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

Survival Effects of pGSN Replenishment

The pGSN levels have been shown to fall in a wide variety of animal models of serious injury by 50-95% (see “Tissue Effects of pGSN Repletion”). This level of depletion is comparable to that reported in patients (see “pGSN Levels in Disease”). Repletion of the pGSN levels using rhu-pGSN (human recombinant form of pGSN, Solinex™) ameliorates much of the progressive systemic tissue injury that results from inappropriate systemic inflammation (see “Tissue Effects of pGSN Repletion”). This improvement in severity of tissue damage translates into marked improvements in survival in two animal models of fatal injury tested to date.

In a peritonitis study, mice underwent surgery in which the cecum was exposed, ligated and punctured allowing stool to spill into the peritoneal cavity. The incision was then closed and a subcutaneous administration of either rhu-pGSN or saline placebo given and treatment was repeated at 24 hours (Lee et al. 2007; Crit Care Med 35: 849-55). All animals rapidly developed polymicrobial peritonitis. Antibiotics were not administered in this model. As can be seen below, placebo animals had a 100% mortality rate by 48 hours while those treated with rhu-pGSN had a statistically significant improvement.

In a lipopolysaccharide (LPS, endotoxin) challenge study, mice were given a lethal dose of LPS and a subcutaneous administration of rhu-pGSN or placebo (either saline or a non-specific protein, bovine serum albumin) and the treatment was repeated at 24 hours (Lee et al. 2007; Crit Care Med 35: 849-55). As expected, in placebo treated animals the pGSN levels fell to about 25% of the normal level by 6 hours while those animals treated with rhu-pGSN had essentially normal levels. As seen below, placebo treatment was associated with a 100% mortality rate by 5-6 days while treatment with rhu-pGSN was associated with a markedly reduced mortality.  

CBC believes that there is compelling evidence to support the hypothesis that rhu-pGSN, when given to patients with critical hypogelsolinemia, can ameliorate the progression of systemic complications and death associated with uncontrolled systemic inflammation. There is abundant evidence in both animals and patients that there is a depletion of pGSN proportional to the degree of tissue injury. The depletion of pGSN below a critical threshold is closely associated with signs of systemic inflammation leading to systemic tissue injury and death. Repletion of the depressed pGSN levels ameliorates much of the systemic tissue damage and positively effects mortality in several animal models.