title: Studies of human pancreatic elastase treatment of rabbit and human vein rings to predict human therapeutic doses.
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.
authors.affiliation: Proteon Therapeutics Waltham Massachusetts.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Burke
authors.affiliation: Biopta, Ltd. Glasgow United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Bunton
authors.affiliation: Biopta, Ltd. Glasgow United Kingdom.
authors.forename: Karen
authors.initials: K
authors.lastname: Bingham
authors.affiliation: Biopta, Ltd. Glasgow United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Moss
authors.affiliation: Proteon Therapeutics Waltham Massachusetts; Present address: Stowers Institute for Medical Research Kansas City MO.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Bland
authors.affiliation: The University of Texas Health Science Center Tyler Texas.
authors.forename: Barry
authors.initials: B
authors.lastname: Starcher
authors.affiliation: Proteon Therapeutics Waltham Massachusetts.
authors.forename: Marco D
authors.initials: MD
authors.lastname: Wong
authors.affiliation: Proteon Therapeutics Waltham Massachusetts; Present address: Flow Forward Medical Olathe KS.
authors.forename: F Nicholas
authors.initials: FN
authors.lastname: Franano
keywords: CELA1; PRT‐201; chymotrypsin‐like elastase family member 1; elastase; elastin; hemodialysis access; vein; vonapanitase