Periodic Reporting for period 3 - ArrestAD (3-O-sulfated heparan sulfate translocation in altered membrane biology: A newstrategy for early population screening and halting Alzheimer’s neurodegeneration)
Berichtszeitraum: 2021-01-01 bis 2022-05-31
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 peptides and tau protein. ArrestAD vision is different, we have developed a new concept based in the biology of heparan sulfates that considers molecular events occurring before detection of the common A-beta and tau-based Alzheimer’s disease hallmarks. Based in this glycanic concept, ArrestAD developed new strategies for detection and treatment of Alzheimer’s disease. This was possible by validating the new links between heparan sulfates biology, Alzheimer’s disease genetics, and disease onset and evolution.
Based on the new ArrestAD glycanic paradigm, we addressed the two major ArrestAD objectives:
1) Demonstrate that a new class of drug candidates can prevent and/or arrest tauopathy in cells and animal models of Alzheimer’s disease.
2) Proving that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells.
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 on the new ArrestAD glycanic paradigm, we addressed the two major ArrestAD objectives:
1) Demonstrate that a new class of drug candidates can prevent and/or arrest tauopathy in cells and animal models of Alzheimer’s disease.
2) Proving that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells.
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.
After five years of research and the development of numerous tools (Damen, Glycobiology. 2024; Su, PeerJ Analytical Chemistry. 2022; Wheeler, Org. Biomol. Chem. 2022; Lima, J. R. Soc. Interface. 2022; Huynh, Sci. Rep. 2022) the ArrestAD consortium allowed to afford key links between HS3ST2 expression in neurons, in engineered cells and in macrophages, with altered expression of AD-causative genes and AD genetic risk factors. We have notably shown that the intracellular accumulation of 3S-HS made by HS3ST2 is associated with the development of tauopathy (Huynh Sci. Rep. 2022) and we highlight that genetic variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfate diversity (Ouidja, Essays Biochem. 2024). This allowed the development of new technologies that will be transferred to the industrial world to bring them to the clinical market to improve conditions of patients with AD and related tauopathies.
Concerning our first objective, to develop a new class of drug candidate, we obtained the proof of concept that the enzyme HS3ST2, which produces the neural 3S-HS, is a druggable target. With this aim, we started to collaborate with Glycanix company issued from the Gly-CRRET laboratory), that has obtained license from the Gly-CRRET patents and developed own small compounds designed to selectively inhibit HS3STs, including HS3ST2. Similarly, with OTR3 company, which has expertise in commercialization in clinics of HS mimetics used as ReGeneraTing Agent (RGTA®). Thanks to ArrestAD, we advanced in the development of these molecules in cellular and murine tauopathy models. In parallel, we are currently performing the studies necessary for approaching a first clinical study in humans with our best compound (Gx or OTR3). This ArrestAD-derived project has recently received (Dec 2024) the NeurAL price from the iPEPs startup incubator from the Brain Institute (ICM), France that will help in the development of this strategy.
Concerning our second objective, which aimed to prove that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells, we obtained proof of concept that our glycanic technology, based in the detection of 3S-HS can be an interesting way to improve diagnosis by strategies different to those currently based in the detection of protein aggregates. Our study also highlights the relevance to combine our glycanic technology with other markers and tools identify during the project (miRNA patent EP3449009, Nagaraj, Int J Mol Sci. 2021, Want, Sci. Rep. 2023). All these markers are noninvasive for the patient and can be combined with classical tools currently used in clinics. This second objective will be considered after the therapeutic approach has advanced.
Globally, the works of the ArrestAD consortium led to 65 scientific publications (April 2025) and have been presented in more than 42 congresses (conference, poster, workshop). In addition, several communication campaigns for the general public have been made including two at the end of the project in Alzheimer’s Europe Journal (https://www.alzheimer-europe.org/news/arrest-ad-project-shows-how-heparan-sulfates-fit-alzheimers-disease-puzzle-and-shares-why-its?language_content_entity=en&language=mt(öffnet in neuem Fenster)) and in Open Access Government (https://www.openaccessgovernment.org/arrestad-exploiting-the-bittersweet-side-of-alzheimers-disease/138849/(öffnet in neuem Fenster)).
