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Published on: April 11, 2012
VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis
Peter Weber1, Ping Wang, Stephane Maddens
1Biology Department, Vertex Pharmaceuticals Europe Limited, Abingdon OX14 4RY, UK. peter_weber@vrtx.com
Introduction:
Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis.
Methods:
VX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP).
Results:
VX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected.
Conclusions:
Our studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.
Insights
VX-166, a broad caspase inhibitor, significantly improved survival in sepsis models when administered post-insult. This sepsis treatment shows promise by reducing lymphocyte apoptosis and improving bacterial clearance without severely impacting immune response.
Area of Science:
- Pharmacology
- Immunology
- Sepsis Research
Background:
- Caspase inhibition is a potential sepsis treatment strategy by preventing lymphocyte apoptosis.
- Previous studies lacked clear evidence of improved survival with post-insult dosing of caspase inhibitors.
- Concerns exist regarding potential immune suppression by caspase inhibitors.
Purpose of the Study:
- To characterize VX-166, a broad caspase inhibitor, as a potential sepsis therapy.
- To evaluate the efficacy of VX-166 in improving survival in sepsis models when dosed post-insult.
- To assess the impact of VX-166 on immune response markers.
Main Methods:
- VX-166 was tested in enzymatic and cellular assays.
- Efficacy was evaluated in murine endotoxic shock (lipopolysaccharide) and rat polymicrobial sepsis (cecal ligation and puncture) models.
- Survival rates, thymic atrophy, lymphocyte apoptosis, plasma endotoxin levels, and cytokine release were assessed.
Main Results:
- VX-166 demonstrated potent in vitro anti-apoptotic activity and inhibited IL-1beta and IL-18 release.
- Significant dose-dependent survival improvement was observed in LPS models with post-insult VX-166 administration.
- VX-166 improved survival in CLP models when initiated 3 hours post-insult, inhibited thymic atrophy, reduced lymphocyte apoptosis, and lowered plasma endotoxin levels.
Conclusions:
- The findings support the use of caspase inhibitors for sepsis treatment.
- VX-166 shows significant therapeutic potential for treating sepsis in humans.
