Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis type I, a randomized, open-label, controlled pilot study

Agnes H. Chen, Paul Harmatz, Igor Nestrasil, Julie B. Eisengart, Kelly E. King, Kyle Rudser, Alexander M. Kaizer, Alena Svatkova, Amy Wakumoto, Steven Q. Le, Jacqueline Madden, Sarah Young, Haoyue Zhang, Lynda E. Polgreen, Patricia I. Dickson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Central nervous system manifestations of mucopolysaccharidosis type I (MPS I) such as cognitive impairment, hydrocephalus, and spinal cord compression are inadequately treated by intravenously-administered enzyme replacement therapy with laronidase (recombinant human alpha-L-iduronidase). While hematopoietic stem cell transplantation treats neurological symptoms, this therapy is not generally offered to attenuated MPS I patients. This study is a randomized, open-label, controlled pilot study of intrathecal laronidase in eight attenuated MPS I patients with cognitive impairment. Subjects ranged between 12 years and 50 years old with a median age of 18 years. All subjects had received intravenous laronidase prior to the study over a range of 4 to 10 years, with a mean of 7.75 years. Weekly intravenous laronidase was continued throughout the duration of the study. The randomization period was one year, during which control subjects attended all study visits and assessments, but did not receive any intrathecal laronidase. After the first year, all eight subjects received treatment for one additional year. There was no significant difference in neuropsychological assessment scores between control or treatment groups, either over the one-year randomized period or at 18 or 24 months. However, there was no significant decline in scores in the control group either. Adverse events included pain (injection site, back, groin), headache, neck spasm, and transient blurry vision. There were seven serious adverse events, one judged as possibly related (headache requiring hospitalization). There was no significant effect of intrathecal laronidase on cognitive impairment in older, attenuated MPS I patients over a two-year treatment period. A five-year open-label extension study is underway.

Original languageEnglish (US)
Pages (from-to)80-90
Number of pages11
JournalMolecular Genetics and Metabolism
Volume129
Issue number2
DOIs
StatePublished - Feb 2020

Bibliographical note

Funding Information:
The research described was supported by the Ryan Foundation; a Sanofi Genzyme/Biomarin JV; the NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881 and UCSF CTSI Grant Number UL1TR000004; the University of Pennsylvania Orphan Disease Center (MDBR-15-214-MPS and MDBR-16-125-MPS), and the Lysosomal Disease Network. The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium is funded through a collaboration between NCATS, NINDS, and NIDDK.

Funding Information:
The research described was supported by the Ryan Foundation ; a Sanofi Genzyme/Biomarin JV ; the NIH / National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881 and UCSF CTSI Grant Number UL1TR000004 ; the University of Pennsylvania Orphan Disease Center ( MDBR-15-214-MPS and MDBR-16-125-MPS ), and the Lysosomal Disease Network . The Lysosomal Disease Network ( U54NS065768 ) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS . This consortium is funded through a collaboration between NCATS , NINDS , and NIDDK .

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Cognitive decline
  • Glycosaminoglycan
  • Hurler
  • Intrathecal enzyme replacement therapy
  • Lysosomal disease
  • Mucopolysaccharidosis

PubMed: MeSH publication types

  • Journal Article
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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