Advancing IntracrAnial Aneurysm Drug Discovery through Human THSD1 Variant Blood-Vessel-on-a-(CHIP) Models. (IA-ADD-CHIP)
The goal is to investigate whether a non-invasive drug compound will reduce the risk of an aneurysmal subarachnoid hemorrhage
Rupture of intracranial aneurysms (IA) causes aneurysmal subarachnoid hemorrhage (ASAH), an often lethal type of stroke. ASAH can be prevented by invasive treatment of IA, but with significant treatment risks. Thus, a non-invasive drug compound to prevent ASAH is urgently needed. The project involves Resiliun, a biopharmaceutical company dedicated to the regulation of vascular repair by focusing on peptides.
IA rupture can currently only be prevented with invasive endovascular or surgical treatment, but these methods carry a considerable risk of disability or death of up to 8%.Therefore, many IAs remain untreated. Since non-invasive drug treatment options to prevent ASAH do not yet exist, these IAs are usually followed over time with serial imaging. If aneurysmal growth occurs, which is a marker of aneurysm instability and a predictor of rupture, these IAs are then treated to prevent rupture. Most patients who do not undergo preventive treatment have small IAs. However, since small IAs with a low risk of rupture are much more prevalent than large IAs with a higher risk of rupture, most instances of ASAH are caused by rupture of small IAs. Moreover, patients with untreated IAs suffer from reduced quality of life because of persistent fear of rupture of these IAs.
We hypothesize that IA progression is driven by excessive vascular repair within intracranial arteries, following the activation of the elastin receptor complex (ERC). (Peri)vascular cells, which all carry the ERC and can contribute to vessel wall weakening, play a crucial role in IA etiology.
We hypothesize that the IA disease process can be counteracted with BA4, a monoclonal antibody (mAb).
We will (1) adapt both existing models by introducing cells heterozygous for the common mutation; and (2) functionally characterize the impact of this mutation on vascular production of elastin proteolysis-derived GxxPG motif peptides, and on ERC activation and effect on vessel stability. Next, we will test the therapeutic potential of mAb BA4 to reverse these effects.
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