Novel Peptides for Therapeutic Treatment of Mesenteric Ischemia & Reperfusion Injury

Reference Number: K 10-19

Inventors: Fleming, Sherry

Owner: Kansas State University Research Foundation

USPTO Link:

Invention Summay

Researchers at Kansas State University have developed potential therapeutic peptides to combat mesenteric ischemia/reperfusion (mesenteric IR). Reperfusion is caused by an excessive immune response to an injury or reintroduction of blood to implanted or injured organs. This response in the intestine sends inflamed cells to surrounding mucosal organs. Research has shown that multiple antibodies recognizing intracellular proteins play a role in inflammation. However, β2-glycoprotein I (β2-GPI) is the only known soluble serum protein which is recognized by the naturally occurring antibodies leading to an inflammatory response and tissue damage. As a soluble protein, development of peptides which compete for ligand or antibody binding is a logical approach to developing a therapeutic.

There are currently no drugs for treating mesenteric IR or multiple organ failure. The mesenteric IR mortality rate is 70-90%.

Advantages

Currently, potential therapeutics that are being investigated by other research teams for mesenteric IR include complement inhibitors and peptides to non-muscle myosin, but these have the following shortcomings:

• Complement inhibitors prevent a broad spectrum innate immune response and can only be used in the short term as they render the patient more susceptible to bacterial infection.
• Non-muscle myosin peptides recognize intracellular components indicating that the cellular injury must have already begun. In addition, there is limited evidence showing that the inflammatory response is attenuated.

Potential advantages of peptides under investigation at Kansas State University include:

• Safer: does not compromise the patient’s immune system
• More Effective: in our mouse model, we show that specific peptides block complement activation and tissue damage and additional peptides block the inflammatory response
• Less Expensive to Manufacture: Previous sequences identified contained cysteine residues which are difficult to synthesize. Our data indicates that peptides in which serine has been substituted for cysteine are equally effective.

Applications

Similar injuries are prominent during organ transplant, heart bypass and stroke suggesting that the peptide therapeutic approach may have a broad use. Recent research indicates that the mechanism of injury is similar between reperfusion damage in the intestine, liver and lungs. In addition, hemorrhage, heat shock and burns also lead to decreased blood flow to the non-vital intestine and peptides may be useful therapeutics for these indications as well.

Peptides and their derivatives may be used in any disease which results in reperfusion injury. This would include:

• Mesenteric ischemia
• Heart attack
• Stroke
• Bypass surgery
• Hemorrhage
• Tourniquet use during trauma
• Organ transplantation
• Heat stroke
• May also be useful for preventing multiple organ failure in response to sepsis
• Traumatic crush injury