Reversal of advanced disease in lysosomal acid lipase deficient mice: a model for lysosomal acid lipase deficiency disease.
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 3.2mg/kg) beginning at 16 weeks (study 1), and with higher dose (10mg/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 (3.2mg/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.
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA; The Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, OH 45229, USA. Electronic address: ying.sun@cchmc.org.
Ying
Y
Sun
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA; The Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, OH 45229, USA.
You-Hai
YH
Xu
The Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5120, USA.
Hong
H
Du
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA.
Brian
B
Quinn
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA.
Benjamin
B
Liou
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA.
Lori
L
Stanton
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA.
Venette
V
Inskeep
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA.
Huimin
H
Ran
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA; University of Cincinnati, OH 45221, USA.
Phillip
P
Jakubowitz
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA; University of Cincinnati, OH 45221, USA.
Nicholas
N
Grilliot
The Division of Human Genetics, Cincinnati Children's Hospital Research Foundation, USA; The Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, OH 45229, USA; Synageva BioPharma Corp., Lexington, MA 02421, USA.
Gregory A
GA
Grabowski
D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D005260:Female; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010641:Phenotype; D002787:Sterol Esterase / Q000008:administration & dosage; D016896:Treatment Outcome; D015223:Wolman Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*
D008055:Lipids; D002787:Sterol Esterase
Cholesterol esters; Enzyme therapy; Lysosomal acid lipase; Lysosome; Triglycerides