Find out our complete list of publication and actuality in the ArrestAD website:
https://arrestad.wordpress.com/(öffnet in neuem Fenster)
Concerning our first objective, to develop a new class of drug candidate, we obtained the proof of concept that the enzyme HS3ST2, which produces the neural 3S-HS, is a druggable target. With this aim, we started to collaborate with Glycanix company issued from the Gly-CRRET laboratory), that has obtained license from the Gly-CRRET patents and developed own small compounds designed to selectively inhibit HS3STs, including HS3ST2. Similarly, with OTR3 company, which has expertise in commercialization in clinics of HS mimetics used as ReGeneraTing Agent (RGTA®). Thanks to ArrestAD, we advanced in the development of these molecules in cellular and murine tauopathy models. In parallel, we are currently performing the studies necessary for approaching a first clinical study in humans with our best compound (Gx or OTR3). This ArrestAD-derived project has recently received (Dec 2024) the NeurAL price from the iPEPs startup incubator from the Brain Institute (ICM), France that will help in the development of this strategy.
Concerning our second objective, which aimed to prove that specific and early diagnosis of Alzheimer’s disease is possible in circulating cells, we obtained proof of concept that our glycanic technology, based in the detection of 3S-HS can be an interesting way to improve diagnosis by strategies different to those currently based in the detection of protein aggregates. Our study also highlights the relevance to combine our glycanic technology with other markers and tools identify during the project (miRNA patent EP3449009, Nagaraj, Int J Mol Sci. 2021, Want, Sci. Rep. 2023). All these markers are noninvasive for the patient and can be combined with classical tools currently used in clinics. This second objective will be considered after the therapeutic approach has advanced.
Globally, the works of the ArrestAD consortium led to 65 scientific publications (April 2025) and have been presented in more than 42 congresses (conference, poster, workshop). In addition, several communication campaigns for the general public have been made including two at the end of the project in Alzheimer’s Europe Journal (https://www.alzheimer-europe.org/news/arrest-ad-project-shows-how-heparan-sulfates-fit-alzheimers-disease-puzzle-and-shares-why-its?language_content_entity=en&language=mt(öffnet in neuem Fenster)) and in Open Access Government (https://www.openaccessgovernment.org/arrestad-exploiting-the-bittersweet-side-of-alzheimers-disease/138849/(öffnet in neuem Fenster)).
Find out our complete list of publication and actuality in the ArrestAD website:
https://arrestad.wordpress.com/(öffnet in neuem Fenster)
After five years of research, the ArrestAD project has concluded that the glycanic approach affords a missing piece of “the Alzheimer disease puzzle", with three mains outcomes:
• the discovery of neural HS biosynthetic enzymes as new drug targets for arresting Alzheimer’s disease and tools to discover related drugs.
• several unrevealed mechanistic steps by which heparan sulfate trigger protein aggregation from the synapse, until the cell dies.
• a raft of diagnostic tools in blood, from the detection of heparan sulfate in cells to miRNA measurement in plasma.
The glycanic approach is new and might fit all known neurodegeneration cascades and afford hope for efficiently treating Alzheimer disease in the future.
Moreover, in the context of an ageing European population with an increased prevalence of Alzheimer disease, our project succeeded to propose a new therapeutic strategy for Alzheimer disease and potentiated its transfer to the industrial arena. In the long term, ArrestAD will greatly contribute to lower risk of cognitive impairment, frailty and social exclusion of older people and increase their independence, quality of life, that of those who care for them, and the sustainability of health and care systems.
• the discovery of neural HS biosynthetic enzymes as new drug targets for arresting Alzheimer’s disease and tools to discover related drugs.
• several unrevealed mechanistic steps by which heparan sulfate trigger protein aggregation from the synapse, until the cell dies.
• a raft of diagnostic tools in blood, from the detection of heparan sulfate in cells to miRNA measurement in plasma.
The glycanic approach is new and might fit all known neurodegeneration cascades and afford hope for efficiently treating Alzheimer disease in the future.
Moreover, in the context of an ageing European population with an increased prevalence of Alzheimer disease, our project succeeded to propose a new therapeutic strategy for Alzheimer disease and potentiated its transfer to the industrial arena. In the long term, ArrestAD will greatly contribute to lower risk of cognitive impairment, frailty and social exclusion of older people and increase their independence, quality of life, that of those who care for them, and the sustainability of health and care systems.