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PubMed2006

Mutational analysis of mucopolysaccharidosis type VI patients undergoing a phase II trial of enzyme replacement therapy.

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (ARSB) gene. These mutations result in a deficiency of ARSB activity. Ten MPS VI patients were involved in a phase II clinical study of enzyme replacement therapy. Direct sequencing of genomic DNA from these patients was used to identify ARSB mutations. Each individual exon of the ARSB gene was amplified by PCR and subsequently sequenced. Thirteen substitutions (c.215T>G [p.L72R] c.284G>A [p.R95Q], c.305G>A [p.R102H], c.323G>T [p.G108V], c.389C>T [p.P130L], c.511G>A [p.G171S], c.904G>A [p.G302R], c.944G>A [p.R315Q], c.1057T>C [p.W353R], c.1151G>A [p.S384N], c.1178A>C [p.H393P], c.1289A>G [p.H430R] and c.1336G>C [p.G446R]), one deletion (c.238delG), and two intronic mutations (c.1213+5G>A and c.1214-2A>G) were identified. Nine of the 16 mutations identified were novel (R102H, G108V, P130L, G171S, W353R, H430R, G446R, c.1213+5G>A and c.1214-2A>G). The two common polymorphisms c.1072G>A [p.V358M] and c.1126G>A [p.V376M] were identified in some of the patients, along with the silent mutations c.972A>G and c.1191A>G. Cultured fibroblast ARSB mutant protein and residual activity were determined for each patient and, together with genotype information, used to predict the expected clinical severity of each patient.

Adolescent↗

PubMed2005

Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey).

BACKGROUND: Fabry disease is an X linked lysosomal storage disease caused by deficiency of the lysosomal enzyme alpha-galactosidase A. This leads to accumulation of globotriaosylceramide in nearly all tissues, including the blood vessels, kidney, myocardium, and nervous system. Symptoms often begin in childhood and include acroparaesthesia, with burning or tingling pain that spreads from the extremities to more proximal sites. AIMS: This study set out to evaluate pain and its influence on quality of life in patients with Fabry disease receiving enzyme replacement therapy (ERT) with agalsidase alfa. METHODS: Data were obtained from the Fabry Outcome Survey. Pain was measured using the Brief Pain Inventory (BPI), and health-related quality of life (HRQoL) was documented with the European Quality of Life Questionnaire (EQ-5D). RESULTS: The mean (SD) score for "pain at its worst" on the BPI prior to ERT was 5.1 (2.7). One year after commencement of ERT, this had improved by 0.5, and improved by a further 0.6 after 2 years (p<0.05). Similar statistically significant improvements were seen for "pain on average" and "pain now" after 2 years of ERT. The mean HRQoL utility score prior to ERT was 0.66 (0.32). After 12 months of treatment with agalsidase alfa, this had improved to 0.74 (0.26; p<0.05); this improvement was maintained after 2 years. CONCLUSIONS: ERT with agalsidase alfa significantly reduces pain and improves quality of life in patients with Fabry disease.

Databases, Factual↗

PubMed2005

Glucose tetrasaccharide as a biomarker for monitoring the therapeutic response to enzyme replacement therapy for Pompe disease.

A tetraglucose oligomer, Glcalpha1-6Glcalpha1-4Glcalpha1-4Glc, designated Glc4, has been shown to be a putative biomarker for the diagnosis of Pompe disease. The purpose of this study was to assess whether Glc4 could be used to monitor the therapeutic response to recombinant human acid alpha glucosidase (rhGAA) enzyme replacement therapy (ERT) in patients with Pompe disease. Urinary Glc4 levels in 11 patients receiving rhGAA therapy was determined by both HPLC-UV and stable isotope dilution ESI-MS/MS. Combined Glc4 and maltotetraose, Glcalpha1-4Glcalpha1-4Glcalpha1-4Glc, (M4) concentrations, designated Hex4, in plasma from these patients were measured by HPLC-UV only. Baseline urinary Glc4 and plasma Hex4 in these patients (mean+/-SD: 34.2+/-11.3 mmol/mol creatinine and 1.7+/-0.8 microM, respectively) were higher than age-matched control values (mean+/-SD, 6.1+/-5.1 mmol/mol creatinine and 0.22+/-0.15 microM, respectively). Both urinary Glc4 and plasma Hex4 levels decreased after initiation of ERT for all patients. In the four patients with the best overall clinical response in both skeletal and cardiac muscle, levels decreased to within, or near, normal levels during the first year of treatment. In contrast, levels fluctuated and were persistently elevated above the control ranges in those patients with a less favorable clinical response (good cardiac response but limited motor improvement). These results suggest that urinary Glc4 and plasma Hex4 could serve as a valuable adjunct to clinical endpoints for monitoring the efficacy of therapeutic interventions such as rhGAA ERT in Pompe disease.

