Targeting Circadian Clock Dysfunction in Alzheimer’s Disease

Project Information

TClock4AD

Grant agreement ID: 101072895

DOI

10.3030/101072895

EC signature date 13 July 2022

Start date 1 March 2023

End date 28 February 2027

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 3 811 636,80

Coordinated by

ALMA MATER STUDIORUM - UNIVERSITA DI BOLOGNA
Italy

Periodic Reporting for period 1 - TClock4AD (Targeting Circadian Clock Dysfunction in Alzheimer’s Disease)

Reporting period: 2023-03-01 to 2025-02-28

Summary of the context and overall objectives of the project

Dementia is a major problem of our time. Alzheimer's disease (AD), the leading cause of dementia, accounts for 60-80% of cases, affecting 7 million people in the EU. This number is expected to double over the next 20 years as the population ages. Despite being described by psychiatrist Alois Alzheimer over a century ago, a cure for Alzheimer's disease remains elusive. Finding effective drugs has been a near-impossible task for industry and academic drug discovery, well described by the metaphor of the Death Valley. In June 2021, the FDA approved the antibody aducanumab, the first new AD drug in 18 years, although concerns remain about its efficacy, safety and cost. This highlights the urgent need to continue the development of AD drugs and to meet the challenge by exploring new avenues beyond the current mainstream. The 2017 Nobel Prize in Physiology and Medicine was awarded to Michael Young, Michael Rosbash and Jeffrey Hall “for their discoveries into the molecular mechanisms controlling circadian rhythm”. Disruptions in sleep-wake cycles and circadian rhythms are emerging as early symptoms of AD and correlate with an increased risk of dementia. New research suggests that circadian disruption may play a key role in the onset and progression of AD, making the circadian clock (CC) a promising therapeutic target. Addressing circadian dysfunction could help treat memory and sleep problems at all stages of the disease, from prodromal to preventative stages. TClock4AD has been designed to provide an excellent training platform for a critical rethink of Alzheimer's research and development under the breakthrough idea of targeting CC dysfunction. TClock4AD will provide a double degree to 17 PhD students whose research is structured around 5 scientific themes corresponding to 5 work packages (WPs): (1) develop novel artificial intelligence-, proteolysis targeting chimeras- multitarget and photoswitches-based strategies for identifying drug candidates for CC (2) develop novel drug delivery nanotechnologies, which take into consideration CC (3) investigate innovative in vitro (stem-cells, 3D cultures) & in vivo (Drosophila), as well as organ-on-chip techniques, for preclinical validation of CC drugs (4) get insight into the molecular mechanisms underlying CC in AD and associated drug response in mice and C. elegans models (5) develop an innovative biotech business model and exploitation strategies.

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

Over the past 24 months, TClock4AD has successfully built a strong network among all the project partners. Co-tutelle agreements for the double degrees have been made, with some adjustments along the way.

In terms of research, the 17 doctoral candidates have made significant individual progress while also collaborating with others, which is crucial for the success of a multidisciplinary project like this.

Regarding research progress:
- WP1 has developed first sets of new multitarget drugs, proteolysis targeting chimeras, and photoswitchable orexin receptor ligands, which have been characterized in vitro. It also created a cutting-edge computational system for drug repurposing, which integrates multiple types of data and structural bioactivity predictors, as well as a new approaches for de novo drug design.
- WP2 has created multifunctional organic nanoparticles to deliver circadian rhythm-targeting compounds and developed nanoemulsion carriers that can transport different type of therapeutics, such as RNA, peptides, small molecules. These could be used for treatments administered through the bloodstream or directly to the brain. Additionally, an animal model has been created to test future therapeutic approaches.
- WP3 has worked with cell lines, cells from Alzheimer's patients and 3D models to study clock gene dysregulation in AD. It has also designed an organ-on-chip device that mimics the blood-brain barrier, allowing to test potential Alzheimer’s treatments. New models of CC dysfunction in Alzheimer's were also developed using fruit flies (Drosophila).
- WP4 has researched how inflammation molecules from white blood cells affect CC pathways and howe CC influences processes like mitophagy and metabolism in the model organism C. elegans.
- WP5 has conducted a literature review highlighting the barriers and facilitators for collaborative innovation in drug discovery and development, which will aid researchers in the technical aspects of the project and beyond. The first steps toward an empirical study have been initiated.

This ongoing work is advancing our understanding of the role of the circadian clock in Alzheimer’s diseases and new therapeutic approaches to counteract it.

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)

TClock4AD is a project focused on Alzheimer's disease (AD), aiming to make significant advances in both research and education, with wide implications. It introduces a new approach by exploring the circadian clock as a key factor that could contribute to AD. This innovative strategy has the potential to lead to new treatments and prevention methods, offering hope for better patient outcomes and marking a potential major breakthrough in the field of AD research.
By the end of the project, the expected results include: 1) the discovery of promising new drug candidates for AD treatment; 2) advanced models of the disease, including 3D models of AD-related circadian clock dysfunction and animal models; 3) new techniques for delivering drugs for the central nervous system; and 4) AI tools and platforms to support AD research.
The long-term impacts might be significant: 1) these innovations (new drugs and technologies) could be commercialized by industry partners; 2) new preclinical models for drug testing will be developed; 3) new computational platforms and databases for analyzing big data could be applied to other common dementias, like Parkinson's disease.
TClock4AD has other ambitious impacts, such as training a new generation of experts in Alzheimer's drug discovery, thereby addressing the significant shortage of young talents in this field.

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