Monitoring of liver lipid accumulation typically involves analysis of biopsy samples, carrying an associated risk to the patient. Magnetic resonance (MR) techniques allow non-invasive, safe and repeatable measurement check details of hepatic lipid content and composition. We investigated the potential of MR spectroscopy for monitoring in LAL deficient patients and in ex vivo LAL deficient rat liver tissue. We assessed the effects of enzyme

replacement therapy with sebelipase alfa (a recombinant human LAL) on hepatic lipid content and composition in the preclinical model using MR spectroscopy. Methods: Two patient cohorts comprising LAL-deficient (n=3) and NAFLD (n=5) were studied. Preclinical studies comprised ex vivo liver samples from wild type, NAFLD, LALdeficient, and LAL-deficient rats receiving 4 weeks of sebelipase alfa treatment. Hepatic 1H MR spectroscopy was performed using 3T (human) and 7Ī (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. Magnitude of signal originating from CH3 and CH2 resonances in lipid species was determined from MR data, and a spectral

model fitted to the data to determine concentrations Cisplatin and ratios of cholesterol and fatty acid chain moieties. Results: Hepatic cholesterol ester accumulation was identified Phospholipase D1 in both human and preclinical studies. LAL deficient patients had ratios of cholesterol: fatty acid moiety of 0.39 ± 0.13, compared to <0.01 in the NALFD group. In preclinical studies

a good correlation was observed between biochemical and MR assay of hepatic cholesterol content (R2 = 0.86), and marked reduction of cholesterol content was observed in LAL deficient animals treated with sebelipase alfa. Conclusions: We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters. 1H MR Spectra from LAL Deficient & NAFLD Patients Disclosures: Mark Leavitt – Employment: Synageva Corp; Stock Shareholder: Synageva Corp Wei Hu – Employment: Synageva BioPharma Corp. Joseph V. Rutkowski – Employment: Synageva BioPharma Andrew M. Blamire – Grant/Research Support: Synageva Anthony G. Quinn – Employment: Synageva BioPharma; Management Position: Synageav BioPharma; Stock Shareholder: Synageva BioPharma The following people have nothing to disclose: Peter E. Thelwall, Fiona E. Smith, Kieren G. Hollingsworth, Christian Thoma, Michael I.