Replacing the Enzyme α- l -Iduronidase at Birth Ameliorates Symptoms in the Brain and Periphery of Dogs with Mucopolysaccharidosis Type I

Abstract

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 ...

Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management

“…Early initiation of ERT is believed to improve clinical outcomes, possibly by preventing irreversible changes that result from GAG accumulation and secondary pathogenic cascade activation. 50,51 This concept is supported by the observations that lysosomal GAG storage in MPS occurs prenatally, 52,53 outcomes are improved with very early treatment in animal models, 54,55 and early vs later treatment improves outcomes in sibling case studies. 47,56,57 The proposed algorithm (Figure) uses IDUA sequencing as a critical component in decision-making.…”

Gene therapy for the neurological manifestations in lysosomal storage disorders

“…This premise was initially based on observations that intravenous injection of very high levels of recombinant lysosomal enzymes can result in partial clearance of lysosomal storage in the CNS of select young animal models of the diseases (75)(76)(77). The viability of early systemic intervention with high levels of enzyme to treat the CNS was further supported by systemic gene therapy studies (which effected continuous hepatic expression of the enzymes) in murine models of MPS I, MPS III, and MPS VII (78)(79)(80).…”

Ocular Lesions in Canine Mucopolysaccharidosis I and Response to Enzyme Replacement Therapy

“…All therapeutic studies were preapproved by the Institutional Animal Care and Use Committee and adhere to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research; further details concerning these animals have been reported elsewhere. [17][18][19][20][21][22] …”

“…17 A more recent study noted some clinical and histologic improvement of corneal lesions with high-dose IV ERT (1.57 mg/kg weekly). 18 We investigated histologic GAG accumulation in ocular tissues archived from MPS I-affected dogs that had received various doses and regimens of ERT to determine the effects of these treatments on reducing corneal GAG accumulation. This is the first large-scale report of corneal response to treatment after IV ERT.…”