systemic administration of tripeptidyl peptidase i in a mouse model of late infantile neuronal ceroid lipofuscinosis effect of glycan modification系统性管理tripeptidyl肽酶在小鼠模型中我的小儿神经ceroid lipofuscinosis多糖改性的效果.pdfVIP

Systemic Administration of Tripeptidyl Peptidase I in a Mouse Model of Late Infantile Neuronal Ceroid Lipofuscinosis: Effect of Glycan Modification 1 1 2 1,3 1,3 Yu Meng , Istvan Sohar , Lingling Wang , David E. Sleat , Peter Lobel * 1 Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, United States of America, 2 Vivarium, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America, 3 Department of Pharmacology, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America Abstract 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