Biomarkers↗

PubMed2003

Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data.

UNLABELLED: Progressive deposition of globotriaosylceramide results in severe complications involving the kidney, heart and brain in both hemizygous male and heterozygous female patients with Fabry disease. Analysis of renal data from FOS--the Fabry Outcome Survey--suggests that enzyme replacement therapy with agalsidase alfa can significantly improve renal function in patients with Fabry disease, at least in those with a mild decrease in glomerular filtration rate, and may also be able to slow down the natural decline in renal function in patients with a moderate reduction in glomerular filtration rate. CONCLUSION: Initial results from the large cohort of patients within FOS indicate that treatment with agalsidase alfa has beneficial effects on kidney function in patients with Fabry disease.

Fabry Disease↗

PubMed2004

Orthopedic considerations in Gaucher disease since the advent of enzyme replacement therapy.

Gaucher disease, the most prevalent lysosomal storage disorder, is characterized by hepatosplenomegaly, hypersplenism, and rarely, neurological involvement. The most variable symptoms relate to skeletal disease, and both onset and progression are difficult to predict on the basis of genotype. This review describes findings from a large referral clinic (> 500 patients) and from the literature in the decade since the advent of specific enzyme replacement therapy. Such therapy is effective in reducing visceral and hematological involvement, but its greatest advantage as regards the skeleton is prevention of irreversible damage. Avascular necrosis of the joints-particularly the hips but also the knees and shoulders-and pathological fractures of the long bones including the ribs, as well as episodic "crises' of bone pain in children and young adults, are common manifestations. Various imaging modalities should be performed at baseline for life-long monitoring, and then as required because of specific complaints. Surgical interventions such as joint arthroplasties are important adjuvant treatments in this population; presurgical hematological profiling plus antibiotic cover and postoperative pain control are equally critical. Opportunities for orthopedic consultations with senior surgeons are not abused by our patients. These reflect disease-related morbidity, with greater numbers of requests being made by patients requiring enzyme therapy, who by definition have more severe disease characteristics.

Adolescent↗

PubMed1996

Regression of skeletal changes in type 1 Gaucher disease with enzyme replacement therapy.

A 9-year-old patient presented with an acute onset of pain of the right femur showing destructive changes with periosteal elevation mimicking osteomyelitis. Technetium-99m sulfur colloid (99mTc SC) marrow scan revealed lack of uptake in the right femoral head and the entire shaft of the right femur. Eight months following enzyme replacement therapy, radiography showed almost complete reconstitution of the femoral shaft, and 99mTc SC marrow scan uptake returned to normal.

Bone Marrow↗

PubMedDate not supplied

Effect of enzyme replacement therapy on gammopathies in Gaucher disease.

Chronic antigenic stimulation by the abnormal lipid storage has been postulated to be the mechanism underlying anecdotal reports of monoclonal and polyclonal gammopathies as well as an increased incidence of multiple myeloma in patients with Gaucher disease of all ages. With the advent of specific enzyme therapy, it has been possible to ascertain whether signs and symptoms associated with Gaucher disease are true features of the disorder by virtue of their responsiveness to treatment. The purpose of this study was to assess the incidence of polyclonal and monoclonal gammopathies in a large cohort of patients and the effect of enzyme treatment. All adult patients whose records of immunoglobulin levels were available at presentation or at the advent of enzyme replacement therapy (ERT), and who had been followed for 2 years or receiving ERT for at least 2 years, respectively, and for whom there were also immunoglobulin levels at their most recent follow-up, were included in the study. The incidence of polyclonal gammopathies ranged between 14% and 25% among treated and untreated patients. There were statistically significant percentage decreases per year of enzyme therapy in polyclonal but not monoclonal (1% of all patients) gammopathies. Among enzyme-treated patients, there was no statistically significant difference among patients with regard to spleen status or relative to other parameters of disease severity, hepatitis status, age or gender. This study represents the largest database of gammopathies among patients with Gaucher disease from a large referral clinic. Because there was no correlation of abnormal immunoglobulin levels with disease severity, etiology may not be related to lipid accumulation per se but perhaps reflects a secondary, enzyme-sensitive process, whereas monoclonal gammopathies remain unaffected.

