ABSTRACT: 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.
Molecular Genetics and Metabolism 05/2012; 107(1-2):213-21. · 3.19 Impact Factor