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Review
. 2020 Jan 8;21(2):400.
doi: 10.3390/ijms21020400.

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

Yuji Sato  1 , Torayuki Okuyama  2
Affiliations
Review

Novel Enzyme Replacement Therapies for Neuropathic Mucopolysaccharidoses

Yuji Sato et al. Int J Mol Sci. .

Abstract

Although the advent of enzyme replacement therapy (ERT) for mucopolysaccharidoses (MPS) has paved the way for the treatment for these hereditary disorders, the blood brain barrier (BBB) has prevented patients with MPS involving the central nervous system (CNS) from benefitting from ERT. Therefore, finding ways to increase drug delivery into the brain across the BBB remains a crucial challenge for researchers and clinicians in the field. Attempts have been made to boost brain uptake of enzymes by targeting various receptors (e.g., insulin and transferrin), and several other administration routes have also been tested. This review summarizes the available information on clinical trials (completed, ongoing, and planned) of novel therapeutic agents with efficacy against CNS symptoms in neuropathic MPS and also discusses the common associated challenges and pitfalls, some of which may help elucidate the pathogenesis of the neurodegeneration leading to the manifold CNS symptoms. A summary of current knowledge pertaining to the neuropathological progression and resultant neuropsychiatric manifestations is also provided, because it should be useful to ERT researchers looking for better approaches to treating CNS lesions in MPS.

Keywords: blood brain barrier; enzyme replacement therapy; insulin receptor; neurodegeneration; neuropathic mucopolysaccharidosis; transcytosis; transferrin receptor.

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Conflict of interest statement

Y.S. is a Board Member of JCR Pharmaceuticals. T.O. reports research grants from Sanofi, JCR Pharmaceuticals, GC Pharma, Dainippon Sumitomo Pharma, Actelion, Alexion, and Anges, along with honoraria from Sanofi, Dainippon Sumitomo Pharma, Actelion, and Anges.

Figures

Figure 1
Figure 1
Neuropathological progression in neuropathic MPS.
Figure 2
Figure 2
Schematic representation of the transcytosis mechanism.
Figure 3
Figure 3
Hierarchical progression of neurodegeneration and CNS manifestations in MPS.
See this image and copyright information in PMC

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