Adolescent↗

PubMed2004

Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I.

Immune responses can interfere with the effective use of therapeutic proteins to treat genetic deficiencies and have been challenging to manage. To address this problem, we adapted and studied methods of immune tolerance used in canine organ transplantation research to soluble protein therapeutics. A tolerization regimen was developed that prevents a strong antibody response to the enzyme alpha-l-iduronidase during enzyme replacement therapy of a canine model of the lysosomal storage disorder mucopolysaccharidosis I. The tolerizing regimen consists of a limited 60-day course of cyclosporin A and azathioprine combined with weekly i.v. infusions of low-dose recombinant human alpha-l-iduronidase. The canines tolerized with this regimen maintain a reduced immune response for up to 6 months despite weekly therapeutic doses of enzyme in the absence of immunosuppressive drugs. Successful tolerization depended on high plasma levels of cyclosporin A combined with azathioprine. In addition, the induction of tolerance may require mannose 6-phosphate receptor-mediated uptake because alpha-l-iduronidase and alpha-glucosidase induced tolerance with the drug regimen whereas ovalbumin and dephosphorylated alpha-l-iduronidase did not. This tolerization method should be applicable to the treatment of other lysosomal storage disorders and provides a strategy to consider for other nontoleragenic therapeutic proteins and autoimmune diseases.

Animals↗

PubMed2006

Enzyme replacement therapy and bony changes in Egyptian paediatric Gaucher disease patients.

BACKGROUND: In Gaucher disease, the infiltration of the bone marrow by glucocerebroside-laden macrophages (Gaucher cells) triggers a diverse pattern of skeletal disease that results in crippling complications. Reliable ascertainment of the severity and pattern of skeletal disease is essential to determine disease status and the response to enzyme replacement therapy (ERT). Although there is ample documentation of reversal of haematological and visceral disease by ERT, there is a paucity of data on skeletal response to ERT in children. AIM: To delineate the pattern of bone disease in children with Gaucher disease in Egypt and to evaluate its response to ERT. METHOD: Twenty-two children with Gaucher disease were treated with ERT. Phenotyping by clinical, laboratory and radiological criteria was performed at baseline and following 11.2 +/- 4 months of ERT. Genotyping for glucocerebrosidase (GBA) mutations was performed by gene sequencing, and genotype-phenotype correlations were performed.Results. Two-thirds of the patients were from consanguineous pedigrees and 14/22 patients were homozygous or compound heterozygous for L444P and D409H mutations. Bone involvement was detected by plain radiology in 11 children (50%) and in 16 (73%) by magnetic resonance imaging (MRI). There was no correlation of severity of bone involvement and GBA genotype. ERT ameliorated bone disease: 10 of the 11 children with abnormal radiographic findings at baseline showed improvement in skeletal lesions; while 9/16 showed improvement of marrow disease by MRI. Radiographic sensitivity and specificity were 62% and 82% compared to MRI for detection of bone involvement in this patient population. At baseline, bone pain was present in 5 patients and ERT resulted in complete symptomatic remission in all of them. ERT was associated with significant improvement in growth parameters and amelioration of haematological and visceral involvement. CONCLUSION: Symptomatic and radiological skeletal disease is common in children with Gaucher disease in Egypt. MRI is the most accurate technique for detecting early skeletal involvement. There was no correlation between severity of skeletal involvement and GBA genotype. ERT was effective in ameliorating radiological manifestations of skeletal disease and achieving complete remission of bone pain.

Adolescent↗

PubMed2005

Safety and efficacy of enzyme replacement therapy in combination with hematopoietic stem cell transplantation in Hurler syndrome.

