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Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice
- Source :
- Molecular therapy : the journal of the American Society of Gene Therapy. 29(5)
- Publication Year :
- 2020
-
Abstract
- Mucopolysaccharidosis II (MPS II), a lysosomal storage disease caused by mutations in iduronate-2-sulfatase (IDS), is characterized by a wide variety of somatic and neurologic symptoms. The currently approved intravenous enzyme replacement therapy with recombinant IDS (idursulfase) is ineffective for CNS manifestations due to its inability to cross the blood-brain barrier (BBB). Here, we demonstrate that the clearance of heparan sulfate (HS) deposited in the brain by a BBB-penetrable antibody-enzyme fusion protein prevents neurodegeneration and neurocognitive dysfunctions in MPS II mice. The fusion protein pabinafusp alfa was chronically administered intravenously to MPS II mice. The drug reduced HS and attenuated histopathological changes in the brain, as well as in peripheral tissues. The loss of spatial learning abilities was completely suppressed by pabinafusp alfa, but not by idursulfase, indicating an association between HS deposition in the brain, neurodegeneration, and CNS manifestations in these mice. Furthermore, HS concentrations in the brain and reduction thereof by pabinafusp alpha correlated with those in the cerebrospinal fluid (CSF). Thus, repeated intravenous administration of pabinafusp alfa to MPS II mice decreased HS deposition in the brain, leading to prevention of neurodegeneration and maintenance of neurocognitive function, which may be predicted from HS concentrations in CSF.
- Subjects :
- Idursulfase
Recombinant Fusion Proteins
Neurocognitive Disorders
Spatial Learning
Alpha (ethology)
Iduronate Sulfatase
Pharmacology
Blood–brain barrier
Antibodies
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Cerebrospinal fluid
Drug Discovery
Receptors, Transferrin
Genetics
Lysosomal storage disease
Medicine
Animals
Humans
Molecular Biology
030304 developmental biology
Glycoproteins
Mucopolysaccharidosis II
0303 health sciences
business.industry
Neurodegeneration
Brain
Heparan sulfate
Enzyme replacement therapy
medicine.disease
Recombinant Proteins
Disease Models, Animal
medicine.anatomical_structure
chemistry
Blood-Brain Barrier
030220 oncology & carcinogenesis
Immunoglobulin G
Molecular Medicine
Administration, Intravenous
Heparitin Sulfate
business
medicine.drug
Subjects
Details
- ISSN :
- 15250024
- Volume :
- 29
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Molecular therapy : the journal of the American Society of Gene Therapy
- Accession number :
- edsair.doi.dedup.....50c859c7c0c81ce55d1348dfde95254d