title: Comparison of five peptide vectors for improved brain delivery of the lysosomal enzyme arylsulfatase A.
abstract: Enzyme replacement therapy (ERT) is a treatment option for lysosomal storage disorders (LSDs) caused by deficiencies of soluble lysosomal enzymes. ERT depends on receptor-mediated transport of intravenously injected recombinant enzyme to lysosomes of patient cells. The blood-brain barrier (BBB) prevents efficient transfer of therapeutic polypeptides from the blood to the brain parenchyma and thus hinders effective treatment of LSDs with CNS involvement. We compared the potential of five brain-targeting peptides to promote brain delivery of the lysosomal enzyme arylsulfatase A (ASA). Fusion proteins between ASA and the protein transduction domain of the human immunodeficiency virus TAT protein (Tat), an Angiopep peptide (Ang-2), and the receptor-binding domains of human apolipoprotein B (ApoB) and ApoE (two versions, ApoE-I and ApoE-II) were generated. All ASA fusion proteins were enzymatically active and targeted to lysosomes when added to cultured cells. In contrast to wild-type ASA, which is taken up by mannose-6-phosphate receptors, all chimeric proteins were additionally endocytosed via mannose-6-phosphate-independent routes. For ASA-Ang-2, ASA-ApoE-I, and ASA-ApoE-II, uptake was partially due to the low-density lipoprotein receptor-related protein 1. Transendothelial transfer in a BBB cell culture model was elevated for ASA-ApoB, ASA-ApoE-I, and ASA-ApoE-II. Brain delivery was, however, increased only for ASA-ApoE-II. ApoE-II was also superior to wild-type ASA in reducing lysosomal storage in the CNS of ASA-knock-out mice treated by ERT. Therefore, the ApoE-derived peptide appears useful to treat metachromatic leukodystrophy and possibly other neurological disorders more efficiently.
authors.affiliation: Institute of Biochemistry and Molecular Biology, Rheinische Friedrich-Wilhelms Universität, D-53115 Bonn, Germany; and Institute of Biochemistry, Westfälische Wilhelms-Universität, D-48149 Münster, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Böckenhoff
authors.forename: Sandra
authors.initials: S
authors.lastname: Cramer
authors.forename: Philipp
authors.initials: P
authors.lastname: Wölte
authors.forename: Simeon
authors.initials: S
authors.lastname: Knieling
authors.forename: Claudia
authors.initials: C
authors.lastname: Wohlenberg
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gieselmann
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Galla
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matzner
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000008:administration & dosage* / Q000172:deficiency / Q000235:genetics; D003412:Cricetulus; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000502:physiology*; D006801:Humans; D007966:Leukodystrophy, Metachromatic / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D010455:Peptides; D017527:Receptor, IGF Type 2; D011993:Recombinant Fusion Proteins; C034304:cation-dependent mannose-6-phosphate receptor; D002553:Cerebroside-Sulfatase
keywords: arylsulfatase A; blood–brain barrier; enzyme replacement therapy; lysosomal storage disease; metachromatic leukodystrophy; peptide vectors