SEFA-6179 Prevents Cholestasis, Steatosis, and Fibrosis in a Preterm Piglet Model of Intestinal Failure-associated Liver Disease
Scott C. Fligor1,2, Savas T. Tsikis1,2, Thomas I. Hirsch1,2, Amy Pan1,2, Paul Mitchell3, Kamila2, Lorena Rincon-Cruz2, Ashlyn Whitlock2, Arthur Nedder4, Kathleen Gura5, Mark Puder1,2
1Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; 2Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; 3Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA; 4Animal Care Resources Children's Hospital, Boston Children's Hospital, Boston, MA, USA; 5Department of Pharmacy and the Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA
Background: Long-term parenteral nutrition (PN) causes intestinal failure-associated liver disease (IFALD), ranging from cholestasis to liver failure requiring transplantation. SEFA-6179 is a synthetic medium chain fatty acid analogue that protects against liver injury in murine models.
Methods: Preterm Yorkshire piglets were delivered by C-section at 111 days gestation. PN/Intralipid was administered via jugular catheter. Piglets were randomized to daily orogastric gavage of medium chain triglyceride (MCT, n=6) vehicle or SEFA-6179 (48mg/kg, n=5) until sacrifice at day of life (DOL) 15. Biochemical markers were measured and histology was assessed by a masked pathologist.
Results: The MCT and SEFA-6179 groups received similar PN volume (133.8 vs. 131.6 ml/kg/day, P=0.73) and gained similar weight (0.50 vs. 0.59 kg, P=0.23). Compared to MCT at DOL 15, SEFA-6179 decreased plasma total and direct bilirubin (Fig 1a-b: 2.58 vs. 0.60 mg/dL, P=0.02; 1.60 vs. 0.26 mg/dL, P=0.02), plasma bile acids (Fig 1c: 17.7 vs. 3.2 umol/L, P=0.03) and plasma GGT (Fig 1d: 189.2 vs. 33.6 IU/L, P=0.03). SEFA-6179 decreased hepatic steatosis (Fig 1e: liver triglyceride content 15.6 vs. 41.2mg triglycerides/g tissue) and decreased Ishak fibrosis score (Fig 1f: median 3 vs. 1, P=0.007).
Conclusion: Despite hepatoprotective strategies, many patients on long-term PN have progressive liver injury and fibrosis. SEFA-6179 prevents cholestasis, steatosis, and fibrosis in a preterm piglet model of IFALD. Based on this work, SEFA-6179 entered a Phase I trial.
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