Therapeutic area
Cardiotrophin-1
Acute liver failure is caused by a variety of insults, including toxic liver damage by poisons or drugs, immune or viral hepatitis, ischemia/reperfusion injury and graft rejection. Hepatic injury by these agents frequently results in cell death. The liver has a remarkable ability to regenerate itself, but it sometimes sustains severe damage that can't be reversed. The consequences of elevated cell death go beyond the simple loss of functional liver mass. Enhanced apoptosis may stimulate fibrogenesis, and increased cell turnover in the context of chronic inflammation may create a favourable scenario for cancer development. Thus, the identification of agents that reduce hepatocellular cell death is the special interest for the development of hepatoprotective therapeutics.
Cardiotrophin-1 (CT-1) belongs to the interleukin (IL-6) family of cytokines, which includes other cytokines such as IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OsM), IL-11, IL-27, cardiotrophin-like-citokine (CLC) and neuropoietin. All cytokines in this family signal through receptor complexes that includes the receptor subunit glycoprotein-130 (gp-130). Cardiotrophin-1 was first identified by its ability to induce hypertrophy of cardiac myocytes and it was later shown to support survival and proliferation of immature cardiomyocytes and developing motoneurons and to protect cardiac cells against thermal and ischemic insults by minimizing the degree of apoptosis.
Our studies have shown that CT-1 is expressed in the liver, mainly in parenchymal cells, and expresses the CT-1 receptors, LIF receptor (LIFR) and gp-130. Binding of CT-1 to its receptor on hepatocytes is followed by activation of the cell survival pathways STAT-3, AKT and ERK1/2 (Figure 1).
We have shown the hepatoprotective role of CT-1 in models of acute liver failure using the exogenous administration of CT-1 in the 90% hepatectomy in rats and in the mice model of concanavalin-A-induced hepatitis by using adenovirus encoding CT-1 (AdCT-1). Because adenoviruses have some limitations for clinical use we have proven that CT-1 given as a recombinant protein could provide protection similar to that observed with AdCT-1. Moreover, we found that treatment with recombinant CT-1 was able not only to prevent Fas-induced apoptosis in mice (another model of acute liver failure) but it also could reduce liver damage when given up to 3 hours after Fas-ligation. This suggests that this cytokine can block the apoptotic process when administered early after injury, a property that may increase its therapeutic potential. Finally, we have demonstrated that CT-1 deficiency is accompanied by a marked enhancement of the sensitivity of the liver to Fas-induced apoptosis, indicating that this cytokine plays an essential role in the natural defense of the liver against apoptosis due in part to deficient STAT-3 activation during the apoptotic process.
DEVELOPMENT
It has been found that treatment with recombinant CT-1 is able not only to prevent Fas-induced apoptosis in various models of acute liver failure but can also reduce liver damage when given up to 3 hours after Fas-ligation, suggesting that CT-1 can block the apoptotic process when administered early after injury, a property that may increase its therapeutic potential.
Digna Biotech, together with Biotecnol, is developing recombinant human CT-1 as a first in class drug to reduce ischemic reperfusion injury in the liver or kidney transplantation field and liver regeneration following hepatectomy. CT-1 has already been granted Orphan Drug Status by the EMEA (Orphan Designation Number EU/3/06/396) for prevention of ischemia/reperfusion injury associated with solid organ transplantation, and a similar request has been lodged with the FDA.
