Abstract
Vascular tissue contains abundant elastic fibers that contribute to vessel elasticity. Vonapanitase (formerly PRT‐201) is a recombinant human chymotrypsin‐like elastase family member 1 (CELA1) shown to cleave the elastin component of elastic fibers, resulting in increased vessel diameter. The purpose of these current studies was to determine vein diameter, wall thickness, elastin content, and vonapanitase potency in veins used in a model of arteriovenous fistula (AVF) and in patients undergoing AVF creation for hemodialysis access to guide dose selection for human trials. Rabbit linguofacial, maxillary, and external jugular veins, and human basilic and upper and lower arm cephalic veins were dissected postmortem and sectioned into 2 mm length rings. Rings were incubated in vonapanitase at 37°C at varying concentrations and times. Elastin content was estimated histologically and by quantifying desmosine, a protein cross‐link unique to elastin. Rabbit veins were substantially thinner and contained less elastin than human veins. In human veins, elastin content was greatest in basilic and least in lower arm cephalic. Vonapanitase removed elastin in a time‐ and concentration‐dependent manner in all vein types. A lower concentration of vonapanitase was required to remove elastin from rabbit relative to human veins. In summary, vonapanitase reduced the elastin content of rabbit and human veins but did so at a lower concentration in the rabbit veins. Rabbit models may overestimate the potency of vonapanitase in humans. These results indicate that human dose selection should be guided by human vein ring experiments.
Highlights
Vonapanitase is a 26-kDa recombinant human chymotrypsin-like elastase family member 1 (CELA1) (Kawashima et al 1992)
Vonapanitase has been studied in human arteriovenous fistula (AVF) and arteriovenous graft (AVG) clinical trials, in which vonapanitase is applied topically to surgically exposed outflow veins immediately after AVF/AVG creation to assess the effects on a 2016 The Authors
Human recombinant chymotrypsinlike elastase family member 1 (CELA1) is under development as a treatment to promote the success of AVF surgery
Summary
Vonapanitase is a 26-kDa recombinant human chymotrypsin-like elastase family member 1 (CELA1) (Kawashima et al 1992). Vonapanitase fragments elastin and removes it from treated tissues, including blood vessels. Removal of elastin with CELA1 has been shown to increase artery and vein diameter (Dobrin et al 1984; Kitoh et al 1993), increase blood flow (Burke et al.2008), relieve vasospasm (Chew et al 2004), and reduce the formation of neointimal hyperplasia following vascular injury (Amabile et al 2002; Wong et al 2002). Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.
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