PURPOSE: Hurler syndrome is a debilitating genetic disease with a typical life span of 5 to 8 years. Early hematopoietic stem cell transplantation (HSCT) mitigates disease symptoms and improves survival. However, morbidity and mortality associated with HSCT can limit its success. We describe the initial experience with combined use of enzyme replacement therapy (ERT, laronidase) and HSCT in Hurler syndrome. METHODS: Thirteen transplants were performed in 12 patients. ERT was given at a standard dose of 0.58 mg/kg per week. Transplant conditioning regimen and donor graft source were determined by institutional protocol. RESULTS: The median age at initiation of ERT was 12 months (range, 8 to 18 months). The median duration of pre-HSCT ERT was 12 weeks (range, 4 to 28). All but 1 patient tested showed decrease in urinary GAG excretion during ERT. ERT infusion-related toxicity was limited to mild reactions. Development of antibodies to laronidase did not correlate with infusion reactions or responses in urinary GAG excretion. ERT was given for a median of 7 weeks (range, 3 to 20) after HSCT. After transplantation, eight patients demonstrated complete donor engraftment and four suffered graft failure. Two patients required ventilator support and three developed acute GVHD. Eleven of the 12 patients are surviving with a median follow-up of 3 months (range, 1 to 7 months). CONCLUSIONS: In children with Hurler syndrome, ERT with HSCT is feasible and well tolerated. Development of antibodies against exogenous enzyme does not appear to correlate with infusion reactions or response to ERT. A prospective study is needed to determine the effect of concomitant ERT on transplant outcomes.

Acute Disease↗

PubMed2004

Relief of gastrointestinal symptoms under enzyme replacement therapy [corrected] in patients with Fabry disease.

Gastrointestinal symptoms, including diarrhoea and abdominal pain, are one of the earliest and most frequently reported signs of Fabry disease, a rare X-linked lipid storage disorder. As the disease progresses, renal, cardiac and cerebrovascular complications develop, resulting in more serious symptoms and early mortality. The present study evaluated the effects of enzyme replacement therapy (ERT) with agalsidase alfa on the gastrointestinal symptoms of Fabry disease. Following 6 months of treatment, both the severity ( p < 0.02) and frequency ( p < 0.02) of abdominal pain decreased. For those patients who had received agalsidase alfa for more than 6 months, the observed improvement was generally maintained. This is the first study indicating a significant beneficial effect of ERT on gastrointestinal symptoms in a group of patients treated for Fabry disease.

Abdominal Pain↗

PubMed2006

Brain development in infantile-onset Pompe disease treated by enzyme replacement therapy.

The primary manifestations of Pompe disease are muscle weakness and cardiomyopathy. Although accumulation of glycogen has also been seen in the nervous system in patients, the significance of brain involvement in infantile-onset Pompe disease is not clear. In this study, brain development in five cases of infantile-onset Pompe disease, whose survivals have been prolonged by enzyme replacement therapy (ERT), were studied by brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). The results revealed delay in myelination milestones in all patients at a median age of 6 mo upon the initiation of treatment. After ERT, four of the five cases showed good progression in myelination, even though mild dilatation of the ventricles was still observed. In the case with no response to ERT in the muscles, however, brain myelination was slow and follow-up MRI and MRS studies suggested both neuron and myelination loss. Therefore, myelination defects are common in infantile-onset Pompe disease. Improvement in brain myelination could be seen in those who survive by effective treatment, although we do not know whether ERT does have a direct therapeutic effect on the brain.

Brain↗

PubMedDate not supplied

MRI of multiple platyspondyly in Gaucher disease: response to enzyme replacement therapy.

Vertebra plana and multiple platyspondyly are complications of aggressive Gaucher disease. Magnetic resonance imaging readily identifies vertebra plana and secondary spinal cord compression. We present a case of a 2-year-old boy with clinically aggressive Type 1 Gaucher disease in whom MRI showed partial reconstitution of the height of a collapsed lumbar vertebral body after 16 months of enzyme replacement therapy.

Child, Preschool↗

PubMed2002

Angiokeratoma corporis diffusum--Fabry disease: historical review from the original description to the introduction of enzyme replacement therapy.

