Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data.

Abstract

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood-brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

• Authors: Roberto Giugliani, Ana Maria Martins, Torayuki Okuyama, Yoshikatsu Eto, Norio Sakai, Kimitoshi Nakamura, Hideto Morimoto, Kohtaro Minami, Tatsuyoshi Yamamoto, Mariko Yamaoka, Toshiaki Ikeda, Sairei So, Kazunori Tanizawa, Hiroyuki Sonoda, Mathias Schmidt, Yuji Sato
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 20 (Oct 10 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34681597 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Recombinant Proteins
• Iduronate Sulfatase

Topics

• Animals
• Biomarkers (cerebrospinal fluid)
• Blood-Brain Barrier (drug effects, metabolism)
• Brain (metabolism)
• Clinical Trials as Topic
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Enzyme Replacement Therapy
• Humans
• Iduronate Sulfatase (genetics, metabolism, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mucopolysaccharidosis II (drug therapy, pathology)
• Recombinant Proteins (adverse effects, pharmacology, therapeutic use)
• Severity of Illness Index