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Cited by 133Lysosomal Storage Disorders ResearchCerebrospinal fluid and hydrocephalusProteoglycans and glycosaminoglycans research

CNS Penetration of Intrathecal-Lumbar Idursulfase in the Monkey, Dog and Mouse: Implications for Neurological Outcomes of Lysosomal Storage Disorder

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Calias, Pericles, Papisov, Mikhail, Pan, Jing, Savioli, Nancy, Belov, Vasily, Huang, Yan, Lotterhand, Jason, Alessandrini, Mary +4 more·2012·PLoS ONE
DOI 10.1371/journal.pone.0030341PMC PMC3261205
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Abstract

A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.

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  • Widespread penetration of substances from CSF into brain parenchyma along perivascular spaces of arteries is well supported by animal studies with a similar experimental setup.

    “Widespread penetration of substances from CSF into brain parenchyma along perivascular spaces of arteries is, however, well supported by animal studies with a similar experimental setup to ours (1, 47-49).”

    From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [47]

    The Discussion reports that CSF-delivered idursulfase reached deep brain tissue and moved within perivascular spaces; the Results also show widespread deposition in monkey and dog brains. The cited passages do not establish that those spaces specifically surround arteries, so the arterial-pathway detail is not supported by this source. (LLM, conf=0.84)

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Authors
Calias, P., Papisov, M., Pan, J., Savioli, N., Belov, V., Huang, Y., Lotterhand, J., Alessandrini, M., Liu, N., Fischman, A. J., Powell, J. L., & Heartlein, M. W.
Affiliations
Harvard University (US)
Corresponding author
Calias, Pericles
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-01-18
Volume
7
Issue
1
Pages
e30341
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0030341
PMC
PMC3261205
OpenAlex
W2172144803
Cited by
133
References
64
Citations by year
2026: 3 · 2025: 2 · 2024: 13 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 9 · 2019: 10 · 2018: 8 · 2017: 12 · 2016: 10 · 2015: 13 · 2014: 11 · 2013: 7 · 2012: 9
FWCI
8.57
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Shire Human Genetic Therapies
Topics
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
Hunter syndrome, iduronate-2-sulfatase, intracerebroventricular administration, brain drug delivery, lysosomal storage disease, glycosaminoglycan storage, oligodendrocytes, neurons, recombinant enzyme therapy
MeSH terms
Animals, Central Nervous System, Dogs, Humans, Iduronate Sulfatase, Immunohistochemistry, Injections, Spinal, Iodine Radioisotopes, Lysosomes, Macaca fascicularis, Neurons, Oligodendroglia, Recombinant Proteins, Species Specificity, Spinal Cord, Tissue Distribution, Mucopolysaccharidosis II, Mice, Knockout, Positron-Emission Tomography, Mice, Enzyme Replacement Therapy

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