RT Journal Article SR Electronic T1 Tralesinidase alfa enzyme replacement therapy prevents disease manifestations in a canine model of mucopolysaccharidosis type IIIB JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP JPET-AR-2022-001119 DO 10.1124/jpet.122.001119 A1 N. Matthew Ellinwood A1 Bethann N Valentine A1 Andrew S Hess A1 Jackie K Jens A1 Elizabeth M Snella A1 Maryam Jamil A1 Shannon J Hostetter A1 Nicholas D Jeffery A1 Jodi D Smith A1 Suzanne T Millman A1 Rebecca L Parsons A1 Mark T Butt A1 Sundeep Chandra A1 Martin T Egeland A1 Ana B Assis A1 Hemanth R Nelvagal A1 Jonathan D Cooper A1 Igor Nestrasil A1 Bryon A Mueller A1 Rene Labounek A1 Amy Paulson A1 Heather Prill A1 Xiao Ying Liu A1 Huiyu Zhou A1 Roger Lawrence A1 Brett E Crawford A1 Anita Grover A1 Ganesh Cherala A1 Andrew C Melton A1 Anu Cherukuri A1 Brian R Vuillemenot A1 Jill CM Wait A1 Charles A. O'Neill A1 Jason Pinkstaff A1 Joseph Kovalchin A1 Eric Zanelli A1 Emma McCullagh YR 2022 UL http://jpet.aspetjournals.org/content/early/2022/06/18/jpet.122.001119.abstract AB 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 non-human 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 to 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 HS-NRE in CSF and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests, 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, pathological, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. Significance Statement This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for MPS IIIB patients by documenting that direct CNS administration to MPS IIIB dogs prevents accumulation of disease-associated GAGs in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.