• 제목/요약/키워드: Enzyme Replacement Therapy

검색결과 71건 처리시간 0.02초

In Vitro N-Glycan Mannosyl-Phosphorylation of a Therapeutic Enzyme by Using Recombinant Mnn14 Produced from Pichia pastoris

  • Kang, Ji-Yeon;Choi, Hong-Yeol;Kim, Dong-Il;Kwon, Ohsuk;Oh, Doo-Byoung
    • Journal of Microbiology and Biotechnology
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    • 제31권1호
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    • pp.163-170
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    • 2021
  • Enzyme replacement therapy for lysosomal storage diseases usually requires recombinant enzymes containing mannose-6-phosphate (M6P) glycans for cellular uptake and lysosomal targeting. For the first time, a strategy is established here for the in vitro mannosyl-phosphorylation of high-mannose type N-glycans that utilizes a recombinant Mnn14 protein derived from Saccharomyces cerevisiae. Among a series of N-terminal- or C-terminal-deleted recombinant Mnn14 proteins expressed in Pichia pastoris, rMnn1477-935 with deletion of N-terminal 76 amino acids spanning the transmembrane domain (46 amino acids) and part of the stem region (30 amino acids), showed the highest level of mannosyl-phosphorylation activity. The optimum reaction conditions for rMnn1477-935 were determined through enzyme assays with a high-mannose type N-glycan (Man8GlcNAc2) as a substrate. In addition, rMnn1477-935 was shown to mannosyl-phosphorylate high-mannose type N-glycans (Man7-9GlcNAc2) on recombinant human lysosomal alpha-glucosidase (rhGAA) with remarkably high efficiency. Moreover, the majority of the resulting mannosyl-phosphorylated glycans were bis-form which can be converted to bis-phosphorylated M6P glycans having a superior lysosomal targeting capability. An in vitro N-glycan mannosyl-phosphorylation reaction using rMnn1477-935 will provide a flexible and straightforward method to increase the M6P glycan content for the generation of "Biobetter" therapeutic enzymes.

Hematopoietic Cell Transplantation in Patients with Mucopolysaccharidosis Type II

  • Song, Ari
    • Journal of mucopolysaccharidosis and rare diseases
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    • 제5권1호
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    • pp.12-16
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    • 2021
  • Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked lysosomal storage disorder caused by deficiency of the enzyme iduronate-2-sulfatase, leading to the accumulation of glycosaminoglycans (GAGs), which affects multiple organs and systems. Current treatments for MPS II include enzyme replacement therapy (ERT) and hematopoietic cell transplantation (HCT) to reduce the accumulation of GAGs. HCT has the potential advantage that donor-derived enzyme-competent cells can provide a continuous secreting source of the enzyme. However, HCT as a treatment for MPS II remains controversial because its effectiveness is unclear, particularly in terms of neurological symptoms. To date, several clinical experiences with HCT in MPS II have been reported. In this paper, we review post-HCT outcomes in the previously published literature and discuss the effects of HCT on each of the clinical signs and symptoms of MPS II.

