OptiLYSE

The INSERM U919 unit, headed by Pr. D. Vivien, has developed new fibrinolytic agents derived from the well-known serine protease tissue plasminogen activator (tPA), which is currently approved as a thrombolytic therapy for myocardial infarction, acute massive pulmonary embolism and ischemic stroke. A patent application to protect these new fibrinolytic agents (named Optimized-tPAs) was performed in September 2011 (EPn°11306119.6). Optimized tPAs have the competitive advantage over tPA of lacking proneurotoxic actions. Indeed beyond its fibrinolytic vascular role, tPA is a positive neuromodulator of the N-methyl-D-aspartate (NMDA)-dependent glutamatergic signaling. Thus, the beneficial effects of tPA-induced fibrinolysis may be counterbalanced by the potentiation of the NMDA receptor-mediated neurotoxicity. This noxious action of tPA-induced fibrinolysis has been clearly documented following ischemic stroke and there is strong evidence that it also occurs in the retina (the target structure of the present project). Indeed, tPA may exert damages to the retina, particularly when it is left in direct contact with neural retinal cells during surgery (such as sub retinal injection). These suspected neurotoxic effects may explain the limited beneficial effect of tPA treatment reported in the clinical setting. Age-related macular degeneration (AMD) is the most common cause of vision loss in the elderly of industrialized countries. “Wet” AMD is characterized by the development of choroidal neovascularization and hemorrhages with subsequent acute photoreceptor loss (which occurs in about 50% of the patients). Here, we propose to use our Optimized-tPAs to drain the hemorrhagic complications, following wet-AMD, but also for the drainage of intravitreal hemorrhages. We have already shown on cortical neuronal cultures and in a model of permanent ischemia that Optimized-tPAs are a major advance over tPA, as they exhibit no neurotoxicity while their high fibrinolytic efficacy is preserved or even improved. These preliminary results suggest a high therapeutic potential of Optimized-tPAs to treat subretinal hemorrhages. The two aims of the present program are: (1) to propose an optimized specifically designed ophthalmic form of tPA and (2) to open new indications for the Optimized-tPA. The expected results of the experiments conducted in the frame ofthis Emergence program should (1) show the lack of the Optimized-tPA-induced toxicity in the retinal chamber and (2) highlight the beneficial ocular therapeutic potential of these new fibrinolytics. The studies will be performed in collaboration between the INSERM U872 unit headed by Pr. F. Behar-Cohen, specialist in therapeutic innovations for ocular pathologies and INSERM U919 a leading group working on fibrinolytics and stroke. This program is a step-forward prior a start-up creation, spin-off of the INSERM U919, specialized in the development of biotherapy for the treatment of thrombotic diseases.