatives and has created numerous career opportunities within the field. Collectively, these contributions are poised to have profound socio-economic impacts and broader societal implications, including potential improvements in treatment strategies and patient care in neurodegenerative diseases.

Annual CROSS-NEUROD Meeting, October 14th 2019, Milan, Italy.