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Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood–brain barrier
Open accessAbstract
To realize the potential of large molecular weight substances to treat neurological disorders, novel approaches are required to surmount the blood–brain barrier (BBB). We investigated whether fusion of a receptor-binding peptide from apolipoprotein E (apoE) with a potentially therapeutic protein can bind to LDL receptors on the BBB and be transcytosed into the CNS. A lysosomal enzyme, α- L -iduronidase (IDUA), was used for biological and therapeutic evaluation in a mouse model of mucopolysaccharidosis (MPS) type I, one of the most common lysosomal storage disorders with CNS deficits. We identified two fusion candidates, IDUAe1 and IDUAe2, by in vitro screening, that exhibited desirable receptor-mediated binding, endocytosis, and transendothelial transport as well as appropriate lysosomal enzyme trafficking and biological function. Robust peripheral IDUAe1 or IDUAe2 generated by transient hepatic expression led to elevated enzyme levels in capillary-depleted, enzyme-deficient brain tissues and protein delivery into nonendothelium perivascular cells, neurons, and astrocytes within 2 d of treatment. Moreover, 5 mo after long-term delivery of moderate levels of IDUAe1 derived from maturing red blood cells, 2% to 3% of normal brain IDUA activities were obtained in MPS I mice, and IDUAe1 protein was detected in neurons and astrocytes throughout the brain. The therapeutic potential was demonstrated by normalization of brain glycosaminoglycan and β-hexosaminidase in MPS I mice 5 mo after moderate yet sustained delivery of IDUAe1. These findings provide a noninvasive and BBB-targeted procedure for the delivery of large-molecule therapeutic agents to treat neurological lysosomal storage disorders and potentially other diseases that involve the brain.
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“Some of those exchangeable apolipoproteins (ApoA1 and ApoE) can cross the blood-brain barrier (BBB) via receptor-mediated transcytosis18–21”
From Brain-targeted drug delivery by manipulating protein corona functions (2019) · cites this paper as [19]
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Metadata
- Authors
- Wang, D., El-Amouri, S. S., Dai, M., Kuan, C.-Y., Hui, D. Y., Brady, R. O., & Pan, D.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Divisions of aExperimental Hematology and Cancer Biology and
- Departments of cPathology and
- National Institutes of Health (US)
- University of Cincinnati (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-02-04
- Volume
- 110
- Issue
- 8
- Pages
- 2999-3004
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3581871
- OpenAlex
- W2058352256
- Cited by
- 159
- References
- 36
- Citations by year
- 2026: 12 · 2025: 5 · 2024: 8 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 19 · 2019: 17 · 2018: 13 · 2017: 8 · 2016: 10 · 2015: 8 · 2014: 17 · 2013: 5
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massachusetts Institute of Technology
- Seattle Children's Research Institute
- Children’s Hospital of Wisconsin Research Institute
- National Institutes of Health (NS064330)
- National Heart, Lung, and Blood Institute (Z01HL006008, U54 HL-06008)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK074932, R01DK074932)
- National Institute of Neurological Disorders and Stroke (NS 064330, R01NS064330)
- Topics
- Health Sciences › Medicine › Genetics (clinical) › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- blood-brain barrier, LDL receptor, receptor-mediated transcytosis, alpha-L-iduronidase, mucopolysaccharidosis type I, lysosomal storage disease, brain drug delivery, fusion protein, glycosaminoglycans, beta-hexosaminidase, lysosomal enzyme trafficking
- MeSH terms
- Animals, Apolipoproteins E, Binding Sites, Blood-Brain Barrier, Disease Models, Animal, Mucopolysaccharidosis I, Lysosomes, Receptors, LDL, Protein Engineering, Mice, Transcytosis
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