Intrathecal/Intracerebroventricular enzyme replacement therapy for the mucopolysaccharidoses: efficacy, safety, and prospects

ABSTRACT

Introduction: The mucopolysaccharidoses (MPS) are lysosomal storage diseases (LSDs) caused by the deficiency of an enzyme involved in the breakdown of glycosaminoglycans (GAGs), which leads to GAG storage and results in multisystemic manifestations. In some of the 11 MPS types, patients could have cognitive involvement and/or secondary neurologic manifestations. Intravenous enzyme replacement therapy (ERT), already approved for several MPS types, is not able to cross the blood–brain barrier and does not address the neurologic manifestations present in most MPS types. Intrathecal (IT) or intracerebroventricular (ICV) administration of the enzyme directly into the cerebrospinal fluid (CSF) has been proposed and experienced in clinical trials and in single cases.

Areas covered: This paper briefly summarizes the development of ERT to treat LSDs, particularly MPS, the technical aspects related to its CSF administration, the experience obtained so far with the IT and ICV use in several MPS types and provides an expert opinion on this subject.

Expert opinion: Treatment of neuropathic MPS remains a challenge. The results of ongoing trials may bring IT and ICV administration of ERT to clinical use in the coming years, making it a therapeutic option for the treatment of neuronopathic patients in several MPS types.

KEYWORDS:

• Mucopolysaccharidoses
• enzyme replacement therapy
• intrathecal
• intracerebroventricular
• glycosaminoglycans
• blood–brain barrier

Article highlights

• In the last 15 years, specific ERTs were approved for several types of MPS.

• Due to the inability to cross the BBB, the effects of ERT have been limited to the somatic manifestations of the MPS.

• In an attempt to provide the enzyme to the CNS, IT and ICV administration of ERT has been performed in several MPS types.

• This paper summarizes the development of ERT for LSDs and MPS in particular, the technical aspects of IT and ICV ERT administration, and the available information on the IT/ICV ERT performed in MPS I, II, IIIA, IIIB, and VI.

• Trials are still ongoing for MPS I and MPS II, with some promising results reported, including decrease of GAG level in CSF, and suggesting that younger patients would get more benefit; the trial for MPS IIIA was closed due to lack of efficacy and the trial for MPS IIIB is still in early stages; for MPS VI only, a single case was reported.

• Treatment of neuronophatic MPS remains a challenge nowadays. The results of trials ongoing may bring IT and ICV administration of ERT to clinical use, and the outcomes will have to be compared with HSCT and the new emerging therapies (Trojan horse, gene therapy, gene edition, among others), when available, regarding safety and efficacy in each specific MPS type.

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Declaration of interests

R Giugliani has received investigator fees and/or educational/travel grants and/or speaker honoraria from Actelion, Amicus, Armagen, BioMarin, JCR, Sanofi-Genzyme, Shire and Ultragenyx. D Horovitz has received investigator fees and/or educational/travel grants and/or speaker honoraria from Sanofi-Genzyme, Biomarin, Shire, Actelion, Alexion, Ultragenyx and Vertex. F Poswar has received investigator fees and/or educational/travel grants and/or speaker honoraria from Sanofi-Genzyme, Biomarin and Shire. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Declaration of interest

No potential conflict of interest was reported by the authors.

Additional information

Funding

This paper received no funded.