title: Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration.
abstract: A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA 98104; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195;
authors.forename: Drew L
authors.initials: DL
authors.lastname: Sellers
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195;
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Bergen
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195;
authors.forename: Russell N
authors.initials: RN
authors.lastname: Johnson
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA 98104; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195;
authors.forename: Heidi
authors.initials: H
authors.lastname: Back
authors.affiliation: Department of Neurosciences, University of California, San Diego, CA 92093;
authors.forename: John M
authors.initials: JM
authors.lastname: Ravits
authors.affiliation: Department of Neurological Surgery, University of Washington, Seattle, WA 98104; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195; Center for Neuroregenerative Medicine, Houston Methodist Research Institute, Houston, TX 77030; spun@uw.edu pjhorner@houstonmethodist.org.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Horner
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98195; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA 98195 spun@uw.edu pjhorner@houstonmethodist.org.
authors.forename: Suzie H
authors.initials: SH
authors.lastname: Pun
mesh_terms: D001369:Axons; D006801:Humans; D019426:Integrases / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D021381:Protein Transport; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism*
chemical_list: D010455:Peptides; C045073:Cre recombinase; D019426:Integrases
keywords: drug delivery; motor neuron; peripheral nerve; phage display