Mucopolysaccharidoses in Taiwan

  • Lin, Hsiang-Yu;Chuang, Chih-Kuang;Lin, Shuan-Pei
    • Journal of mucopolysaccharidosis and rare diseases
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    • 제4권1호
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    • pp.14-20
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    • 2018
  • Mucopolysaccharidoses (MPSs) are a group of rare inherited metabolic disorders caused by specific lysosomal enzyme deficiencies leading to the sequential degradation of glycosaminoglycans, causing substrate accumulation in various cells and tissues and progressive multiple organ dysfunction. The rare disease medical care team at Mackay Memorial Hospital in Taiwan has been dedicated to the study of MPSs for more than 20 years. Since 1999, more than 50 academic papers focusing on MPSs have been published in international medical journals. Topics of research include the following items regarding MPSs: incidence, natural history, clinical manifestations, gene mutation characteristics, cardiac function, bone mineral density, sleep studies, pulmonary function tests, hearing assessments, percutaneous endoscopic gastrostomy, anesthetic experience, imaging analysis, special biochemical tests, laboratory diagnostics, global expert consensus conferences, prenatal diagnosis, new drug clinical trials, newborn screening, and treatment outcomes. Of these published academic research papers, more than half were cross-domain, cross-industry, and international studies with results in cooperation with experts from European, American and other Asian countries. A cross-specialty collaboration platform was established based on high-risk population screening criteria with the acronym "BECARE" (Bone and joints, Eyes, Cardiac and central nervous system, Abdomen and appearance, Respiratory system, and Ear, nose, and throat involvement). Through this platform, orthopedic surgeons, rheumatologists, ophthalmologists, cardiologists, rehabilitation physicians, gastroenterologists, otorhinolaryngologists, and medical geneticists have been educated with regards to awareness of suspected cases of MPSs patients to allow for a further confirmative diagnosis of MPSs. Because of the progressive nature of the disease, an early diagnosis and early multidisciplinary therapeutic interventions including surgery, rehabilitation programs, symptom-based treatments, hematopoietic stem cell transplantation, and enzyme replacement therapy, are very important.

큰 두위를 주소로 내원하여 헌터 증후군으로 일찍 진단된 증례 1례 (A Case of Early Diagnosed Hunter Syndrome Detected by Large Head on Routine Examination)

  • 이승호;박우성;이영석;유지숙
    • 대한유전성대사질환학회지
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    • 제14권2호
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    • pp.156-162
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    • 2014
  • A 25-month-old boy was referred to the hospital due to large head detected on routine physical examination. At visit, dysmorphic facial appearances, including broad nose, prominent forehead, and coarse face, were noted. Nasal obstruction with nasal voice, prominent adenoids, and bilateral middle ear effusions were detected. His abdomen was distended, and liver and spleen were palpated about 3 finger and 2 finger breadths, respectively. He was operated for bilateral inguinal hernias. The motion of both elbow joints was mildly limited on supination and pronation. Urinary level of glycosaminoglycan was elevated and the enzyme activity of iduronate sulfatase in leukocytes was decreased. The mutational analysis of the gene iduronate 2-sulfatase (IDS) revealed c.263G>A (p.Arg88His) mutation. His developmental scale showed delayed development and there was cardiac valvular involvement (tricuspid regurgitation and mitral valve prolapse). After the diagnosis of Hunter syndrome, enzyme replacement therapy started on a weekly basis without progression of any clinical features. Here we report a case of early diagnosed Hunter syndrome detected by large head on routine examination. Thus, it is important to associate Hunter syndrome in the patient with large head especially, if there is the history of bilateral inguinal hernia and prominent adenoids to increase the possibility of early diagnosis and treatment.

리소좀 축적 질환(Lysosomal storage disease)에서의 효소 치료 (Enzyme replacement therapy)

  • 진동규
    • 대한유전성대사질환학회지
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    • 제11권1호
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    • pp.27-32
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    • 2011
  • 최근 유전공학의 발달로 리소좀 축적 질환에서 효소 치료제가 개발되어 실제 치료에 사용되고 있다. 현재 효소 보충 치료가 가능한 리소좀 축적 질환에는 고셔병(Gaucher disease), 파브리병(Fabry disease), 폼페병(Pompe disease), 뮤코다당체침착병(Mucopolysaccharidosis, MPS) 1형, 2형, 6형이 있으며 비교적 안전하면서 증상 완화에도 효과적으로 보인다. 그러나 이미 진행이 된 증상에 대해서는 비가역적이므로 조기에 진단을 하여 치료를 시작하는 것이 중요하다. 효소 보충 치료의 장기간에 걸친 치료 효과에 대해서 지속적인 평가가 필요하며 무엇보다 뼈와 중추신경계에 대한 효과는 제한적이므로 이에 대한 새로운 치료법의 개발이 필요하다.

