Preclinical validation of new targets for therapy to reduce infarct size
1 Purpose
This translational project is part of a larger project with the long-term aim to improve the prognosis for patients with ST-myocardial infarction (STEMI) through improved prognostication and treatment. For this we explore new and promising biomarkers and therapeutic targets. The immune mediators neutrophil extracellular traps (NETs) are recently discovered mediators of the pathophysiology in STEMI, and the project investigates the relevance of NETs in STEMI prognostication and treatment. The experimental part of the project, described in this application, investigates the effect on infarct size from reduction of NETs by a single intracoronary infusion of DNAse at the time of reperfusion after STEMI in pigs.
2 Distress
Some animals in the project will be subjected to procedures of moderate severity, i.e. three separate procedures that involve general anesthesia, and percutaneous invasive procedures with some expected post-operative pain after the first procedure.
3 Expected benefit
In case of positive results, this study will provide evidence for a phase 1 clinical study about the effects of treatment with DNAse in patients with STEMI.
4 Number of animals, and what kind
40 pigs
5 How to adhere to 3R
Replace: Other research groups have convincingly shown the effects of DNAse on infarct size in rodent models. However, experiments with pigs are necessary in preclinical validation of therapeutic strategies that are intended for humans in the long-term, and cannot be entirely replaced.
Reduce: To reduce the number of animals, we build on existing literature, and limit the experiments to key observations with regard to clinically relevant end-points and key observations necessary for evaluation before clinical testing i patients. The protocol is designed to gain as much information from each animal as possible. All personnel are chosen for their procedural skills in order to ensure efficient experiments based on previous refinement of the procedures, and thereby maximum reduction in the number of animals needed.
Refine: We are continuously evaluating our procedures and interventions. This project will build on another project in our institute (FOTS ID 27108) in which we have established a protocol for induction of STEMI and postoperative analgesics and observation. To imrpove animal welfare and academic output from each animal, we have recently aquired a system for continuous telemetric ECG survaillance.
This translational project is part of a larger project with the long-term aim to improve the prognosis for patients with ST-myocardial infarction (STEMI) through improved prognostication and treatment. For this we explore new and promising biomarkers and therapeutic targets. The immune mediators neutrophil extracellular traps (NETs) are recently discovered mediators of the pathophysiology in STEMI, and the project investigates the relevance of NETs in STEMI prognostication and treatment. The experimental part of the project, described in this application, investigates the effect on infarct size from reduction of NETs by a single intracoronary infusion of DNAse at the time of reperfusion after STEMI in pigs.
2 Distress
Some animals in the project will be subjected to procedures of moderate severity, i.e. three separate procedures that involve general anesthesia, and percutaneous invasive procedures with some expected post-operative pain after the first procedure.
3 Expected benefit
In case of positive results, this study will provide evidence for a phase 1 clinical study about the effects of treatment with DNAse in patients with STEMI.
4 Number of animals, and what kind
40 pigs
5 How to adhere to 3R
Replace: Other research groups have convincingly shown the effects of DNAse on infarct size in rodent models. However, experiments with pigs are necessary in preclinical validation of therapeutic strategies that are intended for humans in the long-term, and cannot be entirely replaced.
Reduce: To reduce the number of animals, we build on existing literature, and limit the experiments to key observations with regard to clinically relevant end-points and key observations necessary for evaluation before clinical testing i patients. The protocol is designed to gain as much information from each animal as possible. All personnel are chosen for their procedural skills in order to ensure efficient experiments based on previous refinement of the procedures, and thereby maximum reduction in the number of animals needed.
Refine: We are continuously evaluating our procedures and interventions. This project will build on another project in our institute (FOTS ID 27108) in which we have established a protocol for induction of STEMI and postoperative analgesics and observation. To imrpove animal welfare and academic output from each animal, we have recently aquired a system for continuous telemetric ECG survaillance.