Repurposing of Plasminogen: An Orphan Medicinal Product Suitable for SARS-CoV-2 Inhalable Therapeutics

Abstract

The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered from the COVID-19 disease. Therefore, local pulmonary fibrinolysis can be efficacious in degrading pre-existing fibrin clots and reducing the conversion of lung lesions into lasting scars. Plasminogen is considered a key player in fibrinolysis processes, and in view of a bench-to-bedside translation, we focused on the aerosolization of an orphan medicinal product (OMP) for ligneous conjunctivitis: human plasminogen (PLG-OMP) eye drops. As such, the sterile and preservative-free solution guarantees the pharmaceutical quality of GMP production and meets the Ph. Eur. requirements of liquid preparations for nebulization. PLG-OMP aerosolization was evaluated both from technological and stability viewpoints, after being submitted to either jet or ultrasonic nebulization. Jet nebulization resulted in a more efficient delivery of an aerosol suitable for pulmonary deposition. The biochemical investigation highlighted substantial protein integrity maintenance with the percentage of native plasminogen band > 90%, in accordance with the quality specifications of PLG-OMP. In a coherent way, the specific activity of plasminogen is maintained within the range 4.8–5.6 IU/mg (PLG-OMP pre-nebulization: 5.0 IU/mg). This is the first study that focuses on the technological and biochemical aspects of aerosolized plasminogen, which could affect both treatment efficacy and clinical dosage delivery. Increasing evidence for the need of local fibrinolytic therapy could merge with the availability of PLG-OMP as an easy handling solution, readily aerosolizable for a fast translation into an extended clinical efficacy assessment in COVID-19 patients.

Association between hemostasis and acute mesenteric ischemia: a Mendelian randomization analysis

“…Interestingly, in COVID-19 patients with acute respiratory distress syndrome, plasminogen inhalation improved clinical outcomes possibly due to its brin-degrading effects on pulmonary microcoagulopathy [24,25]. Supplementation of plasminogen to increase the brinolytic activity could be a potentially innovative therapy to reduce intestinal injury caused by mesenteric ischemia and also a possible preventive strategy for high-risk population of AMI.…”

Biopharmaceutical Assessment of Mesh Aerosolised Plasminogen, a Step towards ARDS Treatment

“…Pulmonary delivery of PLG, through the off-label administration of PLG-OMP eye drops, has been considered as a possible therapy for C-ARDS patients [ 1 ]. During the COVID-19 pandemic, several drugs acting on the coagulopathy aspect of the disease were investigated.…”

“…Only when the jet aerosolisation was set to the lowest air pressure, it was possible to preserve 89.8% of PLG proteolytic activity. However, the median diameter value (dv (50) ) resulted 9.2 ± 1.0 µm, which is not suited for pulmonary delivery [ 1 ]. Vibrating-mesh nebulisers, like the Aerogen ® Solo TM , employ perforated plates that vibrate to generate aerosols.…”

“…Acute respiratory distress syndrome (ARDS) is described as noncardiogenic pulmonary oedema accompanied by severe lung inflammation, hypoxemia and decreased lung compliance. Respiratory failure is therefore the consequence of reduced alveolar–capillary oxygen transfer due to inflammation, vascular microthrombus and hyaline membrane/oedema in the alveoli [ 1 , 2 ].…”

“…Eur. requirements for a solution for aerosolisation [ 1 ]. However, part of the enzymatic activity was lost during either ultrasonic or jet nebulisation; it was found a limited correspondence between suitable lung-targeted aerodynamic distribution and activity performance.…”