title: Cargo Delivery into the Brain by in vivo identified Transport Peptides.
abstract: The blood-brain barrier and the blood-cerebrospinal fluid barrier prevent access of biotherapeutics to their targets in the central nervous system and therefore prohibit the effective treatment of neurological disorders. In an attempt to discover novel brain transport vectors in vivo, we injected a T7 phage peptide library and continuously collected blood and cerebrospinal fluid (CSF) using a cisterna magna cannulated conscious rat model. Specific phage clones were highly enriched in the CSF after four rounds of selection. Validation of individual peptide candidates showed CSF enrichments of greater than 1000-fold. The biological activity of peptide-mediated delivery to the brain was confirmed using a BACE1 peptide inhibitor linked to an identified novel transport peptide which led to a 40% reduction of Amyloid-β in CSF. These results indicate that the peptides identified by the in vivo phage selection approach could be useful transporters for systemically administrated large molecules into the brain with therapeutic benefits.
authors.affiliation: Neuroscience Discovery and Translation Area, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Eduard
authors.initials: E
authors.lastname: Urich
authors.affiliation: Pharmaceutical Sciences, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Schmucki
authors.affiliation: Neuroscience Discovery and Translation Area, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Nadine
authors.initials: N
authors.lastname: Ruderisch
authors.affiliation: Medicinal Chemistry, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Kitas
authors.affiliation: Pharmaceutical Sciences, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Certa
authors.affiliation: Neuroscience Discovery and Translation Area, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.affiliation: Neuroscience Discovery and Translation Area, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Schweitzer
authors.affiliation: Pharmaceutical Sciences, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bergadano
authors.affiliation: Pharmaceutical Sciences, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Ebeling
authors.affiliation: Neuroscience Discovery and Translation Area, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Loetscher
authors.affiliation: Neuroscience Discovery and Translation Area, Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Basel, Switzerland.
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Freskgård
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000737:chemistry / Q000378:metabolism; D017123:Bacteriophage T7 / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D061505:Cell Surface Display Techniques; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D056510:Position-Specific Scoring Matrices; D051381:Rats; D015203:Reproducibility of Results
chemical_list: D019151:Peptide Library; D010455:Peptides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat