Replacement therapy in Mucopolysaccharidosis type VI: advantages of early onset of therapy

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Abstract

This study evaluates the immunological response following weekly 2 h infusions of recombinant human N-acetylgalactosamine 4-sulfatase (rh4S) in Mucopolysaccharidosis VI (MPS VI) cats. The results of three trials (Trial “A”: 9 month duration with onset at 3–5 months of age, n=5; and Trials “B” and “C”: 6 month duration starting at birth, n=9) were compared. No detrimental effects were noted throughout Trials B and C. Temporary hypersensitivity reactions (e.g., vomiting, diarrhoea) occurred in four cats in Trial A and were alleviated by increasing the dose of antihistamine premedication and the duration of infusion. All cats in Trial A developed antibodies to rh4S (range of final titres: 1041–134,931). All cats treated from birth showed negligible titres (range: <50–598). In vitro inhibition of rh4S activity (up to 47%) was demonstrated with plasma from four cats with elevated titres. Significant reduction of urinary glycosaminoglycan concentration in all cats indicated the ability of rh4S to metabolize stored substrates regardless of the presence of circulating antibodies. Similarly, lysosomal storage in reticuloendothelial cells and fibroblasts of kidney interstistium, dura and skin was reduced in all cats irrespective of their antibody titre although cats with elevated titre had less beneficial effect on cardiovascular tissues (aorta smooth muscle cells, heart valve fibroblasts). Overall improvement in the disease condition (at physical, neurological, and skeletal levels) was most pronounced for cats treated from birth compared with cats treated at a later age.

Introduction

Mucopolysaccharidosis type VI (MPS VI or Maroteaux-Lamy syndrome) is an inherited lysosomal storage disorder caused by deficient activity of N-acetylgalactosamine 4-sulfatase (4-sulfatase or EC 3.1.6.12). This results in an inability to degrade glycosaminoglycan (GAG) chains and accumulation of dermatan sulfate and chondroitin sulfate within lysosomes in connective tissues [1]. Mutations within the gene encoding 4S account for the decrease or loss of functional enzyme activity in several mammals, including humans. Disease severity is proportional to the levels of enzyme activity in tissues [2] and multiple organ systems are involved.

Severely affected MPS VI patients are usually diagnosed by two years of age, and develop clinical features that include gross abnormalities of the skeleton and heart, joint stiffness, corneal clouding, hepatosplenomegaly, and dermatan sulfaturia. Premature death is usually in late childhood to early adulthood. Mildly affected MPS VI patients live into their forties and fifties. The skeletal and soft tissue pathology in the feline MPS VI model closely resembles the human disease [3].

At present, bone marrow transplantation is the only available therapeutic option for affected children [4], but recent studies treating cats lacking functional endogenous enzyme with recombinant human 4S (rh4S) suggest potential benefit for the human disease [5], [6]. Indeed, significant clinical improvement was achieved in MPS VI cats treated from birth with weekly injections (over 10–20 min) at a dose rate of 1 mg/kg for 6 months. A higher dose of 5 mg/kg produced a small incremental benefit in specific tissues after 11 months of enzyme replacement therapy (ERT). Clearance of stored substrates was demonstrated for all major tissues except cornea and articular cartilage. Urinary GAG concentrations were significantly reduced with 1 or 5 mg/kg weekly treatments however levels achieved throughout 6–11 months of ERT were still above that of normal cats.

There is some evidence that development of antibodies in MPS VI cats to the recombinant human enzyme could potentially impact on clinical benefit [7]. In Gaucher type 1 patients treated with commercially available glucocerebrosidase (Ceredase or Cerezyme, Genzyme), evidence indicates that, in a low percentage of cases, the presence of neutralizing antibodies can be associated with a lack of improvement or progressive disease [8], [9]. Antibodies to adenosine deaminase (ADA) have been reported in human patients treated with animal-derived ADA [10]. More recently, the presence of antibodies to α-l-iduronidase were detected in serum of four out of 10 MPS I patients treated for a year with weekly intravenous recombinant human α-l-iduronidase [11].

Enzyme replacement therapy (ERT) trials using rh4S are currently underway for human MPS VI patients [12]. Since the use of recombinant feline 4S more effectively reduced pathology in MPS VI cats than the use of heterologous enzyme (rh4S), at similar dose rate [13], it is anticipated that delivery of the rh4S to humans would produce a more significant clinical benefit on a per weight basis (by comparison with clinical benefit obtained from using human enzyme in cats).

The aim of this study was to compare safety, efficacy and immunological responses in MPS VI cats given weekly 2 h infusions of rh4S with initiation of therapy either at birth or at 3–5 months of age.

Section snippets

Enzyme preparation

Recombinant human N-acetylgalactosamine 4-sulfatase (rh4S) was derived from a stably transfected Chinese Hamster Ovary (CHO) cell line expressing rh4S. The rh4S preparations were produced and provided by BioMarin Pharmaceutical, Novato, CA, and were shipped and stored at 4 °C until use. Activity of rh4S was determined using a fluorogenic assay as described previously [5], protein concentration in the rh4S preparations was determined using the Lowry method [14], and purity was assessed by

Preliminary trial

From the perspective of safety, no detrimental effects were observed in four MPS VI cats that received a total of five enzyme infusions. One cat receiving 10 min infusions experienced a mild hypersensitivity reaction at the end of the fifth infusion. Symptoms were limited to licking lips, then vomiting (four episodes) over a period of 10 min. Neither respiratory distress nor diarrhoea was observed, and no clinical intervention was necessary. Necropsy and histology assessment of the major organs

Discussion

Weekly infusions over 6–9 months of 1–2 mg/kg rh4S into MPS VI cats were well tolerated, even when ERT was initiated at 3.5–5 months of age instead of a more favourable time such as soon after birth. The clinical improvements produced by ERT were more pronounced in MPS VI cats treated from birth since onset of therapy took place when skeletal pathology was not well established and when the immune system was more amenable to tolerance induction [21].

Indeed, humoral tolerance toward rh4S (as

Acknowledgements

The authors gratefully acknowledge the animal care staff at the Institute of Medical and Veterinary Science for the daily care of the cat colony. We also thank Dr. Stuart Swiedler and Ms. Teresa Johnk from BioMarin Pharmaceutical Inc. for their regular support and input, Dr. Stephen Kania from the Department of Comparative Medicine, University of Tennessee, Knoxville, TN regarding complement assays, Ms. Chris Boulter regarding tissue distribution assay and Ms. Margaret McClaren for assistance

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