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One-year experience of oral substrate reduction therapy in three patients with Gaucher disease type I

  • Sohn, Young Bae;Kim, Yewon;Moon, Ji Eun
    • Journal of Genetic Medicine
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    • 제17권2호
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    • pp.62-67
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    • 2020
  • Purpose: Eliglustat is an oral substrate reduction therapy (SRT) approved for adults with Gaucher disease type I (GD1) who are extensive, intermediate, or poor CYP2D6 metabolizers. Here we report one-year experience of eliglustat switch therapy from long-term enzyme replacement therapy (ERT) in three adult patients with GD1. Materials and Methods: Medical history, clinical (hemoglobin concentration, platelet count, and bone mineral density) and biochemical parameters (angiotensin converting enzyme, total acid phosphatase, and lyso-gb1) of the patients were collected and evaluated by retrospective review of medical records at every 3, 6, or 12 month after switch to SRT. Results: Patient 1 was a 43-year old female diagnosed GD1 and her clinical and biochemical parameters were stabilized for more than 20 years by ERT. Due to the burden of regular hospital visit, she switched to SRT. During one-year of SRT, clinical parameters and biomarkers were maintained stable. However, after suffering acute febrile illness during SRT, she decided to re-switch to ERT due to concerns about drug interaction. Patient 2 was 41-year old male, younger brother of patient 1 and Patient 3 was 31-year old male. They switched to SRT in clinically stable condition with long-term ERT. The one-year SRT was tolerable without specific safety issue and the clinical parameters were maintained stable. Conclusion: One-year eliglustat therapy in three adult patients with GDI was generally tolerable and effective for maintaining the clinical parameters and biomarkers. However, the drug compliance, concurrent drug interactions, and long-term safety of eliglustat should be carefully monitored.

Angiotensin receptor blocker induced fetopathy: two case reports and literature review

  • Jinwoon Joung;Heeyeon Cho
    • Childhood Kidney Diseases
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    • 제27권2호
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    • pp.121-126
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    • 2023
  • The administration of angiotensin type 2 receptor blockers (ARBs) during pregnancy is known to cause ARB fetopathy, including renal insufficiency. We aimed to analyze the outcomes of two patients who survived ARB fetopathy and perform an accompanying literature review. Case 1 was exposed antenatally from a gestational age of 30 weeks to valsartan because of maternal pregnancy-induced hypertension. The patient presented with oliguria immediately after birth, and renal replacement therapy was administered for 24 days. Seven years after birth, renal function was indicative of stage 2 chronic kidney disease (CKD) with impaired urinary concentration. Case 2 had a maternal history of hypertension and transient ischemic attack and was treated with olmesartan until 30 weeks of pregnancy. Renal replacement therapy was performed for 4 days since birth. After 8 years, the patient is with CKD stage 2, with intact tubular function. Recent reports suggest that ARB fetopathy might manifest as renal tubular dysgenesis and nephrogenic diabetes insipidus, in contrast to mild alterations of glomerular filtration. Tubular dysfunction may induce CKD progression and growth retardation. Patients with ARB fetopathy should be monitored until adulthood. The ARB exposure period might be a critical factor in determining the severity and manifestations of fetopathy.

Mucopolysaccharidosis Type III: Overview and Future Therapeutic Approaches

  • Kwak, Min Jung
    • Journal of mucopolysaccharidosis and rare diseases
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    • 제3권1호
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    • pp.1-8
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    • 2017
  • Mucopolysaccharidosis (MPS) type III, or Sanfilippo syndrome is a rare autosomal recessive lysosomal storage disorder. It is caused by a deficiency of one of four enzymes involved in the degradation of the glycosaminoglycan (GAG) heparan sulfate. The resultant cellular accumulation of heparan sulfate causes various clinical manifestations. MPS III is divided into four subtypes depending on the deficient enzyme: MPS IIIA, MPS IIIB, MPS IIIC and MPS IIID. All the subtypes show similar clinical features and are characterized by progressive degeneration of the central nervous system (CNS). Main purpose of the treatment for MPS III is to prevent neurologic deterioration. However, conventional enzyme replacement therapy has a limitation due to inability to cross the blood-brain barrier. Several experimental treatment options for MPS III are being developed.

