Targeting blood vessels to treat dementia

NV-STAB aimed to implement innovative therapeutics complemented with novel ultrasound imaging technologies in dementia. NV-STAB gathered two academic institutes, LUMC and PHYSMED, and one private partner, ICONEUS, that combined their expertise in vascular biology, neurophysiology, medicine, physics, and engineering in the medtech industry. LUMC defined the key problems that were solved by the ultrasound technologies developed by PHYSMED and ICONEUS.

Dementia describes a group of neurological disorders resulting in a progressive loss of cognitive functions. They are a leading cause of death and chronic disability affecting more than 40 million people worldwide. Although the financial burden of dementia remains difficult to quantify, recent publications have estimated that the global cost reaches €743 billion. There is as yet no medical treatment with confirmed efficacy for dementia. We have focussed on the vascular problems that can arise in vascular dementia.

The overall approach was to carry out systemic research on mouse models of cerebral Small Vessel Diseases (sCVD), having mutations that affected different small-sized blood vessels of the brain. We introduced groundbreaking ultrasound-imaging technologies, called functional ultrafast ultrasound (fUS) and functional Ultrasound Localization Microscopy (fULM), capable of monitoring non-invasively the whole brain microvasculature and function down to microscopic resolution to detect and characterize microvascular dysfunction. In addition, we investigated new analogues of thalidomide for their ability to preserve pericyte function. We have generated a small chemical library of 30 compounds. Of the 30 compounds evaluated, RTX-001 has emerged as a promising lead, demonstrating preclinical in vivo efficacy in managing abnormal blood vessel development, an excellent safety profile, and excellent pharmacokinetic/dynamic characteristics.