title: Effective intravenous therapy for neurodegenerative disease with a therapeutic enzyme and a peptide that mediates delivery to the brain.
abstract: The blood-brain barrier (BBB) presents a major challenge to effective treatment of neurological disorders, including lysosomal storage diseases (LSDs), which frequently present with life-shortening and untreatable neurodegeneration. There is considerable interest in methods for intravenous delivery of lysosomal proteins across the BBB but for the most part, levels achievable in the brain of mouse models are modest and increased lifespan remains to be demonstrated. In this study, we have investigated delivery across the BBB using a mouse model of late-infantile neuronal ceroid lipofuscinosis (LINCL), a neurodegenerative LSD caused by loss of tripeptidyl peptidase I (TPP1). We have achieved supraphysiological levels of TPP1 throughout the brain of LINCL mice by intravenous (IV) coadministration of recombinant TPP1 with a 36-residue peptide that contains polylysine and a low-density lipoprotein receptor binding sequence from apolipoprotein E. Importantly, IV administration of TPP1 with the peptide significantly reduces brain lysosomal storage, increases lifespan and improves neurological function. This simple "mix and inject" method is immediately applicable towards evaluation of enzyme replacement therapy to the brain in preclinical models and further exploration of its clinical potential is warranted.
authors.affiliation: Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Sohar
authors.affiliation: Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Sleat
authors.affiliation: Department of Environmental and Occupational Medicine, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Richardson
authors.affiliation: Department of Pharmacology & Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Reuhl
authors.affiliation: Department of Experimental Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Department of Experimental Pathology, Mayo Clinic, Rochester, Minnesota, USA; Department of Orthopedics, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Gobinda
authors.initials: G
authors.lastname: Sarkar
authors.affiliation: Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey, USA; Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, New Jersey, USA. Electronic address: lobel@cabm.rutgers.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Lobel
mesh_terms: D061605:Administration, Intravenous; D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D016466:CHO Cells; D003412:Cricetulus; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D010455:Peptides / Q000008:administration & dosage*; D011994:Recombinant Proteins; D057057:Serine Proteases / Q000378:metabolism*; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D001057:Apolipoproteins E; D010455:Peptides; 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