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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

Model for diagnosis and treatment of patients with MPS IVA.Notes: *KS and C6S, which are stored in MPS IVA patients, are normalized or subnormalized naturally after synthesis of these GAGs is decreased with age (after teenage). Therefore, ERT may not be required for the group of patients who may have established bone lesions without risk of lung issue and may not be required permanently once lung issue is resolved. Especially, after 20 years of age with normalized KS and C6S, the cost/benefit of ERT should be evaluated carefully.Abbreviations: MPS, mucopolysaccharidosis; KS, keratan sulfate; C6S, chondroitin 6-sulfate; GAGs, glycosaminoglycans; ERT, enzyme replacement therapy; NBS, newborn screening; HSCT, hematopoietic stem cell transplantation.
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f6-dddt-9-1937: Model for diagnosis and treatment of patients with MPS IVA.Notes: *KS and C6S, which are stored in MPS IVA patients, are normalized or subnormalized naturally after synthesis of these GAGs is decreased with age (after teenage). Therefore, ERT may not be required for the group of patients who may have established bone lesions without risk of lung issue and may not be required permanently once lung issue is resolved. Especially, after 20 years of age with normalized KS and C6S, the cost/benefit of ERT should be evaluated carefully.Abbreviations: MPS, mucopolysaccharidosis; KS, keratan sulfate; C6S, chondroitin 6-sulfate; GAGs, glycosaminoglycans; ERT, enzyme replacement therapy; NBS, newborn screening; HSCT, hematopoietic stem cell transplantation.

Mentions: Resolution of bone and cartilage lesions remains an unmet challenge for patients with MPS IVA. Patients with MPS IVA have severe progressive skeletal dysplasia that leads to significant morbidity and handicap with poor ADL. Management should be a multidisciplinary approach to care for patients, particularly those who have serious issues, such as spinal cord compression, ambulatory problems, and restrictive and obstructive lung issues. A comprehensive assessment of the individual patient at initial diagnosis is required with continuous follow-up by experienced clinicians. Supportive management, physiotherapy, and appreciation of possible complications can also improve the quality of life of patients with MPS IVA and their families. Families of the patients should become aware of management measures, including genetic counseling, ERT (already approved), HSCT, future gene therapy or anti-inflammatory drug, supportive therapies, physiotherapies, and orthopedic interventions (Figure 6). Physicians who take care of patients with MPS IVA should be familiar with the most common complications, diagnosis of the disease, and locations of expert centers, as well as available therapies. Hopefully, this will lead to earlier diagnosis for patients, resulting in better comprehensive therapy and avoidance of progression to irreversible damage. Although the current treatments will not cure the disease, they provide the potential to rescue most patients from consequences of the disease and to improve the quality of life if treatment starts at an early stage. Therapy for established systemic bone dysplasia remains a serious challenge, and robust, innovative approaches, such as bone targeting, should be further developed. Longitudinal observation of patients with MPS IVA under current optional therapies provides more precise and valuable information regarding the appropriate assessment, including biomarkers, physical activity, supportive treatment, efficacy of therapy, and the clinical endpoints.


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)

Model for diagnosis and treatment of patients with MPS IVA.Notes: *KS and C6S, which are stored in MPS IVA patients, are normalized or subnormalized naturally after synthesis of these GAGs is decreased with age (after teenage). Therefore, ERT may not be required for the group of patients who may have established bone lesions without risk of lung issue and may not be required permanently once lung issue is resolved. Especially, after 20 years of age with normalized KS and C6S, the cost/benefit of ERT should be evaluated carefully.Abbreviations: MPS, mucopolysaccharidosis; KS, keratan sulfate; C6S, chondroitin 6-sulfate; GAGs, glycosaminoglycans; ERT, enzyme replacement therapy; NBS, newborn screening; HSCT, hematopoietic stem cell transplantation.
© Copyright Policy
Related In: Results  -  Collection

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

f6-dddt-9-1937: Model for diagnosis and treatment of patients with MPS IVA.Notes: *KS and C6S, which are stored in MPS IVA patients, are normalized or subnormalized naturally after synthesis of these GAGs is decreased with age (after teenage). Therefore, ERT may not be required for the group of patients who may have established bone lesions without risk of lung issue and may not be required permanently once lung issue is resolved. Especially, after 20 years of age with normalized KS and C6S, the cost/benefit of ERT should be evaluated carefully.Abbreviations: MPS, mucopolysaccharidosis; KS, keratan sulfate; C6S, chondroitin 6-sulfate; GAGs, glycosaminoglycans; ERT, enzyme replacement therapy; NBS, newborn screening; HSCT, hematopoietic stem cell transplantation.
Mentions: Resolution of bone and cartilage lesions remains an unmet challenge for patients with MPS IVA. Patients with MPS IVA have severe progressive skeletal dysplasia that leads to significant morbidity and handicap with poor ADL. Management should be a multidisciplinary approach to care for patients, particularly those who have serious issues, such as spinal cord compression, ambulatory problems, and restrictive and obstructive lung issues. A comprehensive assessment of the individual patient at initial diagnosis is required with continuous follow-up by experienced clinicians. Supportive management, physiotherapy, and appreciation of possible complications can also improve the quality of life of patients with MPS IVA and their families. Families of the patients should become aware of management measures, including genetic counseling, ERT (already approved), HSCT, future gene therapy or anti-inflammatory drug, supportive therapies, physiotherapies, and orthopedic interventions (Figure 6). Physicians who take care of patients with MPS IVA should be familiar with the most common complications, diagnosis of the disease, and locations of expert centers, as well as available therapies. Hopefully, this will lead to earlier diagnosis for patients, resulting in better comprehensive therapy and avoidance of progression to irreversible damage. Although the current treatments will not cure the disease, they provide the potential to rescue most patients from consequences of the disease and to improve the quality of life if treatment starts at an early stage. Therapy for established systemic bone dysplasia remains a serious challenge, and robust, innovative approaches, such as bone targeting, should be further developed. Longitudinal observation of patients with MPS IVA under current optional therapies provides more precise and valuable information regarding the appropriate assessment, including biomarkers, physical activity, supportive treatment, efficacy of therapy, and the clinical endpoints.

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