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Novel Peptides for Treatment of Ischemia & Reperfusion Injuries, Inflammation, and Cancer

Researchers at Kansas State University (K-State) have developed therapeutic peptides to combat excessive inflammation and tissue damage in response to ischemia/reperfusion (IR). Reperfusion (the return of blood flow) significantly magnifies ischemia (lack of blood flow) induced tissue damage in multiple clinical conditions including myocardial infarction, trauma and hemorrhage. During reperfusion, antibody recognition of endogenous damage-associated proteins, is followed by an excessive inflammatory response frequently resulting in multiple organ failure and death.

Although multiple intracellular antigens are recognized by the antibodies, β2-glycoprotein I (β2-GPI) is the only known serum protein recognized by the naturally occurring antibodies. Antibody binding to membrane-bound β2-GPI leads to an excessive inflammatory response resulting in tissue damage. Development of peptides which compete for the β2-GPI cell surface receptor is a logical approach for developing candidate therapeutics. β2-GPI also is critical to formation of new blood vessels in tumors suggesting the peptides under development at K-State may also decrease tumor growth.

ADVANTAGES:

-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.

-Longer Half Life: Using the reverse sequence and D amino acids, the peptide retains biological activity while being more resistant to degradation.

-Therapeutic Administration Retains Activity: Peptides administered during reperfusion retain activity.

APPLICATIONS:

-Cancer treatment

-Treating mesenteric IR. The mortality rate of mesenteric IR remains >70%

IR TREATMENT RESULTS:

image 1

Representative intestinal sections. Wildtype mice were subjected to Sham or IR treatment in the presence or absence of peptide (296c-s or p9). After 30 min ischemia and 2 hr reperfusion, intestinal tissue was collected and H&E stained.

Treatment Injury score (0-5 pt scale) Villus height/Crypt depth PGE2 (pg/mg tissue) IL-6 (pg/mg tissue)
Sham 0.55±0.04 3.2±0.1 2432±300 0.56±0.18
IR 2.1±0.1 1.9±0.2 6560±90 8.4±0.9
Peptide 296c-s + IR 1.1±0.3 3.0±0.3 1068±200 2.0±0.2
Peptide 9 + IR 1.5±0.1 3.5±0.1 1341±300 0.90±0.49
Peptide RD-p9 +IR 1.5±0.1 3.0±0.1 1021±80 0.66±0.31

Mice were subjected to Sham (control surgery without ischemia) or IR (30 min ischemia followed by 2 hr reperfusion) with or without peptide treatment prior to ischemia. After euthanization, the intestinal tissue was removed and formalin fixed for injury score and villus height/crypt depth determination. Additional tissue sections were incubated at 37oC for 20 min to determine Prostaglandins E2 (PGE2) and Interleukin 6 (IL-6). Each secretion is expressed per mg of tissue protein per 20 min.

Myocardial IR:Similar to mesenteric IR, myocardial infarction is an ischemic event and treatment with either bypass surgery or placing of stents results in reperfusion-induced damage. Based on the literature, excessive inflammation mediates this tissue damage. Therefore, peptide treatment prior to surgical treatment is expected to significantly reduce tissue damage.(We have established the model and will have data soon.)

HEMORRHAGE TREATMENT RESULTS:

Hemorrhage:  When blood volume decreases during hemorrhage, the remaining blood is shunted to the vital organs. This causes an ischemic gut which is reperfused when blood volume is increased therapeutically. Similar to mesenteric IR, local intestinal damage occurs due to an excessive inflammatory response. Subsequently, a systemic inflammatory response may result in multiple organ damage (MOD) and death. Thus, attenuating the excessive intestinal damage by therapeutic peptide treatment may prevent both local and systemic tissue damage.

image 2

Peptide 296c-s prevents hemorrhage induced intestinal damage and inflammation. Wildtype mice were subjected to hemorrhage (HS) with removal of 30% blood volume. Following 2 hrs of reperfusion intestinal tissue was analyzed for mucosal injury (A), prostaglandin E2 (B) and interleukin 6 (C) as markers of tissue damage and inflammation. PGE2 and IL-6 are expressed as pg/mg tissue/20 min. * indicates significant difference from hemorrhage treatment. n= 7-10 animals per treatment.

  • Transplantation:As organ transplant involves significant ischemia followed by reperfusion, it is likely that the peptides will improve organ survival rates by attenuating reperfusion damage.
  • Cancer: Excessive tissue within tumors frequently become hypoxic as the tumor outgrows the normal vascular system. The tumor responds with the production of angiogenic factors which results in reperfusion of the tumor tissue. As such, treatment with the current peptides demonstrated a reduction in tumor size in mouse models of melanoma and breast cancer.  

TUMOR TREATMENT RESULTS:

image 3

Peptide treatment decreases tumor size. Mice were injected s.q. with B16F10 melanoma cells and treated with or without peptide 296c-s on days 1,2,3,4,6,and 8. Each bar represents the mean ± SEM of 4-5 tumors. Photomicrographs (10X) of representative B16-F10 tumors extracted from C57Bl/6 wildtype mice were taken with a Nikon CoolSnap CF camera and an Olympus SZ61 microscope.

image 5image 6

Peptide treatment decreases new blood vessel formation as indicated by CD31 and Pan-endothelial marker expression.Mice were injected s.q. with B16F10 melanoma cells and treated with or without peptide 296c-s on days 1,2,3,4,6,and 8. Tissues were cryopreserved and stained for CD31 expression to indicate endothelial junctions and with a pan-endothelial antibody to identify small vessel formation. As a marker of vascularity, endoglin was evaluated by qRT-PCR and is reported as fold change compared to cultured B16F10 melanoma cells which are set as 1. Each bar represents the mean ± SEM of 4-5 tumors. Photomicrographs (200X) are representative of 3 experiments with 4-5 fields per slide and were taken with a Nikon CoolSnap CF camera and an Olympus SZ61 microscope.

  • Systemic Inflammatory response (SIRS): As systemic inflammation results from immune complex formation and excessive complement activation, it is possible that the peptides will decrease the excessive response and attenuate SIRS after sepsis and trauma.
  • Stroke:Stroke by definition includes ischemic brain tissue and current therapeutics may result in reperfusion. Therefore, the peptides may decrease reperfusion injury after stroke as well.

In addition, 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.

PATENT STATUS:

-U.S. patent #8,895,502 issued on November 25, 2014.

Additional Details

Owner

Kansas State University

Intellectual Property Protection

Patent Issued



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