CYCLOsporine A neuroprotection in a Primate Stroke model with imaging – CYCLOPS

Stroke is the third cause of mortality and the first cause of handicap. Thrombectomy is about to change patient care in emergency. In this context close to myocardial ischemia-reperfusion (IR), treating reperfusion injury is crucial as it contributes to cell damage extension and to inflammation. In stroke, the majority of pre-clinical assays have failed in clinical translation because of the differences between rodent stroke models and the clinical situation and between methods to evaluate therapeutic effects. Imaging is the method of choice in patients: the new challenge is to provide an optimal characterization of the actors of post-reperfusion damage, i.e. mitochondria and inflammation. Surrogate inflammation imaging markers are desired but very difficult to establish in the clinical arena. Cyclosporin A (CsA), the first generation of drug targeting the mitochondria, is suspected to affect also inflammation. Our teams contributed to two essential findings in this field: 1/ the first clinical evidence of CsA efficiency to reduce infarct size in a sub-group of stroke patients (large IR), 2/ inflammation imaging in stroke. We now propose to develop translational inflammation imaging with the new PET/MRI technology and dual imaging agents in a non human primate (NHP) stroke model treated with CsA.
For inflammation, we will use VCAM-1 targeted MRI particles, validated in mice for early endothelial activation, and a PET inflammation radiotracer targeting a mitochondrial protein for late macrophage activation. The blood brain barrier (BBB) status is also important for drug access to the brain. We will quantify BBB permeability over time using new PET/MRI nanoparticles (NPs) and kinetic analysis. These NPs, already tested in NHP (dynamic MRI after bolus injection), are ready for a clinical trial in neurological applications. CYCLOPS involves four academic labs (with researchers and physicians in medical imaging, cardio- and neuro-vascular physiopathology, and imaging agents chemistry), and European collaborations for new imaging development. Two SMEs located in Lyon, CYNBIOSE and Nano-H, will develop the NHP model and the NPs respectively. CYCLOPS is within the Equipex LILI (a PET/MRI scanner in a collaborative project with Siemens). The stroke NHP model will be performed by minimally invasive endovascular IR and characterized by imaging. PET/MRI will enable combined measurements of the factors describing the IR damage, i.e. multiparametric imaging including perfusion, tissue oxygenation, diffusion, infarction and penumbrae volume, as well as endothelial and macrophage activation, and BBB damage with the new dual Gd/68Ga NPs. Protocol validity will be demonstrated by studying a CsA treated group versus a non-treated. Spatio-temporal follow-up by imaging biomarkers, such as permeability and inflammation, is expected to provide new insights in CsA effects in the highly dynamic context of cerebral IR. PET/MRI biomarkers will be essential for treatment eligibility and drug effects monitoring in future clinical trials.