Periodic Reporting for period 2 - ArrestAD (3-O-sulfated heparan sulfate translocation in altered membrane biology: A newstrategy for early population screening and halting Alzheimer’s neurodegeneration)
Période du rapport: 2019-01-01 au 2020-12-31
ArrestAD proposes a novel and visionary thinking resulting from the demonstration of the central role of heparan sulfate in the molecular mechanisms leading to Alzheimer’s disease and in the observation of related molecular events in circulating cells from Alzheimer’s disease patients. Alzheimer’s disease is a societal challenge for which there is neither prevention nor possible cure. Research in the field aiming to develop diagnostic and therapeutic strategies has long been refining classic concepts based on the aggregation, seeding, and spreading of A-beta and tau protein. ArrestAD vision is different, based in the biology of heparan sulfates, we have developed a new concept that considers molecular events occurring before detection of A-beta and tau-based Alzheimer’s disease hallmarks. Based in this glycanic concept, ArrestAD is underpinning the development of new strategies for detection and treatment of Alzheimer’s disease by validating the new links between heparan sulfates biology, Alzheimer’s disease genetics, and disease onset and evolution.
Based in the new ArrestAD glycanic paradigm, we are addressing the two ArrestAD major objectives:
1) Proving that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells.
2) Demonstrate that a new class of drug candidates can prevent and/or arrest tauopathy in cells and animal models of Alzheimer’s disease.
To reach these objectives, ArrestAD brings together a consortium of academic and clinical research teams of high levels coming from different European universities assuring an international-multidisciplinary working group of recognized experts in Alzheimer’s disease clinics and diagnosis, heparan sulfate biology, transcriptomics, interactomics, carbohydrate chemistry, enzymology, cell biology, animal experimentation with Alzheimer’s disease models, and an industrialization of biotechnology, is our main strengths to succeed in this high-risk character project with high socio-economic impact.
Indirect objectives:
In addition to its major objectives, ArrestAD comprises indirect applications as the development of tools allowing the study of the mechanistic leading to disease. This will allow us to better understand the central role of heparan sulfate as a catalyst of biochemical and cellular processes leading to disease development.
Based in the new ArrestAD glycanic paradigm, we are addressing the two ArrestAD major objectives:
1) Proving that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells.
2) Demonstrate that a new class of drug candidates can prevent and/or arrest tauopathy in cells and animal models of Alzheimer’s disease.
To reach these objectives, ArrestAD brings together a consortium of academic and clinical research teams of high levels coming from different European universities assuring an international-multidisciplinary working group of recognized experts in Alzheimer’s disease clinics and diagnosis, heparan sulfate biology, transcriptomics, interactomics, carbohydrate chemistry, enzymology, cell biology, animal experimentation with Alzheimer’s disease models, and an industrialization of biotechnology, is our main strengths to succeed in this high-risk character project with high socio-economic impact.
Indirect objectives:
In addition to its major objectives, ArrestAD comprises indirect applications as the development of tools allowing the study of the mechanistic leading to disease. This will allow us to better understand the central role of heparan sulfate as a catalyst of biochemical and cellular processes leading to disease development.
During the first years of the project, important advance on both major objectives have been realized.
1) Proving that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells.
Concerning ethics issues, we have obtained all accreditations for studying human blood samples from well characterized cohorts of Alzheimer’s disease patients and control individuals in France and Poland. Concomitantly, tools development advanced, with the implementation of quality control production and characterization of ArrestAD used antibodies. In the other hand, we have established experimental protocols for blood handing, samples analysis, and management of results. This allowed us to start the validation studies of ArrestAD glycanic marker in blood samples of Alzheimer’s disease patients, with first un-blinding part and analysis scheduled for the beginning of 2019. In addition to the glycanic characterization of samples, banks of RNA and protein extracts were also generated for omics studies.
2) New class of drug candidates able to prevent and/or arrest AD-neurodegeneration:
Regarding this objective, during this first year of the ArrestAD project we advanced in the implementation and setup of tools necessaries for compounds screening: we implemented/developed an enzymatic activity assay, two cell models, and two animal models of Alzheimer’s disease related tauopathy. The enzymatic activity assay showed to be efficient for the screening of heparan sulfate inhibitors. Concerning cells, two models are in development: one tauopathy model using primary cell cultures from brain of a tauopathy mice model, and a second model using neuro-differentiated cell lines in where tauopathy is induced by oxidative stress. Similarly, two animal models were implemented for specific breading for the ArrestAD project and the corresponding disease evolution red-outs are being validated at different ages to assess disease evolution.
To succeed in this challenging project, we defined: data management plan and dissemination and exploitation plan, in order to allow ArrestAD project to generate FAIR data which will be published in open access journal. To conveniently assure management of the different task of the project and assure strong collaboration between European partners, we planned regular ArrestAD technical meeting under different means (physical, call conference, training and transfer of technology).
1) Proving that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells.
Concerning ethics issues, we have obtained all accreditations for studying human blood samples from well characterized cohorts of Alzheimer’s disease patients and control individuals in France and Poland. Concomitantly, tools development advanced, with the implementation of quality control production and characterization of ArrestAD used antibodies. In the other hand, we have established experimental protocols for blood handing, samples analysis, and management of results. This allowed us to start the validation studies of ArrestAD glycanic marker in blood samples of Alzheimer’s disease patients, with first un-blinding part and analysis scheduled for the beginning of 2019. In addition to the glycanic characterization of samples, banks of RNA and protein extracts were also generated for omics studies.
2) New class of drug candidates able to prevent and/or arrest AD-neurodegeneration:
Regarding this objective, during this first year of the ArrestAD project we advanced in the implementation and setup of tools necessaries for compounds screening: we implemented/developed an enzymatic activity assay, two cell models, and two animal models of Alzheimer’s disease related tauopathy. The enzymatic activity assay showed to be efficient for the screening of heparan sulfate inhibitors. Concerning cells, two models are in development: one tauopathy model using primary cell cultures from brain of a tauopathy mice model, and a second model using neuro-differentiated cell lines in where tauopathy is induced by oxidative stress. Similarly, two animal models were implemented for specific breading for the ArrestAD project and the corresponding disease evolution red-outs are being validated at different ages to assess disease evolution.
To succeed in this challenging project, we defined: data management plan and dissemination and exploitation plan, in order to allow ArrestAD project to generate FAIR data which will be published in open access journal. To conveniently assure management of the different task of the project and assure strong collaboration between European partners, we planned regular ArrestAD technical meeting under different means (physical, call conference, training and transfer of technology).
At the end of the 4 years project, ArrestAD should make available a prototype diagnostic kit for Alzheimer’s disease as well as the in vivo proof of concept that targeting the new ArrestAD glycanic target with result in tauopathy arrest by pharmacological means.
In its long term-vision, we aim to establishing a wide European consortium for multicenter validation of the ArrestAD Alzheimer’s disease diagnosis and therapeutic technologies. Thus, based on ArrestAD technology, we will build a diverse portfolio of future projects that will result in a long-term benefit for citizens, economy and society and will have major impact for the world’s ageing population.
In its long term-vision, we aim to establishing a wide European consortium for multicenter validation of the ArrestAD Alzheimer’s disease diagnosis and therapeutic technologies. Thus, based on ArrestAD technology, we will build a diverse portfolio of future projects that will result in a long-term benefit for citizens, economy and society and will have major impact for the world’s ageing population.