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Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome.

Tomatsu S, Sawamoto K, Alméciga-Díaz CJ, Shimada T, Bober MB, Chinen Y, Yabe H, Montaño AM, Giugliani R, Kubaski F, Yasuda E, Rodríguez-López A, Espejo-Mojica AJ, Sánchez OF, Mason RW, Barrera LA, Mackenzie WG, Orii T - Drug Des Devel Ther (2015)

Bottom Line: Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes.When treatment was initiated at birth, reduction of storage materials in tissues was even greater.Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting.

View Article: PubMed Central - PubMed

Affiliation: Nemours/Alfred I duPont Hospital for Children, Wilmington, DE, USA ; Department of Pediatrics, Gifu University, Gifu, Japan.

ABSTRACT
Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21 (DE3) (erGALNS) and in the methylotrophic yeast Pichia pastoris (prGALNS) has been produced as an alternative to the conventional production in Chinese hamster ovary cells. Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting. Although only a limited number of patients with MPS IVA have been treated with hematopoietic stem cell transplantation (HSCT), beneficial effects have been reported. A wheelchair-bound patient with a severe form of MPS IVA was treated with HSCT at 15 years of age and followed up for 10 years. Radiographs showed that the figures of major and minor trochanter appeared. Loud snoring and apnea disappeared. In all, 1 year after bone marrow transplantation, bone mineral density at L2-L4 was increased from 0.372 g/cm(2) to 0.548 g/cm(2) and was maintained at a level of 0.48±0.054 for the following 9 years. Pulmonary vital capacity increased approximately 20% from a baseline of 1.08 L to around 1.31 L over the first 2 years and was maintained thereafter. Activity of daily living was improved similar to the normal control group. After bilateral osteotomies, a patient can walk over 400 m using hip-knee-ankle-foot orthoses. This long-term observation of a patient shows that this treatment can produce clinical improvements although bone deformity remained unchanged. In conclusion, ERT is a therapeutic option for MPS IVA patients, and there are some indications that HSCT may be an alternative to treat this disease. However, as neither seems to be a curative therapy, at least for the skeletal dysplasia in MPS IVA patients, new approaches are investigated to enhance efficacy and reduce costs to benefit MPS IVA patients.

No MeSH data available.


Related in: MedlinePlus

Physiological effects of ERT or HSCT and potential monitoring markers in Morquio A.Abbreviations: ERT, enzyme replacement therapy; HSCT, hematopoietic stem cell transplantation; GALNS, N-acetylgalactosamine-6-sulfate sulfatase; GAGs, glycosaminoglycans; KS, keratan sulfate; C6S, chondroitin 6-sulfate; ECM, extracellular matrix; ROM, range of motion; 6MWT, 6-minute walk test; 3MSCT, 3-minute stair climb test; PFT, pulmonary function test; BMD, bone mineral density; MRI, magnetic resonance imaging.
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f5-dddt-9-1937: Physiological effects of ERT or HSCT and potential monitoring markers in Morquio A.Abbreviations: ERT, enzyme replacement therapy; HSCT, hematopoietic stem cell transplantation; GALNS, N-acetylgalactosamine-6-sulfate sulfatase; GAGs, glycosaminoglycans; KS, keratan sulfate; C6S, chondroitin 6-sulfate; ECM, extracellular matrix; ROM, range of motion; 6MWT, 6-minute walk test; 3MSCT, 3-minute stair climb test; PFT, pulmonary function test; BMD, bone mineral density; MRI, magnetic resonance imaging.

Mentions: A surrogate endpoint is deemed as a biomarker intended to substitute for a clinical endpoint. Biomarkers are used for diagnosing, staging, and monitoring the progress of a disease and its response to therapy. In general, biomarkers are cheaper and easier to measure than true endpoints and can be assayed over a shorter period.121,122 In clinical trials, an ideal biomarker is a measure of effect of a specific treatment that may correlate with a real clinical endpoint (Figures 4 and 5). The first step in identifying suitable biomarkers is to understand the pathophysiology of the disease and to find factors that determine it. The next step is to identify potential biomarkers based on the mechanism of action of the intervention related to the pathophysiology of the disease. The last step is to determine the extent to which the putative marker correlates with the process and how useful it is in predicting the outcome.


