TY - JOUR
T1 - 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
AU - Hu, Jie
AU - Lu, Jui Yun
AU - Wong, Andrew M S
AU - Hynan, Linda S.
AU - Birnbaum, Shari G.
AU - Yilmaz, Denis S.
AU - Streit, Barbara M.
AU - Lenartowicz, Ewelina M.
AU - Thompson, Thomas C M
AU - Cooper, Jonathan D.
AU - Hofmann, Sandra L.
N1 - Funding Information:
The authors wish to thank Dr. Mark Sands for advice in the experimental design and instruction in the superficial temporal vein injection technique, Dr. James Richardson and John Shelton of the UT Southwestern Molecular Pathology Core for advice and preparation of visceral tissue specimens and microscopy, and Ami Pettersen for performing the behavioral tests. This work was funded by Taylor's Tale , the Batten Disease Support and Research Association , the National Institute for Neurological Disorders and Stroke ( NS036867 ) (S.L.H.), the Batten Disease Family Association , the Natalie Fund and the Bletsoe Family (J.C.).
PY - 2012/9
Y1 - 2012/9
N2 - 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 5. months of age and death by around 8. months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3. mg, corresponding to 12. mg/kg or 180 U/kg for a 25. g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8 weeks 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 271. days (p < 0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8 weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3. months in mice treated from birth, and although this improvement persisted it was attenuated by 7. months. 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.
AB - 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 5. months of age and death by around 8. months. In the current study, PPT1 knockout mice were treated with purified recombinant PPT1 (0.3. mg, corresponding to 12. mg/kg or 180 U/kg for a 25. g mouse) administered intravenously weekly either 1) from birth; or 2) beginning at 8 weeks 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 271. days (p < 0.001) and the onset of motor deterioration was similarly delayed. In mice treated beginning at 8 weeks, no increases in survival or motor performance were seen. An improvement in neuropathology in the thalamus was seen at 3. months in mice treated from birth, and although this improvement persisted it was attenuated by 7. months. 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.
KW - Batten disease
KW - Enzyme replacement therapy
KW - Infantile neuronal ceroid lipofuscinosis
KW - Lysosomal storage disorder
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U2 - 10.1016/j.ymgme.2012.05.009
DO - 10.1016/j.ymgme.2012.05.009
M3 - Article
C2 - 22704978
AN - SCOPUS:84866171062
SN - 1096-7192
VL - 107
SP - 213
EP - 221
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 1-2
ER -