A Basic ApoE-Based Peptide Mediator to Deliver Proteins across the Blood-Brain Barrier: Long-Term Efficacy, Toxicity, and Mechanism

Mol Ther. 2017 Jul 5;25(7):1531-1543. doi: 10.1016/j.ymthe.2017.03.037. Epub 2017 Apr 26.


We have investigated delivery of protein therapeutics from the bloodstream into the brain using a mouse model of late-infantile neuronal ceroid lipofuscinosis (LINCL), a lysosomal disease due to deficiencies in tripeptidyl peptidase 1 (TPP1). Supraphysiological levels of TPP1 are delivered to the mouse brain by acute intravenous injection when co-administered with K16ApoE, a peptide that in trans mediates passage across the blood-brain barrier (BBB). Chronic treatment of LINCL mice with TPP1 and K16ApoE extended the lifespan from 126 to >294 days, diminished pathology, and slowed locomotor dysfunction. K16ApoE enhanced uptake of a fixable biotin tracer by brain endothelial cells in a dose-dependent manner, suggesting that its mechanism involves stimulation of endocytosis. Pharmacokinetic experiments indicated that K16ApoE functions without disrupting the BBB, with minimal effects on overall clearance or uptake by the liver and kidney. K16ApoE has a narrow therapeutic index, with toxicity manifested as lethargy and/or death in mice. To address this, we evaluated variant peptides but found that efficacy and toxicity are associated, suggesting that desired and adverse effects are mechanistically related. Toxicity currently precludes direct clinical application of peptide-mediated delivery in its present form but it remains a useful approach to proof-of-principle studies for biologic therapies to the brain in animal models.

Keywords: blood brain barrier; enzyme replacement therapy; intravenous; tripeptidyl peptidase 1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aminopeptidases / deficiency
  • Aminopeptidases / genetics*
  • Animals
  • Apolipoproteins E / chemistry
  • Apolipoproteins E / pharmacokinetics*
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Brain / drug effects
  • Brain / enzymology
  • Brain / pathology
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / deficiency
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics*
  • Disease Models, Animal
  • Drug Carriers*
  • Endocytosis
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Enzyme Replacement Therapy / methods
  • Gene Expression Regulation
  • Humans
  • Infant
  • Injections, Intravenous
  • Mice
  • Neuronal Ceroid-Lipofuscinoses / enzymology
  • Neuronal Ceroid-Lipofuscinoses / genetics
  • Neuronal Ceroid-Lipofuscinoses / pathology
  • Neuronal Ceroid-Lipofuscinoses / therapy*
  • Peptides / chemistry
  • Peptides / pharmacokinetics*
  • Serine Proteases / deficiency
  • Serine Proteases / genetics*
  • Survival Analysis
  • Treatment Outcome


  • Apolipoproteins E
  • Drug Carriers
  • Peptides
  • Serine Proteases
  • Aminopeptidases
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • tripeptidyl-peptidase 1