Systemic administration of tripeptidyl peptidase I in a mouse model of late infantile neuronal ceroid lipofuscinosis: effect of glycan modification.
Late-infantile neuronal ceroid lipofuscinosis (LINCL) is a recessive genetic disease of childhood caused by deficiencies in the lysosomal protease tripeptidyl peptidase I (TPP1). Disease is characterized by progressive and extensive neuronal death. One hurdle towards development of enzyme replacement therapy is delivery of TPP1 to the brain. In this study, we evaluated the effect of modifying N-linked glycans on recombinant human TPP1 on its pharmacokinetic properties after administration via tail vein injection to a mouse model of LINCL. Unmodified TPP1 exhibited a dose-dependent serum half-life of 12 min (0.12 mg) to 45 min (2 mg). Deglycosylation or modification using sodium metaperiodate oxidation and reduction with sodium borohydride increased the circulatory half-life but did not improve targeting to the brain compared to unmodified TPP1. Analysis of liver, brain, spleen, kidney and lung demonstrated that for all preparations, >95% of the recovered activity was in the liver. Interestingly, administration of a single 2 mg dose (80 mg/kg) of unmodified TPP1 resulted in ∼10% of wild-type activity in brain. This suggests that systemic administration of unmodified recombinant enzyme merits further exploration as a potential therapy for LINCL.
Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, United States of America.
Yu
Y
Meng
Istvan
I
Sohar
Lingling
L
Wang
David E
DE
Sleat
Peter
P
Lobel
D061605:Administration, Intravenous; D000626:Aminopeptidases / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D016466:CHO Cells; D002241:Carbohydrates / Q000737:chemistry; D006224:Cricetinae; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D004795:Enzyme Stability; D006207:Half-Life; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D057057:Serine Proteases / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000091346:Tripeptidyl-Peptidase 1
D002241:Carbohydrates; D011134:Polysaccharides; D011994:Recombinant Proteins; C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human