Lysosomal storage disorders are genetic diseases that are caused by a deficiency of one or more degradative enzymes necessary for normal cell metabolism (Table 1)1. In mucopolysaccharidosis type VI (MPS-VI; Maroteaux–Lamy syndrome), an autosomal recessive disease, deficiency of N-acetylgalactosamine-4-sulfatase leads to the accumulation of its substrate, dermatan sulfate, in the lysosomes of many cell types2. Patients show severe skeletal abnormalities as well as widespread soft-tissue pathology, such as heart valve thickening, and severely affected patients usually die between late childhood and early adulthood from cardiac or respiratory complications2.
For the majority of lysosomal storage disorders, the only treatment option available is bone-marrow transplantation (BMT)1, 2. However, in the early 1990s, following decades of research, it was demonstrated that replacement of the deficient enzyme involved in the lysosomal storage disorder Gaucher disease, 
-glucocerebrosidase, could successfully treat the disease1. This provided the impetus for the development of enzyme-replacement therapies for other lysosomal storage disorders, such as the mucopolysaccharidoses.
Basis of discovery
Mucopolysaccharides, also known as glycosaminoglycans (GAGs), are linear polymers of modified aminosugars and acidic sugars that are important for the structure and function of all tissues. GAGs are recycled by uptake into the lysosome, where they are degraded sequentially by specific enzymes. Deficiency in any one of these enzymes leads to accumulation of the respective GAG substrate, and causes the various mucopolysaccharidoses, such as MPS-VI2 (Table 1).
In contrast to some lysosomal storage disorders, MPS-VI is not characterized by significant neurological involvement, and so it is a possible candidate for enzyme-replacement therapy. This led researchers to assess the potential of recombinant N-acetylgalactosamine-4-sulfatase, referred to as galsulfase, for the treatment of MPS-VI3. After uptake, the enzyme was processed normally in both normal and MPS-VI fibroblasts, and was shown both to correct the enzymatic defect and to initiate degradation of dermatan sulfate in MPS-VI fibroblasts3. Studies in a cat model of MPS-VI also indicated that enzyme-replacement therapy would result in a significant reduction in disease progression and tissue pathology in patients with MPS-VI, and that early intervention would be more successful4, 5.
Drug properties
Galsulfase is a normal variant form of human N-acetylgalactosamine 4-sulfatase that is produced by recombinant DNA technology in a Chinese hamster ovary cell line6. Galsulfase is a glycoprotein comprising 495 amino acids, and contains six asparagine-linked glycosylation sites, four of which carry a bis-mannose-6-phosphate mannose7 oligosaccharide for specific cellular recognition6. Post-translational modification of cysteine-53 produces the catalytic amino acid residue C
-formylglycine, which is required for enzyme activity6.
Clinical data
Galsulfase has been studied in several trials involving patients with MPS-VI6, 7. The majority of patients had severe manifestations of the disease, as evidenced by poor performance on tests of physical endurance6.
In a randomized, double-blind, placebo-controlled trial, 39 patients (aged 5–29 years) with MPS-VI received either galsulfase (1 mg per kg as an intravenous infusion) or placebo once-weekly for 24 weeks6. After this time, patients that received galsulfase showed greater mean increases in the distance walked in 12 minutes (109 
154 m) and in the rate of stair climbing in a 3-minute stair climbing test (7.4 9.9 stairs per minute) compared with those receiving placebo (26 122 m and 2.7 6.9 stairs per minute, respectively)6. Urinary GAG levels, which were used as a measure of bioactivity, decreased in patients treated with galsulfase compared with those treated with placebo6.
Following the double-blind period, 38 patients received open-label galsulfase for 24 weeks6. Patients who were initially randomized to galsulfase and who continued to receive it showed increases in the distance walked in 12 minutes and in the rate of stair climbing compared with the start of the open-label period (36 97 m and 3 7 stairs per minute, respectively), as did patients who had been randomized initially to placebo (66 133 m and 6 8 stairs per minute, respectively)6.
Indications
Galsulfase is approved by the FDA for patients with MPS-VI6. Galsulfase has been shown to improve walking and stair-climbing capacity6.
Drugs for lysosomal storage disorders
Analysing clinical issues in the treatment of lysosomal storage disorders is Professor John Hopwood, Ph.D., Head of the Lysosomal Diseases Research Unit, Women's and Children's Hospital, North Adelaide, Australia.
What are the current needs and challenges in the development of therapies for lysosomal storage disorders?
The ability to treat lysosomal storage disorders (LSD) has improved dramatically over the past 10–15 years. Enzyme-replacement therapy (ERT) has been trialled and/or approved for clinical use for several disorders, namely Gaucher disease, Fabry disease, MPS-I, MPS-II, MPS-VI and Pompe disease. Other forms of therapy, such as small-molecule chaperone therapy and substrate deprivation, are also in trials, and are likely to provide useful adjunct methods of treatment. One such drug, miglustat (Zavesca; Actelion), has been approved for the treatment of type I Gaucher disease. Gene therapy is perhaps the ultimate treatment method for LSD, and current research is directed towards evaluating the use of various types of viral vectors.
In their current forms, however, each of these therapies have significant limitations, and several challenges remain. First is the ability to treat all sites of pathology. For example, intravenously administered lysosomal enzymes are rapidly taken out of circulation by a receptor-mediated process4. In addition, the transfer of administered enzyme from the circulation to areas such as the central nervous system (CNS) or to joint capsules is poor because of the blood–brain barrier (BBB) and the poor vascularization of joint tissues, respectively. At present, only direct injection of enzyme into the cerebrospinal fluid has been shown to significantly reduce lysosomal storage in the brain of MPS-I dogs8.
Second is the ability to provide a single-step therapy to continuously provide enzyme to all sites of pathology. At present, ERT requires weekly or fortnightly injections of enzyme and up to a day-stay in hospital. Over the long-term, this can negatively affect therapy compliance. Gene therapy options are considered the probable solution to this problem, but significant technical and safety problems need to be addressed before this approach lives up to its promise.
Third is the ability to predict the presence and nature of irreversible pathology. For example, it is expected that some CNS and skeletal pathologies may become irreversible in MPS-I patients in the first year of life; similarly, maximum benefit in relief of skeletal pathology in MPS-VI requires ERT to begin at birth in asymptomatic cats5. So, to maximize the benefits of therapy in LSD it is essential that patients are identified as early as possible, ideally in the newborn period when most seem asymptomatic. Several methods using dried blood spots have recently been proposed to enable screening of the newborn population9, 10.
Finally, the ability to predict the rate of clinical progression of pathology in individuals detected during an asymptomatic period will become an important issue for clinicians upon the introduction of newborn screening for these disorders and will affect the choice of appropriate treatment and when it should commence. See Box 1.
