Tralesinidase alfa enzyme replacement therapy prevents disease manifestations in a canine model of mucopolysaccharidosis type IIIB

N Matthew Ellinwood, Bethann N Valentine, Andrew S Hess, Jackie K Jens, Elizabeth M Snella, Maryam Jamil, Shannon J Hostetter, Nicholas D Jeffery, Jodi D Smith, Suzanne T Millman, Rebecca L Parsons, Mark T Butt, Sundeep Chandra, Martin T Egeland, Ana B Assis, Hemanth R Nelvagal, Jonathan D Cooper, Igor Nestrasil, Bryon A Mueller, Rene LabounekAmy Paulson, Heather Prill, Xiao Ying Liu, Huiyu Zhou, Roger Lawrence, Brett E Crawford, Anita Grover, Ganesh Cherala, Andrew C Melton, Anu Cherukuri, Brian R Vuillemenot, Jill Cm Wait, Charles A O'Neill, Jason Pinkstaff, Joseph Kovalchin, Eric Zanelli, Emma McCullagh

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects.

Original languageEnglish (US)
Pages (from-to)277-286
Number of pages10
JournalThe Journal of pharmacology and experimental therapeutics
Issue number3
Early online dateJun 18 2022
StatePublished - Sep 1 2022

Bibliographical note

Funding Information:
This work was funded by BioMarin Pharmaceutical Inc. and Allievex Corporation. ISU authors acknowledge support from the ISU College of Agriculture and Life Sciences, the ISU College of Veterinary Medicine, the Hatch Act, and the State of Iowa. The MPS IIIB dog colony was founded at the University of Pennsylvania and was supported by the National Institutes of Health Referral Center – Animal Models of Human Genetic Disease [Grant P40OD010939]. The University of Minnesota Foundation funded the purchase of anesthesia and monitoring machines for MRI analyses.

Publisher Copyright:
Copyright © 2022 by The Author(s)


  • Animals
  • Brain/metabolism
  • Child
  • Disease Models, Animal
  • Dogs
  • Enzyme Replacement Therapy
  • Glycosaminoglycans/metabolism
  • Heparitin Sulfate/cerebrospinal fluid
  • Humans
  • Mucopolysaccharidosis III/drug therapy

PubMed: MeSH publication types

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


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