This paper gives a brief historical overview of Fabry disease. First described in 1898 and called angiokeratoma corporis diffusum, a succession of observations and pioneering clinical research over the past 100 years has led to our present understanding of the disease. The major milestones during this time are described, as is the work that resulted in the successful introduction of enzyme replacement therapy.

Fabry Disease↗

PubMed1999

Direct correlation between hyperoxaluria/oxalate stone disease and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: possible prevention by gut recolonization or enzyme replacement therapy.

Oxalobacter formigenes is a specific oxalate-degrading, anaerobic bacterium inhabiting the gastrointestinal tracts of vertebrates, including humans. This bacterium maintains an important symbiotic relationship with its host by regulating oxalate homeostasis, primarily by preventing enteric absorption. Increased absorption of oxalate can lead to multiple complications associated with hyperoxaluria, especially recurrent calcium oxalate urolithiasis. Detection of O. formigenes in the gastrointestinal tract has attracted attention because the absence of this bacterium appears to be a risk factor for development of hyperoxaluria and/or recurrent calcium oxalate kidney stone disease. In the present study, epidemiologic studies with patients at high risk for calcium oxalate urolithiasis showed a direct correlation between the number of recurrent kidney stone episodes and the lack of O. formigenes colonization. As expected, the lack of O. formigenes revealed a clear association with prophylactic antibiotic therapy. To confirm the importance of O. formigenes in regulating hyperoxaluria, laboratory rats known to be noncolonized were colonized with live bacteria or treated with a preparation of oxalate-degrading enzymes derived from O. formigenes to determine any subsequent increased resistance to high oxalate challenge. Rats receiving either bacteria or enzyme replacement therapy excreted far lower levels of oxalate, did not develop the crystalluria observed with control rats, and resisted the formation of calcium oxalate crystals in their nephrons. These observations, taken together, support the concept that O. formigenes is important in maintaining oxalate homeostasis, that its absence from the gut increases the risk for hyperoxaluria and recurrent kidney stone disease, and that replacement therapy is an efficient procedure to prevent hyperoxaluria and its complications.

Adult↗

PubMed2006

Electrocardiographic response to enzyme replacement therapy for Pompe disease.

PURPOSE: Electrocardiogram (ECG) abnormalities are universal in infantile Pompe disease or glycogen storage disease type II, a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). Hallmarks of this disease include a shortened PR interval, an increased QT dispersion (QTd), and large left ventricular (LV) voltages. We evaluated the effect of recombinant human GAA (rhGAA) enzyme replacement therapy (ERT) on these ECG parameters in patients with infantile-onset Pompe disease. METHODS: A total of 134 ECGs were evaluated from 19 patients (5 females and 14 males) with a median age of 5.5 months at the time of enrollment in open-label clinical trials exploring the safety and efficacy of ERT at a single center from 1999 to 2004. rhGAA was purified from genetically engineered Chinese hamster ovary cells overproducing GAA and infused intravenously at doses ranging from 10 mg/kg per week to 20 to 40 mg/kg every 2 weeks in patients with infantile-onset Pompe disease. The PR interval, QTd (longest to shortest QT), and LV voltage (SV1 + RV6) were blindly determined by two independent observers. RESULTS: The median follow-up period was 6 months (range 2-30 months). The PR interval lengthened from 83 (42-110) ms to 107 (95-130) ms (P < .001), and the QTd decreased from 83 (40-125) ms to 53 (20-80) ms (P = .003). There were significant decreases in LV voltage (67 [17-83] mV vs. 48 [18-77] mV, P = .03), which correlated with decrease in LV mass on two-dimensional echocardiogram. There was no evident change in the QTc interval (429 [390-480] ms vs. 413 [370-450] ms, P = not significant). CONCLUSION: rhGAA ERT for infantile Pompe disease results in an increase in PR interval and a decrease in both the QTd and the LV voltage. These results suggest that these ECG parameters may be useful markers of the severity of cardiac disease and the response to ERT treatment in patients with infantile Pompe disease.

Cohort Studies↗

PubMed2005

Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase.

