Emergence - Emergence

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

Submission summary

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.

Project coordinator

Monsieur Sébastien GIBOT (UNIVERSITE DE NANCY I [HENRY POINCARE]) – s.gibot@chu-nancy.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Inserm U961 UNIVERSITE DE NANCY I [HENRY POINCARE]
CNRS UMR 7565 UNIVERSITE DE NANCY I [HENRY POINCARE]
Inserm U961 UNIVERSITE DE NANCY I [HENRY POINCARE]
inserm Transfert INSERM TRANSFERT

Help of the ANR 248,186 euros
Beginning and duration of the scientific project: December 2010 - 24 Months

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