• BMB Reports
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• v.48 no.8
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• pp.438-444
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• 2015

Lysosomal storage diseases (LSDs) are a group of inherent diseases characterized by massive accumulation of undigested compounds in lysosomes, which is caused by genetic defects resulting in the deficiency of a lysosomal hydrolase. Currently, enzyme replacement therapy has been successfully used for treatment of 7 LSDs with 10 approved therapeutic enzymes whereas new approaches such as pharmacological chaperones and gene therapy still await evaluation in clinical trials. While therapeutic enzymes for Gaucher disease have N-glycans with terminal mannose residues for targeting to macrophages, the others require N-glycans containing mannose-6-phosphates that are recognized by mannose-6-phosphate receptors on the plasma membrane for cellular uptake and targeting to lysosomes. Due to the fact that efficient lysosomal delivery of therapeutic enzymes is essential for the clearance of accumulated compounds, the suitable glycan structure and its high content are key factors for efficient therapeutic efficacy. Therefore, glycan remodeling strategies to improve lysosomal targeting and tissue distribution have been highlighted. This review describes the glycan structures that are important for lysosomal targeting and provides information on recent glyco-engineering technologies for the development of therapeutic enzymes with improved efficacy. [BMB Reports 2015; 48(8): 438-444]

• Clinical and Experimental Pediatrics
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• v.50 no.2
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• pp.213-217
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• 2007

Pompe disease is a genetic disorder caused by a deficiency of acid ${\alpha}$-glucosidase (GAA). Infantile onset Pompe disease is uniformly lethal. Affected infants generally present in the first few months of life with hypotonia, generalized muscle weakness, and a hypertrophic cardiomyopathy, which is rapidly followed by death, usually by the age of one. The late-onset form is characterized less severe symptoms and prognosis. Therapy for Pompe disease is intended to directly address the underlying metabolic defect via intravenous infusions of recombinant human GAA to replace the missing enzyme. We report a case of atypical infantile-onset Pompe disease that presented symptoms in infancy but had less severe clinical manifestations and improved after GAA enzyme replacement ($Myozyme^{(R)}$, Genzyme Co., MA, USA) therapy. It is very important that pediatricians become aware of signs and symptoms of Pompe disease, such as a nasal voice or a waddling gait at an early stage so that these patients can benefit from appropriate GAA replacement therapy as soon as possible.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.17 no.2
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• pp.55-62
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• 2017

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by beta-glucosidase deficiency. An 18 month-old male with hepatosplenomegaly, anemia, thrombocytopenia, and growth retardation referred to our hospital. The patient showed neurological symptoms, such as supranuclear gaze palsy and developmental delay. Bone marrow biopsy performed to rule out malignancy and the results revealed no malignant cell; however, abnormal histiocytes suggesting storage disease was noted. Based on hepatosplenomegaly, bicytopenia and unexplained neurologic manifestations, enzyme activity and genetic analysis were conducted emergently with a strong suspicion of GD. Beta-glucosidase activity in leukocyte was decreased. GBA sequencing to confirm the diagnosis revealed compound heterozygous pathogenic variants (i.e., c.754T>A, c.887G>A), both previously reported as the cause of neuronopathic GD. Under the diagnosis of type 3 GD, the patient immediately received enzyme replacement therapy (ERT). After 17 months of ERT, the size of spleen decreased, and hemoglobin and platelet count returned to normal. In addition, the activity of chitotriosidase and angiotensin converting enzyme decreased. However, myoclonic movement and generalized seizure occurred at the age of 19 months and antiepileptic drug was started. Other neurological deterioration including supranuclear gaze palsy and developmental delay also persisted. A new therapy to overcome neurologic problems should be developed for patients with type 3 GD.

• Journal of mucopolysaccharidosis and rare diseases
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• v.4 no.2
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• pp.37-41
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• 2018

Mucopolysaccharidosis III (MPS III, Sanfilippo syndrome) is a rare autosomal recessive disease caused by a deficiency of one of four enzymes involved in the degradation of glycosaminoglycan (GAG). The resultant cellular accumulation of GAG causes various clinical manifestations. MPS III is divided into four subtypes depending on the deficient enzyme. All the subtypes show similar clinical features and are characterized by progressive degeneration of the central nervous system. A number of genetic and biochemical diagnostic methods have been developed. However, there is no effective therapy available for any form of MPS III, with treatment currently limited to clinical management of neurological symptoms. Main purpose of the treatment for MPS III is to prevent neurologic deterioration. Because conventional intravenous enzyme replacement therapy (ERT) has a limitation due to inability to cross the blood-brain barrier, several innovative therapeutic approaches for MPS III are being developed. This review covers the currently developing new therapeutic options for MPS III including high dose ERT, substrate reduction therapy, intrathecal or intraventricular ERT, fusion protein delivery using bioengineering technology, and gene therapy.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.10 no.1
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• pp.59-66
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• 2010