OBJECTIVE: Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (ASB). This enzyme deficiency leads to a progressive disorder with multiple tissue and organ involvement. The disease is rare and is heterogeneous in its clinical presentation and progression. A potential treatment for this disease exists in the form of enzyme-replacement therapy (ERT) with recombinant human ASB (rhASB), and a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients showed the treatment at 48 weeks to be well tolerated. Greater biochemical efficacy based on a urine glycosaminoglycan occurred in the high-dose (1 mg/kg) group, and functional improvement seemed greater in patients in the high-dose group with rapidly advancing disease. On the basis of the phase 1/2 results, a phase 2, open-label study in patients with rapidly advancing disease was initiated primarily to evaluate efficacy variables that measure endurance, mobility, and joint function in a larger group of patients. METHODS: This was an open-label, multinational study of 10 MPS VI patients who received 48 weekly intravenous treatments with 1.0 mg/kg rhASB and had assessments of biochemical and clinical responses at regular intervals. RESULTS: After 24 weeks of treatment, each patient on average experienced a 155-m (98%) improvement in the 12-minute walk, a 64-m (62%) improvement at the 6-minute time point of the 12-minute walk, and a 48-stair (110%) gain in the 3-minute stair climb versus the baseline mean values. Additional improvements after 48 weeks of treatment were observed, including mean values of 211 m (138%) in the 12-minute walk, 75 m (80%) at the 6-minute time point of the 12-minute walk, and 61-stair (147%) gain in the 3-minute stair climb versus the baseline mean values. Joint Pain and Stiffness Questionnaire scores improved by at least 50% by week 24 and were maintained at week 48, whereas there were only small improvements in active shoulder range of motion (<10 degrees ) and in the time taken to stand, walk, and turn starting from a seated position (Expanded Timed Get-Up and Go test). Improvement in pulmonary function based on forced vital capacity and forced expiratory volume at 1 minute in the absence of growth was observed in 3 of 6 patients, and the observed gains occurred in the 24- to 48-week treatment interval. A mean decrease of 76% in urinary excretion of glycosaminoglycans indicated that a satisfactory biochemical response was achieved and the ERT was well tolerated. CONCLUSIONS: The results suggest that a 12-minute walk extends the dynamic range of the conventional 6-minute walk and, along with the 3-minute stair climb, provide a robust approach to documenting the improvement in endurance in MPS VI patients who undergo ERT with rhASB.

Adolescent↗

PubMed1997

Effect of enzyme replacement therapy on bone formation in a feline model of mucopolysaccharidosis type VI.

A range of skeletal abnormalities are evident in mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) including short stature and dysostosis multiplex, resulting from a deficiency in the lysosomal hydrolase N-acetylgalactosamine-4-sulphatase (4S). In this article, bone pathology was assessed in a feline model of MPS VI to evaluate the efficacy of enzyme replacement therapy (ERT) as a treatment modality for this genetic disorder. Osteopenia is clearly evident in MPS VI animals, with bone mineral volume (BV/TV) falling well below that of normal animals (4.39% vs. 20.11%, respectively). Trabecular bone architecture was also affected in MPS VI with fewer, thinner, and more widely spaced trabeculae apparent. Bone formation rate (BFR/BS) was also lower in MPS VI animals than controls (0.0011 mm3/mm2 per day vs. 0.008 mm3/mm2 per day, respectively). Vertebral and tibial bone length in MPS VI animals progressively fell behind normal values with increasing age, as did cortical bone thickness. Vertebral body shape was also altered. ERT with recombinant human 4S (rh4S) resulted in a vertebral BV/TV of 8.23% in animals treated with an intravenous enzyme dose of 1 mg/kg and a BV/TV of 14.33% in animals treated with a dose of 5 mg/kg. BFR/BS also increased to 0.0034 mm3/mm2 per day in animals treated with enzyme doses of either 1.0 or 5.0 mg/kg rh4S. All other affected histomorphometric parameters also improved with ERT to a level intermediate between MPS VI untreated animals and normals. However, individual animals treated with 0.2 mg/kg rh4S intravenously or 1.0 mg/kg rh4S administered subcutaneously did not exhibit an improvement over untreated MPS VI animals. Vertebral and tibial bone lengths, tibial cortical bone thickness, and vertebral body shape also responded to ERT, with a trend away from the untreated group. Thus, ERT had a positive effect on bone development in MPS VI animals that was dependent upon the dose of enzyme administered and the route of administration.

Animals↗