Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice

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 fo...

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Published in:Molecular therapy 2021-05, Vol.29 (5), p.1853-1861
Main Authors: Morimoto, Hideto, Kida, Sachiho, Yoden, Eiji, Kinoshita, Masafumi, Tanaka, Noboru, Yamamoto, Ryuji, Koshimura, Yuri, Takagi, Haruna, Takahashi, Kenichi, Hirato, Tohru, Minami, Kohtaro, Sonoda, Hiroyuki
Format: Article
Language:English
Subjects:
blood-brain barrier
enzyme-replacement therapy
heparan sulfate
mucopolysaccharidosis II
neurocognitive impairment
neurodegeneration
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Summary: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. [Display omitted] A blood-brain-barrier-penetrable enzyme clears heparan sulfate (HS) in the brain, prevents neurodegeneration, and maintains neurocognitive function in mucopolysaccharidosis II mice. Brain HS deposition is the primary cause of CNS manifestations. The CNS disease progression and drug efficacy are shown to be predictable based on HS concentrations in cerebrospinal fluid.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2021.01.027