Enzyme replacement of therapy (ERT) is one of the most promising therapeutic strategies for the treatment of lysosomal storage disorders. ERT is available in three types of Mucopolysaccharidosis (MPS): for MPS I (Aludrazyme$^{(R)}$), MPS II (Elaprase$^{(R)}$) and MPS VI (Naglazyme$^{(R)}$) patients who are over 5 years old. But recently, early diagnosis can be done by expert clinicians and even in prenatal case. We describe the case of ERT under 5 years old MPS patients. Up to June, 2010 in Samsung Medical Center, there are 6patients who were diagnosed as MPS and started ERT under 5 years old. 3 patients were MPS I, 3 patients were MPS II. 2 patient who was diagnosed as MPS I was female and others were male. Their age at diagnosis were 4 to 37month-old (4, 13, 16, 25, 27, 37 month-old) and they are now 9 to 60 month-old (9, 39, 32, 81, 60 month-old). The youngest patient was started ERT at 4 month-old and others were started at their 13 to 49 month-old (13, 29, 27, 28, 49 month-old). First manifested symptoms of patients were macrocephaly, kyphosis and coarse face appearance. Especially, in 2 of them, one was MPS I and the other was MPS II had elder brother with same disease. And the youngest one was diagnosed by the iduronate-2-sulfatase (IDS) gene analysis from chorionic villi sampling. His mother knew that she was a heterozygous carrier of IDS gene mutation because her younger brother died from MPS II. All of them confirmed as MPS by the enzyme assay in leukocytes and fibroblast skin culture. We started ERT with ${\alpha}$-L-iduronidase(Aldurazyme$^{(R)}$) to MPS I and did recombinant human iduronate-2-sulfatase (Elaprase$^{(R)}$) to MPS II patients as recommended dose as over 5 years old. But for MPS II patient who was 4 month old, we started ERT by recombinant human IDS (Elaprase$^{(R)}$) with reduced dose 0.1 mg/kg and increased dose every 2 weeks by 0.1mg/kg up to 0.5mg/kg IV infusion. During ERT, all patients had no adverse effects and the excretion of GAGs were decreased. We have evaluated other clinical symptoms such as liver/ spleen volume, heart function and neurologic evaluation. We describe a successful ERT to MPS I and MPS II patient under 5 years old without any adverse event. It indicates that ERT in young children are well tolerated and that it has several effects which may confer clinical benefits with long-term therapy.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.14 no.2
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• pp.178-181
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• 2014

Hunter syndrome (mucopolysaccharidosis type II, MPS II) is a X-linked lysosomal storage disease caused by a deficiency in the lysosomal enzyme, iduronate-2-sulfatase (IDS), leading to accumulation of glycosaminoglycans within lysosomes of many organs and tissues. Since the enzyme replacement therapy was approved and available in the treatment of MPS I, II, VI, early diagnosis and early therapy can bring the better prognosis of disease and the better quality of life in patients. We described a 2.5 year old child presented with frequent otitis media and developmental delay including speech impairment, who was diagnosed as Hunter syndrome with IDS NM_000202.5:c. 263G>A(p.Arg88His) mutation.

• Journal of mucopolysaccharidosis and rare diseases
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• v.4 no.1
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• pp.7-10
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• 2018

Rare diseases are life threatening or chronically debilitating diseases with a low prevalence (less than 2,000 people in a population), which includes lysosomal storage diseases. These diseases are often seen as unimportant especially in developing countries, such as Indonesia, due to small number of patients. National Rare Disease Center in Indonesia was pioneered almost 20 years ago and officially established in 2017 by the Indonesian Minister of Health. Lysosomal storage disease become the most commonly found inborn errors of metabolism (IEM) in Indonesia due to easily accessible diagnostic facilities. Currently there are 7 patients receiving ERT in this mixed-donation scheme, one patient with Gaucher disease and 6 patients with MPS type II. Few challenges for ERT in Indonesia include importation through special access scheme, preparation of ERT infusion in intensive care settting, and cost of treatment. Even with limited resources, healthcare professionals in Indonesia have been giving the best care possible for rare disease patients, especially to provide diagnostic facilities through collaboration and treatment options for treatable rare diseases. Improvements in care for rare disease patients are still needed.

• BMB Reports
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• v.46 no.3
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• pp.157-162
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• 2013

Human ${\alpha}$-galactosidase A (GLA) has been used in enzyme replacement therapy for patients with Fabry disease. We expressed recombinant GLA from Chinese hamster ovary cells with very high productivity. When compared to an approved GLA (agalsidase beta), its size and charge were found to be smaller and more neutral. These differences resulted from the lack of terminal sialic acids playing essential roles in the serum half-life and proper tissue targeting. Because a simple sialylation reaction was not enough to increase the sialic acid content, a combined reaction using galactosyltransferase, sialyltransferase, and their sugar substrates at the same time was developed and optimized to reduce the incubation time. The product generated by this reaction had nearly the same size, isoelectric points, and sialic acid content as agalsidase beta. Furthermore, it had better in vivo efficacy to degrade the accumulated globotriaosylceramide in target organs of Fabry mice compared to an unmodified version.

• Annals of Clinical Neurophysiology
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• v.23 no.1
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• pp.29-34
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• 2021

New therapeutics in neurology are expanding at an unprecedented pace. In addition to the classic enzyme-replacement therapies, monoclonal antibodies are increasingly being used to modulate autoimmunity. RNA therapeutics are an emerging class, together with gene and cell therapies. The nomenclature of international nonproprietary names helps us to recognize these new drugs according to their class and function. Suffixes denote major categories of the drug, while infixes provide additional information such as the source and target.

• Journal of mucopolysaccharidosis and rare diseases
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• v.5 no.1
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• pp.22-28
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• 2021

Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan-inherited lysosomal storage disease. It is one of the most common MPS subtypes. The classical presentation is an infantile-onset neurodegenerative disease characterized by intellectual regression, behavioral and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease-modifying therapy has been approved. Here, we review the curative therapy developed for MPS III, from historically ineffective hematopoietic stem cell transplantation and substrate reduction therapy to the promising enzyme replacement therapy or adeno-associated/lentiviral vector-mediated gene therapy. Preclinical studies are presented with recent translational first-in-man trials. We also present experimental research with preclinical mRNA and gene-editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of early therapy before extensive neuronal loss. Disease-modifying therapy for MPS III will likely mandate the development of new early diagnosis strategies.