Reversal of advanced disease in lysosomal acid lipase deficient mice: A model for lysosomal acid lipase deficiency disease

Ying Sun, You Hai Xu, Hong Du, Brian Quinn, Benjamin Liou, Lori Stanton, Venette Inskeep, Huimin Ran, Phillip Jakubowitz, Nicholas Grilliot, Gregory A. Grabowski

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Lysosomal acid lipase (LAL) is an essential enzyme that hydrolyzes triglycerides (TG) and cholesteryl esters (CE) in lysosomes. Mutations of the LIPA gene lead to Wolman disease (WD) and cholesterol ester storage disease (CESD). The disease hallmarks include hepatosplenomegaly and extensive storage of CE and/or TG. The effects of intravenous investigational enzyme therapy (ET) on survival and efficacy were evaluated in Lipa knock out, lal-/- mice with advanced disease using recombinant human LAL (rhLAL). Comparative ET was conducted with lower doses (weekly, 0.8 and 3.2 mg/kg) beginning at 16 weeks (study 1), and with higher dose (10. mg/kg) in early (8-weeks), middle (16-weeks) and late (24-weeks) disease stages (study 2). In study 1, rhLAL extended the life span of lal-/- mice in a dose dependent manner by 52 (0.8 mg/kg) or 94 (3.2 mg/kg) days. This was accompanied by partial correction of cholesterol and TG levels in spleen and liver. In study 2, the high dose resulted in a significant improvement in organ size (liver, spleen and small intestine) and tissue histology as well as significant decreases in cholesterol and TG in all three groups. In the treated livers and spleens the cholesterol and TG levels were reduced to below treatment initiation levels indicating a reversal of disease manifestations, even in advanced disease. ET diminished liver fibrosis and macrophage proliferation. These results show that LAL deficiency can be improved biochemically and histopathologically by various dosages of ET, even in advanced disease.

Original languageEnglish (US)
Pages (from-to)229-241
Number of pages13
JournalMolecular Genetics and Metabolism
Volume112
Issue number3
DOIs
StatePublished - Jul 2014

Keywords

  • Cholesterol esters
  • Enzyme therapy
  • Lysosomal acid lipase
  • Lysosome
  • Triglycerides

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

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    Sun, Y., Xu, Y. H., Du, H., Quinn, B., Liou, B., Stanton, L., Inskeep, V., Ran, H., Jakubowitz, P., Grilliot, N., & Grabowski, G. A. (2014). Reversal of advanced disease in lysosomal acid lipase deficient mice: A model for lysosomal acid lipase deficiency disease. Molecular Genetics and Metabolism, 112(3), 229-241. https://doi.org/10.1016/j.ymgme.2014.04.006