Impact of enzyme replacement therapy and hematopoietic stem cell transplantation in patients with Morquio A syndrome.

Tomatsu S, Sawamoto K, Alméciga-Díaz CJ, Shimada T, Bober MB, Chinen Y, Yabe H, Montaño AM, Giugliani R, Kubaski F, Yasuda E, Rodríguez-López A, Espejo-Mojica AJ, Sánchez OF, Mason RW, Barrera LA, Mackenzie WG, Orii T - Drug Des Devel Ther (2015)

Physiological effects of ERT or HSCT and potential monitoring markers in Morquio A.Abbreviations: ERT, enzyme replacement therapy; HSCT, hematopoietic stem cell transplantation; GALNS, N-acetylgalactosamine-6-sulfate sulfatase; GAGs, glycosaminoglycans; KS, keratan sulfate; C6S, chondroitin 6-sulfate; ECM, extracellular matrix; ROM, range of motion; 6MWT, 6-minute walk test; 3MSCT, 3-minute stair climb test; PFT, pulmonary function test; BMD, bone mineral density; MRI, magnetic resonance imaging.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4389814&req=5

f5-dddt-9-1937: Physiological effects of ERT or HSCT and potential monitoring markers in Morquio A.Abbreviations: ERT, enzyme replacement therapy; HSCT, hematopoietic stem cell transplantation; GALNS, N-acetylgalactosamine-6-sulfate sulfatase; GAGs, glycosaminoglycans; KS, keratan sulfate; C6S, chondroitin 6-sulfate; ECM, extracellular matrix; ROM, range of motion; 6MWT, 6-minute walk test; 3MSCT, 3-minute stair climb test; PFT, pulmonary function test; BMD, bone mineral density; MRI, magnetic resonance imaging.
Mentions: A surrogate endpoint is deemed as a biomarker intended to substitute for a clinical endpoint. Biomarkers are used for diagnosing, staging, and monitoring the progress of a disease and its response to therapy. In general, biomarkers are cheaper and easier to measure than true endpoints and can be assayed over a shorter period.121,122 In clinical trials, an ideal biomarker is a measure of effect of a specific treatment that may correlate with a real clinical endpoint (Figures 4 and 5). The first step in identifying suitable biomarkers is to understand the pathophysiology of the disease and to find factors that determine it. The next step is to identify potential biomarkers based on the mechanism of action of the intervention related to the pathophysiology of the disease. The last step is to determine the extent to which the putative marker correlates with the process and how useful it is in predicting the outcome.

Bottom Line: Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes.When treatment was initiated at birth, reduction of storage materials in tissues was even greater.Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting.

View Article: PubMed Central - PubMed

Affiliation: Nemours/Alfred I duPont Hospital for Children, Wilmington, DE, USA ; Department of Pediatrics, Gifu University, Gifu, Japan.

ABSTRACT
Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21 (DE3) (erGALNS) and in the methylotrophic yeast Pichia pastoris (prGALNS) has been produced as an alternative to the conventional production in Chinese hamster ovary cells. Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting. Although only a limited number of patients with MPS IVA have been treated with hematopoietic stem cell transplantation (HSCT), beneficial effects have been reported. A wheelchair-bound patient with a severe form of MPS IVA was treated with HSCT at 15 years of age and followed up for 10 years. Radiographs showed that the figures of major and minor trochanter appeared. Loud snoring and apnea disappeared. In all, 1 year after bone marrow transplantation, bone mineral density at L2-L4 was increased from 0.372 g/cm(2) to 0.548 g/cm(2) and was maintained at a level of 0.48±0.054 for the following 9 years. Pulmonary vital capacity increased approximately 20% from a baseline of 1.08 L to around 1.31 L over the first 2 years and was maintained thereafter. Activity of daily living was improved similar to the normal control group. After bilateral osteotomies, a patient can walk over 400 m using hip-knee-ankle-foot orthoses. This long-term observation of a patient shows that this treatment can produce clinical improvements although bone deformity remained unchanged. In conclusion, ERT is a therapeutic option for MPS IVA patients, and there are some indications that HSCT may be an alternative to treat this disease. However, as neither seems to be a curative therapy, at least for the skeletal dysplasia in MPS IVA patients, new approaches are investigated to enhance efficacy and reduce costs to benefit MPS IVA patients.

No MeSH data available.


Related in: MedlinePlus