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

Authors :
Masafumi Kinoshita
Kohtaro Minami
Kenichi Takahashi
Tohru Hirato
Haruna Takagi
Sachiho Kida
Ryuji Yamamoto
Yuri Koshimura
Eiji Yoden
Hiroyuki Sonoda
Hideto Morimoto
Noboru Tanaka
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.

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