title: Low doses of the novel caspase-inhibitor GS-9450 leads to lower caspase-3 and -8 expression on peripheral CD4+ and CD8+ T-cells.
abstract: Chronic hepatitis C virus (HCV) infection is characterized by increased rates of apoptotic hepatocytes and activated caspases have been shown in HCV-infected patients. GS-9450, a novel caspase-inhibitor has demonstrated hepatoprotective activity in fibrosis/apoptosis animal models. This study evaluated the effects of GS-9450 on peripheral T-cell apoptosis in chronic HCV-infected patients. As sub study of the GS-US-227-0102, a double-blind, placebo-controlled phase 2a trial evaluating the safety and tolerability of GS-9450, apoptosis of peripheral CD4+ and CD8+ T-cells was measured using activated caspase-3, activated caspase-8 and CD95 (Fas). Blood samples were drawn at baseline, day 14 after therapy and at 5 weeks off-treatment follow-up in the first cohort of 10 mg. In contrast to the placebo-treated patients, GS-9450 caused a median of 46% decrease in ALT-values from baseline to day 14 in all treated patients (median of 118-64 U/l) rising again to a median of 140 U/l (19%) at 5 weeks off-treatment follow-up. In GS9450-treated patients, during treatment and follow-up, percentages of activated caspase-3+ and caspase-8 expression tended to decrease, in contrast to placebo-treated patients. Interestingly, compared to healthy controls, higher percentages of caspase-3 and caspase-8 positive CD4+ and CD8+ T-cells were demonstrated in HCV-infected patients at baseline. Decreased ALT-values were observed in all HCV-infected patients during treatment with low dose of the caspase-inhibitor GS-9450 accompanied by a lower expression of caspase-3 and -8 on peripheral T-cells. Furthermore, at baseline percentages of activated caspase-3, activated caspase-8 and CD95+ T-cells were higher in chronic HCV-infected patients compared to healthy controls.
authors.affiliation: Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht (UMCU), Heidelberglaan, GA, Utrecht, The Netherlands. j.e.arends@umcutrecht.nl
authors.forename: J E
authors.initials: JE
authors.lastname: Arends
authors.forename: A I M
authors.initials: AI
authors.lastname: Hoepelman
authors.forename: N M
authors.initials: NM
authors.lastname: Nanlohy
authors.forename: F J P
authors.initials: FJ
authors.lastname: Höppener
authors.forename: K R
authors.initials: KR
authors.lastname: Hirsch
authors.forename: J G
authors.initials: JG
authors.lastname: Park
authors.forename: D
authors.initials: D
authors.lastname: van Baarle
mesh_terms: D000328:Adult; D017209:Apoptosis; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000472:pathogenicity; D019698:Hepatitis C, Chronic / Q000097:blood / Q000150:complications / Q000188:drug therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D019562:Viral Load; D019014:fas Receptor / Q000378:metabolism
chemical_list: D015415:Biomarkers; D004791:Enzyme Inhibitors; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8