Recombinant human microplasmin: production and potential therapeutic properties

Area of Science:

• Biochemistry
• Pharmacology
• Thrombosis Research

Background:

• Ischemic stroke and arterial thrombosis are critical conditions requiring effective therapeutic interventions.
• Current treatments like recombinant tissue plasminogen activator (rt-PA) have limitations, including a narrow therapeutic window and increased bleeding risk.
• Microplasminogen (micro Plg), a truncated form of plasminogen, offers potential as a thrombolytic agent.

Purpose of the Study:

• To evaluate the efficacy and safety of recombinant human microplasmin (micro Pli) in preclinical models of ischemic stroke and arterial thrombosis.
• To compare the therapeutic effects of micro Pli with rt-PA.

Main Methods:

• Recombinant human microplasminogen (micro Plg) was expressed in Pichia pastoris, purified, and converted to microplasmin (micro Pli).
• Efficacy was assessed in middle cerebral artery ligation models in mice, measuring infarct size after treatment with micro Pli or rt-PA.
• Thrombolytic activity and bleeding risk were evaluated in an extracorporeal loop thrombosis model in rabbits using micro Pli and rt-PA.

Main Results:

• Micro Pli significantly reduced infarct size in mice at 24 hours post-occlusion, with efficacy observed up to 10 hours after MCA ligation.
• In rabbits, micro Pli induced 51% clot lysis, comparable to intact plasmin, and did not prolong bleeding times.
• Equipotent doses of rt-PA showed less efficacy in stroke models and were associated with increased bleeding in rabbits.

Conclusions:

• Recombinant micro Pli demonstrates potent thrombolytic activity in both ischemic stroke and arterial thrombosis models.
• Micro Pli offers a potentially safer and more effective alternative to rt-PA, with a broader therapeutic window.
• These findings support the further development of micro Pli for clinical application in treating thrombotic events.