Matrix therapy for stroke: a new opportunity to protect the suffering brain tissue and to promote its recovery? – MAESTRO

Stroke is the third leading cause of death and of major disabilities in the industrialized countries, with 15 million people suffering stroke worldwide each year. Stroke is either ischemic in 80% of cases or hemorrhagic in 20%. The only treatment presently approved by the Health Authorities for ischemic stroke is thrombolysis with the tissue plasminogen activator (t-PA), which can be administered only within the first 4 hours after the onset of symptoms and can thus be applied solely to a minority (5%) of the patients. Besides this vascular treatment, many potential neuroprotective molecules were tested in stroke patients but with disappointed results Proof of evidence indicates that the pathogenesis of ischemia-induced brain damage involves complex interactions between many components of the cerebral tissue, including the ExtraCellular Matrix (ECM), an important constituent of the so-called neurovascular unit. Among these ECM regulatory elements, GlycosAminoGlycans (GAGs) participate to the accurate scaffold organization of the ECM, protect and enhance the bioavailability of Heparin Binding Growth Factors (HBGF) and other heparin binding proteins (HBP). Several of these HBP, as FGF and VEGF, are recognized for their abilities to protect tissue against the ischemic lesions, while others, as BDNF, GDNF, and pleiotrophin, are recognized as neuroprotectors/neuroregulators. After stroke, the ECM’s components are modified, proteases and glycanases are activated, and endogenous GAGs are degraded with elimination of fragments into the circulation, becoming potential stroke markers. The HBP in the ischemic tissue are not anymore protected from enzymatic degradations. This results in the reduction of their bioavailability with negative consequences on recovery of the injured tissue. Thus, Matrix Therapy technology based on the use of analogues of GAG, also known as RGTA® (for Regenerating Agents) is an interesting strategy. The mode of action of RGTA®, polysaccharides resistant to glycanases, is based on the replacement of destroyed GAGs and of the protection of HBGF/HBP against degradation. This protection restores the scaffold matrix and cellular communication leading to tissue repair.
This project aims to demonstrate the neuroprotective and neuroregenerative effects of RGTA®-based ‘Matrix Therapy’ in stroke pathology by reestablishing the structure and functionality of brain tissue GAGs. The project is based on the complementarities of the 3 project partner’s expertise including one SME. Many clinical trials in stroke have failed, in part, because of the inadequacy of the employed animal models of stroke that lack comorbidity factors such as chronic arterial hypertension (CAH). Partner 1 is specialized in advanced preclinical animal models of stroke (rodents with or without CAH and non-human primates, recommended for current preclinical investigations), in brain imaging, behavior and immuno-histological tests required for stroke studies. Partner 2 is specialist of GAG-mimetics and has brought RGTA® matrix therapy in clinics. One RGTA® lead molecule is currently a component of CE mark treatments for chronic skin and corneal ulcers. Partner 3 is specialized in the structural and functional characterization of the GAG component of the ECM. The structure and functionality of GAGs before and after ischemia and the presence of GAG’s fragments in the bloodstream, reflecting the glycosaminoglycanic ECM quality in brain, will be easily characterized by the Partner 3. Thus, the finality of this project is divided in 2 points: 1) the demonstration that ‘Matrix Therapy’ constitutes a new effective opportunity to promote the functional recovery of ischemic cerebral tissue after stroke and 2) the determination of a specific blood glycanic marker of the brain ECM quality after stroke and the therapy follow-up. At the end of these studies, a clinical trial will be planed to confirm the relevance of this “Matrix Therapy” for cerebral ischemia.