The efficacy of intracerebroventricular idursulfase‐beta enzyme replacement therapy in mucopolysaccharidosis II murine model: heparan sulfate in cerebrospinal fluid as a clinical biomarker of neuropathology

Abstract

Mucopolysaccharidosis II (MPS II) is caused by a deficiency of iduronate-2-sulfatase that results in accumulation of glycosaminoglycans (GAG), including heparan sulfate (HS), which is considered to contribute to neuropathology. We examined the efficacy of intracerebroventricular (ICV) enzyme replacement therapy (ERT) of idursulfase-beta (IDS-β) and evaluated the usefulness of HS as a biomarker for neuropathology in MPS II mice. We first examined the efficacy of three different doses (3, 10, and 30 μg) of single ICV injections of IDS-β in MPS II mice. After the single-injection study, its long-term efficacy was elucidated with 30 μg of IDS-β ICV injections repeated every 4 weeks for 24 weeks. The efficacy was assessed by the HS content in the cerebrospinal fluid (CSF) and the brain of the animals along with histologic examinations and behavioral tests. In the single-injection study, the 30 μg of IDS-β ICV injection showed significant reductions of HS content in brain and CSF that were maintained for 28 days. Furthermore, HS content in CSF was significantly correlated with HS content in brain. In the long-term repeated-injection study, the HS content in the brain and CSF was also significantly reduced and correlated. The histologic examinations showed a reduction in lysosomal storage. A significant improvement in memory/learning function was observed in open-field and fear-conditioning tests. ICV ERT with 30 μg of IDS-β produced significant improvements in biochemical, histological, and functional parameters in MPS II mice. Furthermore, we demonstrate for the first time that the HS in the CSF had significant positive correlation with brain tissue HS and GAG levels, suggesting HS in CSF as a useful clinical biomarker for neuropathology.

Assessment of Activity of Daily Life in Mucopolysaccharidosis Type II Patients with Hematopoietic Stem Cell Transplantation

“…Newborn screening for MPS is essential to promote early diagnosis [38][39][40]. New delivery strategies of the enzymes into the central nervous system are also under developing [41][42][43][44][45][46][47][48][49][50][51][52][53].…”

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

“…With the aim of making ERT efficacious for the CNS compartment, different routes have been tested, including intracerebroventricular (ICV) and intrathecal (IT) administrations. ICV administration in MPS II murine models of 30 µg of idursulfase beta, every 4 weeks for 24 weeks, produced a reduction of HS in CSF and brain tissue and a significant improvement in the memory/learning functions evaluated by open-field and fear-conditioning tests [125]. A phase I/II clinical trial with idursulfase beta delivered by ICV administration is ongoing [126].…”

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

“…(2) Modified routes of administration: Intrathecal [6,7], intracisternal [33], and intracerebroventricular [8] administrations have been attempted to deliver enzymes directly by circumventing the cerebrovascular circulation involving the BBB.…”

“…Positive results have been reported in preclinical and clinical studies on MPS-I [3] and MPS-II [4,5]. Administration routes other than intravenous injection (e.g., intrathecal [6,7] and intracerebroventricular [8] injections) have also been attempted with the aim of delivering enzymes directly into the brain, but they invariably involve significant practical difficulties for both physicians and patients. Based on reports of completed, ongoing, and planned clinical trials, this paper summarizes recent advances in novel BBB penetrating ERTs to address neurodegeneration and CNS symptoms in neuropathic MPS.…”