Burt AD

Canty D

Hu W

Leavitt MC

Quinn AG

Rutkowski JV

We previously described the liver abnormalities and effects of SBC-102, a recombinant human LAL (rhLAL) in a rat model of LAL Deficiency. SBC-102 produced dose dependent improvements in serum transaminases, liver size and liver pathology. The aim of this study was to further characterize the histopathological abnormalities in the disease model and to examine the effects of SBC-102 on liver fibrosis. A detailed histological assessment was performed on paraffin and epon resin embedded samples. Liver tissue was collected from untreated LAL deficient rats at approximately 8 weeks of age and rats treated with SBC-102 (1, 3 or 5 mg/kg, qw or qow) for ~ 19 weeks. Samples were stained with H&amp;E, Picro Sirius red or by immunohistochemistry [SMA, CD68 and LAMP-1]. Untreated rats showed extensive Kupffer cell (KC) expansion, with evidence of surrounding hepatocyte injury and disruption of normal hepatocellular architecture. Bridging and pericellular fibrosis was observed in close proximity to KC aggregates. In contrast, SBC-102 treatment resulted in marked improvements and, in most animals, resolution of KC aggregation and fibrosis. The co-localization of liver fibrosis with KC aggregates in untreated LAL deficient rats and the observed concordant decreases in fibrosis and cellular aggregates after administration of SBC-102 suggest that macrophages with abnormal substrate accumulation may exert a paracrine effect on myofibroblasts in this disease. Given the increased morbidity and mortality in patients with LAL Deficiency due to cirrhosis and other liver complications, the importance of macrophages in the pathogenesis of liver fibrogenesis in humans with this disease warrants further investigation

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Co-localization of macrophage aggregation and fibrosis in a rat model of lysosomal acid lipase (LAL) deficiency and the effects of enzyme replacement with SBC-102

Co-localization of macrophage aggregation and fibrosis in a rat model of lysosomal acid lipase (LAL) deficiency and the effects of enzyme replacement with SBC-102

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