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

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.