Summary
Atherosclerosis, the underlying cause of the majority of cardiovascular diseases, is a lipid driven, inflammatory disease of
the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of
atherosclerosis induced cardiovascular disease risk remains unaddressed. Therefore, characterizing mediators of the
inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications. Blocking the
co-stimulatory CD40L-CD40 dyad reduces atherosclerosis. However, long-term inhibition of CD40L or its receptor CD40
results in suppression of the immune system and poses a risk for thromboembolic events. Therefore, we focused on the
downstream signaling pathways of CD40, and found that the interaction between CD40 and TNF-receptor-associated factor
6 (TRAF6) is the driving force for atherosclerosis. Using virtual ligand screening, we identified several small molecule
inhibitors termed TRAF-STOPs that were modeled to bind to the CD40-binding domain of TRAF6. TRAF-STOPs significantly
reduce (existing) atherosclerosis and treatment was well tolerated. The first toxicology results in mice show that there are no
side effects. Here we pursue the hypothesis that TRAF-STOPs are excellent candidates to pass the translational pipeline
towards a clinical application to treat atherosclerotic cardiovascular disease. Prof. Lutgens is one of the founders of the
recently established start-up company Cartesio Therapeutics to be able to valorise our novel TRAF-STOPs. By the end of
the PoC grant, we expect to have an oral drug available and to have completed toxicology and bio-distribution analysis in a
large animal model (mini-pig) and have tested TRAF-STOPs in a pig model of atherosclerosis. This way, we hold a solid
business case in our hands. The resulting business- and (pre-)clinical development plan and patent portfolio will then be
ready for seed investment and venture capital funding.
the large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of
atherosclerosis induced cardiovascular disease risk remains unaddressed. Therefore, characterizing mediators of the
inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications. Blocking the
co-stimulatory CD40L-CD40 dyad reduces atherosclerosis. However, long-term inhibition of CD40L or its receptor CD40
results in suppression of the immune system and poses a risk for thromboembolic events. Therefore, we focused on the
downstream signaling pathways of CD40, and found that the interaction between CD40 and TNF-receptor-associated factor
6 (TRAF6) is the driving force for atherosclerosis. Using virtual ligand screening, we identified several small molecule
inhibitors termed TRAF-STOPs that were modeled to bind to the CD40-binding domain of TRAF6. TRAF-STOPs significantly
reduce (existing) atherosclerosis and treatment was well tolerated. The first toxicology results in mice show that there are no
side effects. Here we pursue the hypothesis that TRAF-STOPs are excellent candidates to pass the translational pipeline
towards a clinical application to treat atherosclerotic cardiovascular disease. Prof. Lutgens is one of the founders of the
recently established start-up company Cartesio Therapeutics to be able to valorise our novel TRAF-STOPs. By the end of
the PoC grant, we expect to have an oral drug available and to have completed toxicology and bio-distribution analysis in a
large animal model (mini-pig) and have tested TRAF-STOPs in a pig model of atherosclerosis. This way, we hold a solid
business case in our hands. The resulting business- and (pre-)clinical development plan and patent portfolio will then be
ready for seed investment and venture capital funding.
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| Web resources: | https://cordis.europa.eu/project/id/862506 |
| Start date: | 01-01-2020 |
| End date: | 31-12-2021 |
| Total budget - Public funding: | - 150 000,00 Euro |
Cordis data
Original description
Atherosclerosis, the underlying cause of the majority of cardiovascular diseases, is a lipid driven, inflammatory disease ofthe large arteries. Despite a 25% relative risk reduction achieved by lipid-lowering treatment, the vast majority of
atherosclerosis induced cardiovascular disease risk remains unaddressed. Therefore, characterizing mediators of the
inflammatory aspect of atherosclerosis is a widely recognized scientific goal with great therapeutic implications. Blocking the
co-stimulatory CD40L-CD40 dyad reduces atherosclerosis. However, long-term inhibition of CD40L or its receptor CD40
results in suppression of the immune system and poses a risk for thromboembolic events. Therefore, we focused on the
downstream signaling pathways of CD40, and found that the interaction between CD40 and TNF-receptor-associated factor
6 (TRAF6) is the driving force for atherosclerosis. Using virtual ligand screening, we identified several small molecule
inhibitors termed TRAF-STOPs that were modeled to bind to the CD40-binding domain of TRAF6. TRAF-STOPs significantly
reduce (existing) atherosclerosis and treatment was well tolerated. The first toxicology results in mice show that there are no
side effects. Here we pursue the hypothesis that TRAF-STOPs are excellent candidates to pass the translational pipeline
towards a clinical application to treat atherosclerotic cardiovascular disease. Prof. Lutgens is one of the founders of the
recently established start-up company Cartesio Therapeutics to be able to valorise our novel TRAF-STOPs. By the end of
the PoC grant, we expect to have an oral drug available and to have completed toxicology and bio-distribution analysis in a
large animal model (mini-pig) and have tested TRAF-STOPs in a pig model of atherosclerosis. This way, we hold a solid
business case in our hands. The resulting business- and (pre-)clinical development plan and patent portfolio will then be
ready for seed investment and venture capital funding.
Status
CLOSEDCall topic
ERC-2019-POCUpdate Date
27-04-2024
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