Summary
Background
MicroRNA‐122 (miR‐122) is an important host factor for hepatitis C virus replication. Administration of miravirsen, an anti‐miR‐122 oligonucleotide, resulted in a dose dependent and prolonged decrease in HCV RNA levels in chronic hepatitis C patients.
Aim
To assess the plasma level of various miRNAs in patients dosed with miravirsen.
Methods
We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) miravirsen or placebo (n = 4) over a 4‐week period in a double‐blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with miravirsen or placebo.
Results
Median plasma miR‐122 level at baseline in patients receiving miravirsen was 3.9 × 103 compared to 1.3 × 104 copies/4 μL in placebo‐dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with miravirsen had respectively a median 72‐fold, 174‐fold, 1109‐fold and 552‐fold lower expression of miR‐122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA‐profiling demonstrated a significant lower expression of miR‐210 and miR‐532‐5p compared to baseline (3.0 and 4.7‐fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR‐210 and miR‐532‐5p plasma levels throughout the study period.
Conclusions
We demonstrated a substantial and prolonged decrease in plasma miR‐122 levels in patients dosed with miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR‐122.
ABSTRACT:We aimed to determine motor, cognitive, and behavioral outcome at school age of children who had either necrotizing enterocolitis (NEC) or spontaneous intestinal perforation (SIP). This case-control study included infants with NEC Bell's stage IIA onward, infants with SIP, and matched controls (1996 -2002). At school age, we assessed motor skills, intelligence, visual perception, visuomotor integration, verbal memory, attention, behavior, and executive functions. Of 93 infants with NEC or SIP, 28 (30%) died. We included 52 of 65 survivors for follow-up. At mean age of 9 y, we found that 68% of the children had borderline or abnormal scores on the Movement Assessment Battery for Children (versus 45% of controls). Their mean total intelligence quotient (IQ) was 86 Ϯ 14 compared with 97 Ϯ 9 in the controls. In addition, attention and visual perception were affected (p Ͻ 0.01 and p ϭ 0.02). In comparison to controls, surgically treated children were at highest risk for adverse outcome. In conclusion, at school age, the motor functions and intelligence of many children with NEC or SIP were borderline or abnormal and, specifically, attention and visual perception were impaired. Children with NEC or SIP form a specific risk group for functional impairments at school age even though the majority does not have overt brain pathology. (Pediatr Res 70: 619-625, 2011)
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