Intravenous high-dose enzyme replacement therapy with recombinant palmitoyl-protein thioesterase reduces visceral lysosomal storage and modestly prolongs survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA.
Molecular Genetics and Metabolism (Impact Factor: 2.63). 05/2012; 107(1-2):213-21. DOI: 10.1016/j.ymgme.2012.05.009
Source: PubMed


PPT1-related neuronal ceroid lipofuscinosis (NCL) is a lysosomal storage disorder caused by deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). Enzyme replacement therapy (ERT) has not been previously examined in a preclinical animal model. Homozygous PPT1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5months of age and death by around 8months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3mg, corresponding to 12mg/kg or 180 U/kg for a 25g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8weeks of age. The treatment was surprisingly well tolerated and neither anaphylaxis nor antibody formation was observed. In mice treated from birth, survival increased from 236 to 271days (p<0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3months in mice treated from birth, and although this improvement persisted it was attenuated by 7months. Outside the central nervous system, substantial clearance of autofluorescent storage material in many tissues was observed. Macrophages in spleen, liver and intestine were especially markedly improved, as were acinar cells of the pancreas and tubular cells of the kidney. These findings suggest that ERT may be an option for addressing visceral storage as part of a comprehensive approach to PPT1-related NCL, but more effective delivery methods to target the brain are needed.

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    ABSTRACT: The infantile form of neuronal ceroid lipofuscinosis (ie, infantile Batten disease) is the most rapidly progressing type and is caused by an inherited deficiency in the lysosomal enzyme palmitoyl protein thioesterase 1. The absence of enzyme activity leads to progressive accumulation of autofluorescent material in many cell types, particularly neurons of the central nervous system. Clinical signs of infantile neuronal ceroid lipofuscinosis appear between 6 months and 1 year of age and include vision loss, cognitive decline, motor deficits, seizures, and premature death, typically by 3 to 5 years of age. There is currently no effective treatment. However, preclinical experiments in the murine model of infantile neuronal ceroid lipofuscinosis have shown that gene therapy, enzyme replacement, stem cell transplantation, and small-molecule drugs, alone or in combination, can significantly slow disease progression. A more thorough understanding of the underlying pathogenesis of infantile neuronal ceroid lipofuscinosis will identify new therapeutic targets.
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