Development of Modified Phenylalanine Ammonia-lyase for the Treatment of Phenylketonuria

  • Kim, Woo-Mi
    • Biomolecules & Therapeutics
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    • 제17권1호
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    • pp.104-110
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    • 2009
  • Phenylketonuria (PKU) is an inherited metabolic disorder caused by mutations in the phenylalanine catabolic enzyme, phenylalanine hydroxylase (PAH). The use of phenylalanine ammonia-lase (PAL) by oral and parenteral routes as a therapeutic drug for PKU has been severely limited due to inactivation by intestinal proteolysis and immune reactions. PEGylation was applied to PAL to reduce the degrees of antigenicity and proteolytic inactivation. Kinetic experiments with native PAL and pegylated PALs were performed, and pH stability, temperature stability, and protease susceptibility were evaluated. Enzyme linked immunosorbent assay (ELISA) was carried out to measure the immune complex between pegylated PALs and antiserum that had been extracted from a PAL-immunized mouse. Pegylated PAL, especially branched pegylated PAL (10 kDa, 1:32), was more active for phenylalanine and more stable in pancreatic proteases than native PAL. Native PAL was optimal at pH 8.5, corresponding to the average pH range of the small intestine; the same finding was noted for pegylated PALs. All linear and branched pegylated PALs had low reactivity with mouse antiserum, especially the 1:16 formulation with linear 5-kDa PEG and the 1:32 formulation with branched 10-kDa PEG. Therefore, we suggest the 1:32 formulation with branched 10-kDa PEG as the most promising formulation for enzyme replacement therapy.

파브리병 환자의 진단과 선별검사의 최신지견 (A Recent Insight into the Diagnosis and Screening of Patients with Fabry Disease)

  • 윤혜란;조지훈
    • 대한유전성대사질환학회지
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    • 제24권1호
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    • pp.17-25
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    • 2024
  • 파브리병은 X염색체-연관 리소좀 축적 장애이다. 이는 α-갈락토시다제 A(α-Gal A)의 활성이 없거나 결핍되어있는 α-갈락토시다제 A 유전자의 돌연변이로 인해 발생한다. 이러한 효소활성의 저하로 인해 대사되지 못한 지질인 globotiaosylceramide (Gb3)가 다양한 인체 조직에 점진적으로 축적된다. 파브리병의 조기진단 시기를 놓치는 경우 신장 및 심장 기능의 점진적인 손상이 심각하게 발생한다. 환자는 말초 근육 통증, 위장 장애, 일과성 허혈 발작 및 뇌졸중을 경험하기도 한다. 피부, 눈, 귀, 폐 및 뼈 등에서 이 병의 진행으로 인한 추가 증상이 종종 나타난다. 치료과정 없이 병이 진행되면 심장이나 신장의 개입으로 인해 기대 수명이 단축되는 치명적인 결과를 초래한다. 따라서 파브리병을 조기에 발견하는 것이 발병율과 사망율을 감소시키는 데 매우 중요하다. 비정형성 파브리병의 변이를 식별하기 위한 globotriaosysphingosine(lyso-Gb3)과 심장 침범을 식별할 수 있는 고감도로 탐지할 수 있는 트로포닌 T(hsTNT)는 모두 중요한 진단 마커이다. 효소 대체 치료(enzyme replacement therapy) 또는 샤페론 치료(chaperone therapy)는 파브리병 치료의 주요 두 가지 방법이다. 질환이 드물기도 하지만 진단이 제대로 잘 되지 않는 놓치기 쉬운 질환이기도 하다. 따라서 이종설의 목적은 파브리병의 조기 진단과 진단에 대한 최근의 업데이트된 현황 보고와 진단을 위한 기본 자료를 제공하는 데 있다. 또한 효소 대체 치료 및 일반적인 진단 알고리즘과 그에 연관된 필요한 정보를 제공한다.

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