Engineered Protein Tames Bleeding In Haemophiliacs and Targets Angiogenesis in Cancer


Project ID: D2007-12


U.S. Patent #8,211,858; Canada, European patents pending

U.S. Patent #7,592,422; Canada, France, Germany, Netherlands, UK patents pending



Modified plasminogen activator inhibitor type I (PAI- 1) with significantly increased in vivo half-life and decreased activity to urokinase plasminogen activator, tissue plasminogen activator, and vitronectin.


Invention Description:

The present technology describes a patented method of engineering a modified protein, 99.5% homologous to native human plasminogen activator inhibitor-1 (PAI-1). In the human body, PAI-1 loses 50% of its activity in just two hours. By mutating two amino acids of human PAI-1, researchers at the University of Toledo have produced a very long half-life PAI-1 protein (VLHL PAI-1--half-life 700 hours), similar to the native protein and highly specific to proteolytic enzymes responsible for blood lysis and angiogenesis. The modified PAI-l protein of the present invention may be useful for the treatment, prophylaxis, management and amelioration of cardiovascular diseases including, but not limited to those that are related to hyperfibrinolysis, haemophilia, and vessel leakage syndrome. It may also be used for inhibition of angiogenesis or other functions mediated or influenced by PAI-1, uPA, tPA or Vn, including but not limited to cell proliferation, cell migration, granulation tissue development, and/or inflammation, in conditions including psoriasis, chronic inflammation, tumor invasion and metastasis and conditions in which angiogenesis is pathogenic.


Applications and Advantages:

Haemophilia and Uncontrolled Bleeding

·       May be used as systemically as a treatment or to prevent Haemophilia A and B and to promote wound healing in patients with these conditions.

·       May be used topically to control localized bleeding and reduce blood loss after surgery or accident.

·       Prevents hemorrhage in the case of surgery, accidental wounds, postpartum bleeding, or menorrhea in patients with PAI-1-deficiency--a rare, hereditary condition resulting in frequent bleeding episodes.

·       Experiments done on mice showed significant reduction in bleeding time and total blood loss in animals treated with VLHL PAI-1.

·       No side effects of treatment in preliminary animal studies compared to aprotinin (removed from the market due to side effects).

·       Better efficacy in ex vivo studies than currently available compound (aminocaproic acid which shows limited efficacy for the control of localized bleeding in a surgical setting).

·       Prevents blood clot lysis to avoid rebleeding.


Solid Cancers

·       Inhibits angiogenic proteolytic activity in solid cancers to prevent blood vessel growth needed for nutrient and oxygen delivery.

·       Inhibition of angiogenesis and metastasis demonstrated through in vitro and in vivo (chick embryo, rat and mouse models).

·       Attacks angiogenesis, not the cancer itself, which frequently develops a resistance to treatment.

·       May be used in combination with many other anti-cancer agents and treatment types to increase efficacy.



·       May be used to treat cardio-vascular diseases such as, but not limited to those that are related to hyperfibrinolysis, promoting wound-clotting, and vessel leakage syndrome.


1.     A novel form of the plasminogen activator inhibitor created by cysteine mutations extends its half-life: relevance to cancer and angiogenesis.

2.     Plasminogen activator inhibitor type-1 mutants regulate angiogenesis of human umbilical and lung vascular endothelial cells.

3.     Very long half-life plasminogen activator inhibitor type 1 reduces bleeding in a mouse model.

4.     Recombinant PAI-1 inhibits angiogenesis and reduces size of LNCaP prostate cancer xenografts in SCID mice.

5.     Highly stable plasminogen activator inhibitor type one (VLHL PAI-1) protects fibrin clots from tissue plasminogen activator-mediated fibrinolysis.


Patent Information:
For Information, Contact:
Stephen Snider
AVP Tech Transfer
The University of Toledo
419 530 6225
Jerzy Jankun
Steven Selman
Ewa Skrzypczak-Jankun