Plasma gelsolin (pGSN)
Quick links:
-> Proposed Mechanism of Action
-> General Gelsolin Information
-> Gelsolin Binding
-> pGSN Levels in Disease
-> Tissue Effects of pGSN Repletion
-> Survival Effects of pGSN Repletion
General Gelsolin Information
Cellular gelsolin was discovered in 1979 and was characterized as a cellular actin binding protein involved in the remodeling of cellular actin filaments. These changes to the cell’s cytoskeleton are associated with cell shape changes and movement. Gelsolin is unique among mammalian proteins in having a secreted isoform of its cellular form called plasma gelsolin (“pGSN”). Both cellular and plasma isoforms originate from the same gene on chromosome 9, and alternative mRNA metabolism explains their different deployments.
Plasma gelsolin is a bona fide secreted protein with a processed signal sequence. It is otherwise identical to the cellular form with the exception of a 25 amino acid stretch at the molecule’s amino terminus, designated the “plasma extension”. Therefore, the plasma form of gelsolin is slightly larger (84 kDa) than the cellular variant (82kDa). Cellular gelsolin has a six-fold sequence repeat structure that is highly conserved among gelsolins of vertebrate species. The plasma extension, however, is more variable between different organisms. Many tissues secrete plasma gelsolin. Since muscle usually is the largest portion of human tissue, it appears to be the major source of plasma gelsolin.
Plasma gelsolin (pGSN) circulates in human and rodent blood at concentrations of 250 ± 50 mg/L. This makes pGSN the fourth most common plasma protein. The delay in identification of this common protein is attributed to the fact that anti-pGSN antibodies have not been described in either multiply transfused patients or multiparous women. This apparent lack of immunogenicity is consistent with the remarkable evolutionary conservation of the protein’s structure. There are only minor differences in gelsolin structure between human and mouse gelsolin molecules.
In 1993 it was shown that pGSN diminished the viscosity of thick airway secretions from patients with cystic fibrosis, presumably because actin filaments contribute to this viscosity. This led to pGSN technology being licensed by a major Boston teaching hospital to a reputable biotechnology company that developed proprietary methods for the production of recombinant human plasma gelsolin (rhu-pGSN) in E. coli. It was found that E. coli does not properly pair sulfhydryl groups during secretion but that treatment of the secreted product with oxidized glutathione leads to the correct orientation. Instillation of rhu-pGSN into rodents and Cynomologous monkeys, both intravenously and by inhalation, revealed no toxicities. Human volunteers receiving rhu-pGSN in a formulation containing Tween by inhalation had no toxic reactions. Consequently, a small (16-patient) phase 2 dose-escalation trial of inhaled rhu-pGSN was carried out in cystic fibrosis patients in Canada. Although two patients receiving the highest doses showed significant improvements in airway resistance (FEV1), the phase 2 trial was too small to conclude with any confidence that rhu-pGSN is effective as a mucolytic in cystic fibrosis and so the licensee, when faced with more compelling later-stage opportunities, gave back the licensed intellectual property, including the relevant manufacturing methods and cell lines. This original IP and know-how, together with substantial new IP pertaining to pGSN’s role in predicting and suppressing systemic pathological responses to infections, inflammatory diseases and other conditions has since been licensed to CBC.
