Galectin-3 is normally found in most tissues at low concentration, but is up-regulated (increases) in response to injury. Several recent publications have suggested that an increase in circulating galectin-3 correlates with an increase in fibrogenesis leading to organ failure including chronic kidney disease, chronic liver disease, pulmonary and cardiac disease. We hypothesize that modulation of galectin-3 during renal transplantation and recovery may result in decreased fibrosis and thus overall improved kidney function over time. Our pipeline inlcudes our lead compound, GCS-100, a first-in-class galectin-3 antagonist which is currenlty being tested in patients with chronic kidney disease. In addition, we are developing other galectin antogonists.
Publications on the role of galectins in chronic organ failure can be found here.
Galectin 3 and Chronic Kidney Disease
Recent studies have shown that increased circulating levels of galectin-3 are associated with poorer outcomes in the general population (de Boer, 2012) and patients with end-stage-renal disease (de Boer, 2011). As reported, these studies, which utilized an FDA approved assay for galectin-3, examined the circulating galectin-3 levels in patients with end-stage renal disease on dialysis and showed galectin-3 to be very elevated in this population. In addition, this study showed that high levels of galectin-3 are independently associated with stroke, cardiovascular events, all-cause and infectious mortality in dialysis patients.
In addition to the human data that correlates elevated levels of galectin-3 with poor outcome, a number of preclinical studies using multiple animal models including unilateral ureteric obstruction (UUO), ischemia reperfusion (I/R) and renal transplant have demonstrated a direct, causal role of galectin-3 expression and secretion by macrophages in the formation of tissue fibrosis leading to kidney failure (Henderson et al, 2008; Bertocchi et al, 2008; and Dang, 2012). Specifically, animals that have been genetically engineered to lack galectin-3 show reduced fibrosis after kidney injury and allogeneic transplantation. Other studies have demonstrated reduced inflammatory cytokine expression and preserved kidney function after insult. Following are summaries of the aforementioned studies.
For example, in one study by Henderson et al, a unilateral ureteric obstruction (UUO) model was used to simulate chronic kidney disease in galectin-3 knockout mice vs. wild-type. As indicated in the figure (above right), the degree of fibrosis (as measured by collagen and procollagen is significantly lower in mice without galectin-3.
In another model of renal transplant rejection, by Dang et al, galectin-3 was shown to promote the rejection of kidney transplants in mouse models by promoting fibrosis and tubular atrophy. Both are common problems of kidney transplantation. is
Galectin 3 and Chronic Liver Disease
A recent study showed a higher levels of galectin-3 were negatively associated with liver function in patients with liver cirrhosis(Wanninger et al., 2011).
In addition to this human data that correlates elevated levels of galectin-3 with poor outcome, a number of preclinical studies using multiple animal models have demonstrated a causal role of galectin-3 expression and secretion by macrophages in the formation of fibrosis leading to liver disease (Henderson et al., 2006, Iacobini et al., 2011). Specifically, animals that have been genetically engineered to lack galectin-3 show reduced fibrosis after liver injury