Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-L-iduronidase and attendant accumulation of the glycosaminoglycans dermatan and heparan sulfates. Current treatments are suboptimal and leave residual disease including corneal clouding, skeletal deformities, valvular heart disease and cognitive impairment. We treated neonatal mucopolysaccharidosis I dogs with intravenous recombinant α-L-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 65-81 weeks. In contrast to previous results in animals and patients treated at a later age, all animals failed to mount an antibody response to enzyme therapy, consistent with neonatal tolerization. The higher dose of enzyme led to complete normalization of lysosomal storage in liver, spleen, lung, kidney, synovium and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and Author contributions: NME and PID conceived and designed the study, analyzed data and wrote the manuscript. ADD performed experiments and data analysis and wrote the manuscript. MFM, CAV, and AF-W performed pathology. CHV, WG, and EAR performed radiology and MRIs. MP, SS, AHC and SL performed biochemistry. JKJ and EMS conducted animal work. KLK, JDP, and JAW conducted veterinary neurology procedures and support. WAW and LEM conducted veterinary cardiology procedures and support. RDW, DMB and AMB conducted veterinary ophthalmology procedures and support.Publisher's Disclaimer: 'This manuscript has been accepted for publication in Science Translational Medicine. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencetranslationalmedicine.org.The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS.' natural history study to measure intellectual function over time in these patients is ongoing. In the canine model, even a larger 2 mg/kg weekly dose of ERT was not sufficient to clear accumulated GAG from the heart valve in older animals, though it was able to improve histologic evidence of lysosomal storage efficacy(12,13). It is possible that some MPS I pathology, including valvular disease, may be difficult or impossible to reverse. NIH Public AccessWhile some MPS I disease is not readily reversed by IV ERT, prevention may be easier to achieve. In particular, we were intrigued by reports that early or high-dose IV ERT could treat lysosomal storage in the brain in mice (14-20). We therefore treated MPS I dogs shortly after birth to determine whether hard-to-treat disease including cardiac valvular disease, skeletal disease, and corneal clouding, would respond to early initiation of therapy, and whether treating them would require a higher dose. We also sought to compare early, high-dose IV ERT to ERT administered directly into spinal fluid (intrathecally, IT) (21,22) for treatment of lysosomal storage in ...

Enzyme replacement therapy (ERT) with intravenous recombinant human alpha-

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Mucopolysaccharidosis type IIIB (MPS IIIB) causes progressive mental degeneration and early death due to lysosomal accumulation of heparan sulfate resulting from deficient activity of N‐acetyl‐α‐D‐glucosaminidase. Lysosomal accumulation of GM2 and GM3 gangliosides by unknown mechanism also occurs. We tested the benefit of eliminating GM2 storage in MPS III, by breeding MPS IIIB/GalNAc transferase double knockout (KO) mice. Rather than an improved outcome, double KO mice were short lived (p < 0.0001); 20 ± 3.4 wks, versus 45 ± 6.9 wks (MPS IIIB). Double KO mice had hind limb ataxia and hyper‐extension in contrast to single KO or normal mice, which appeared normal. Brain tissue of MPS IIIB‐affected, GalNAcT deficient, double KO, or wild‐type mice was examined histologically. In double KO mice, white matter showed prominent vacuolization and degeneration of nerve fibers. In contrast, MPS IIIB mice showed only intracytoplasmic vacuoles of many neurons and glia. Double KO mice likely succumbed to axonopathic and neuropathic effects in white matter tracts. This double KO model may prove useful as an improved model to investigate neuropathology and to assess therapy for MPS IIIB. Funded by the Sanfilippo Children's Research Foundation, the Lysosomal Storage Disease Research Consortium, the Center for Integrated Animal Genomics at ISU, and the State of Iowa Board of Regents.

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