Preclinical study of a new innovative peptide therapy for a causative treatment of sepsis – LR17 peptide therapy in sepsis

Sepsis exemplifies a complex clinical syndrome that results from a harmful and damaging host response to severe infection. Sepsis develops when the initial, appropriate host response to systemic infection becomes amplified and then dysregulated. One of the amplifiers of the inflammatory response is the Triggering Receptor Expressed on Myeloid cells-1 (TREM-1). Indeed, TREM-1 and TLRs appear to cooperate in a synergistic way. The role of TREM-1 as an amplifier of the immune response has been confirmed in a mouse model of septic shock in which blocking signaling through TREM-1 partially protected animals from death.
TLT-1 (TREM Like Transcript-1) is a platelet specific receptor that belongs to the TREM family. The recent characterization of the TLT-1 extracellular domain has uncovered evidence that suggests a role of TLT-1 during the onset and progression of sepsis. Indeed, we have shown that TLT-1 and a TLT-1 derived peptide, LR17, exhibit anti-inflammatory properties by dampening TREM-1 signaling and thus behave as a naturally occurring TREM-1 inhibitor. LR17 decreased in vitro TREM-1- and LPS-induced neutrophil activation (intracellular signaling, NFkB activation, cytokine production, ROS production, etc), acting like a decoy receptor and competing against TREM-1 receptor. As a result of this activity, both early and late LR17 administration to septic mice modulate in vivo the proinflammatory cascade triggered by infection, thus preventing from hyper-responsiveness, organ damage and coagulation abnormalities, and finally improve survival (by more 60% vs controls).
The aim of the current proposal is to optimize LR17 sequence (length, kinetics, etc) and complete preclinical study. First, we want to reduce LR17 length and then optimize its stability by evaluating its pharmacokinetics/dynamics (PK/PD) properties and toxicity in vitro and in vivo, and in fine optimize therapeutic doses. We also propose to evaluate the protective effect of LR17 during sepsis in non-murine species (pig).
This LR17 peptide is already the subject of an invention submission process in collaboration with Inserm Transfert. This project should lead to the creation of Biotech Company.