A Filter to Remove HMGB1

DESCRIPTION (provided by applicant): Sepsis, a clinical syndrome associated with infection, is a major complication that can develop after surgery or trauma. It affects roughly 700,000 patients annually with an associated annual cost of 16.7 billion. Septic patients can develop multiple organ failure and face significant morbidity and mortality despite advances in intensive care and advanced supportive treatments. There is only one FDA approved treatment for sepsis, activated protein C, but it is minimally effective and approved for use only in a subset of patients with severe sepsis. The pathogenesis of severe sepsis is not well understood. We identified that high levels of HMGB1 are produced in humans and animals with sepsis, and neutralization of HMGB1 is significantly protective. Our previous studies have demonstrated that inhibiting HMGB1 after induction of sepsis significantly rescues animals from death, even when the treatment begins 24 hours after surgery. These results suggest that HMGB1 can be targeted to therapeutic advantage in a potentially relevant time frame (24 hours) during sepsis and that its removal should reduce the severity of the inflammatory cascade and improve patient outcome. We propose to bring to the clinical market an extracorporeal system that removes HMGB1 protein from the plasma of septic patients unresponsive to standard treatment. The key to the system is a filter that selectively removes HMGB1 protein from the plasma. Should that be successful, then the use of the filter would easily adapt to already present dialysis hardware systems as well as most of the disposables used for dialysis. Only the dialyzer would be modified and perhaps, the easy to adjust, flow conditions. The presence of such a large base of systems in the health centers and that health providers are comfortable using, would allow a proven filter to be readily accepted into clinical use without the need for capital expenditure. PUBLIC HEALTH RELEVANCE Sepsis affects roughly 700,000 patients annually, is the 10th leading cause of death overall in the United States, its incidence is rising and its annual cost is over 17 billion. We propose to bring to the clinical market a filter that removes High-Mobility Group B1 (HMGB1), a cellular protein associated with increased lethality of septic patients.