Investigation of Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL) using induced pluripotent stem cell modelling and targeted therapeutic research

Project Information

CADASIL-iMATTR

Grant agreement ID: 101111254

DOI

10.3030/101111254

Project closed

EC signature date 14 March 2023

Start date 1 May 2023

End date 30 June 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 278 571,36

Coordinated by

UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN
Ireland

Periodic Reporting for period 2 - CADASIL-iMATTR (Investigation of Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL) using induced pluripotent stem cell modelling and targeted therapeutic research)

Reporting period: 2025-07-01 to 2026-06-30

Summary of the context and overall objectives of the project

This project aims to understand the underlying cause of stroke and cognitive impairment. These conditions can be caused by changes in the blood vessels of the brain. Patients with a genetic condition known as CADASIL or Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy suffer from strokes and cognitive impairment. This condition is caused by a mutation in a gene called NOTCH3. This causes alterations in the blood vessels that carry nutrients to the brain.

There remains much to discovered in how damage of the blood vessels occurs, how strokes occur and how cognitive impairment occurs. Currently, there are no cures or treatments available for CADASIL. There are also a lack of cell and animal models available to test potential new treatments.
Our first aim is to understand as much about the disease in humans as possible through an in depth analysis of blood samples and brain samples. Secondly we aim to develop a cell model in a dish to mimic the dysfunction occurring in patients with CADASIL and to see if we can apply new and existing therapies to repair any dysfunction. Thirdly, we aim to use a specific type of fish, a Zebrafish, with fluorescent blood vessels, to see if we can establish an animal model of CADASIL for testing of therapies.

We anticipate that this project will have a significant impact on the CADASIL community of patients and researchers and beyond. Outcomes from this project will not only enhance our understand of the disease in early and late stage but also form the basis of establishing pre-clinical models for testing of potential treatments for CADASIL. We would like to thank all the people who donated biospecimens to this research project.

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

The activities performed include the in depth analysis of proteins and immune cells in the blood of patients with early stage CADASIL. Additionally analysis of all the genes changed in the post-mortem brain tissue of patients with CADASIL was performed. We have also created disease relevant cell types from patient derived stem cells carrying the NOTCH3 mutation.

The main achievements include identification of specific proteins and biological processes that are dysregulated in the early stages of disease. We have also established a cell model in a dish using patient derived cells that reveals cellular dysfunction. From this we analysed all the genetic changes in this model of dysfunction to understand which genes were dysregulated. We have identifed an FDA-approved therapeutic that rescued this cellular dysfunction in the established CADASIL model.

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)

Our results go beyond the state of the art as here we performed the first analysis of over 7000 proteins in the blood of patients with CADASIL and compared them to age matched healthy patients. We identified specific proteins that were significantly changed which have also been shown to be implicated in this disease and thus have potential as biomarkers for monitoring progression and therapeutic response. Additionally, we have identified several biological processes that are disrupted in CADASIL providing valuable information on the early stages of this disease. Analysis of the immune cells in the blood yielded a few significant differences that require further experimentation and study participants to interpret and validate. Notably we identified alterations in how the cells of a blood vessel network interact through use of patient derived stem cells. This went beyond the state of the art as cells were used in which the NOTCH3 genetic mutation was corrected which acted as a suitable comparison group. Furthermore, we identified specific genes that are likely driving this dysfunction. From the analysis of these genes we identified several potential therapeutic strategies to rescue the blood vessel network impairment. We have identifed an FDA-approved therapeutic that rescued cellular dysfunction in the established CADASIL model. Future work will test these therapeutics in more complex models of CADASIL.