• 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.

• Journal of Genetic Medicine
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• v.13 no.2
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• pp.59-64
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• 2016

Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder caused by deficiency of acid ${\beta}$-glucosidase. The diminished enzyme activity leads to the accumulation of substrates and results in multi-systemic manifestations including hepatosplenomegaly, anemia, thrombocytopenia, and bone diseases. Enzyme replacement therapy (ERT) by infusion of recombinant protein has been the standard treatment for over 20 years. Despite the successful long-term treatment with ERT, several unmet needs remain in the treatment of GD1 such as severe pulmonary and skeletal manifestations. Substrate reduction therapy (SRT) reduces the accumulation of substrates by inhibiting their biosynthesis. Eliglustat, a new oral SRT, was approved in United States and Europe as a first-line therapy for treating adult patients with GD1 who have compatible CYP2D6 metabolism phenotypes. Although eliglustat is not yet available in Korea, introduction and summary of this new treatment modality are provided in this paper by review of literatures. Despite the fact that there are only limited studies to draw resolute conclusions, the current data demonstrated that eliglustat is not inferior to ERT in terms of its clinical efficacy. The approval of eligustat enables eligible adult GD1 patients to have the option of oral therapy although it still needs further studies on long-term outcomes. The individual patient should be assessed carefully for the choice of treatment modality when eliglustat becomes available in Korea. Furthermore, the clinical guidelines for Korean patients with GD1 regarding the use of eliglustat needs to be developed in near future.

• Journal of mucopolysaccharidosis and rare diseases
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• v.5 no.1
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• pp.1-7
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• 2021

Gaucher disease (GD, OMIM #230800 OMIM#230800) is a rare, autosomal recessive inherited metabolic disorder caused by mutation in GBA1 encoding the lysosomal enzyme, glucocerebrosidase. The deficiency of glucocerebrosidase leads to an accumulation of its substrate, glucosylceramide in macrophages of various tissues. Common clinical manifestations include cytopenia, splenomegaly, hepatomegaly, and bone lesions. The phenotype of GD is classified into three clinical categories: Type 1 (non-neuronopathic) is characterized by involvements on the viscera, whereas types 2 and 3 (neuronopathic) are associated with not only visceral symptoms but also neurological impairment, either severe in type 2 or variable in type 3. A diagnosis of GD can be confirmed by demonstrating the deficiency of acid glucocerebrosidase activity in leukocytes. Mutations in the GBA1 should be identified as they may be of prognostic value in some cases. Biomarkers including Chitotriosidase, CCL18, and glucosylsphingosine (lyso-GL1) are useful in diagnosis and treatment monitoring. Currently available disease-specific treatment in Korea consists of intravenous enzyme replacement therapy and substrate reduction therapy. For enhancing long-term prognosis, the onset of Parkinson's disease and Lewy body dementia, or the occurrence of a blood disease or cancer (hepatocellular carcinoma) should be monitored in older patients. The development of new strategies that can modify the neurological phenotype are expected, especially in Asia including Korea, where the prevalence of neuronopathic GD is relatively higher than that in western countries.

• Journal of Genetic Medicine
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• v.20 no.1
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• pp.6-14
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• 2023

Fabry disease (FD), a rare X-linked lysosomal storage disorder, is caused by mutations in the α-galactosidase A gene gene encoding α-galactosidase A (α-Gal A). The functional deficiency of α-Gal A results in progressive accumulation of neutral glycosphingolipids, causing multi-organ damages including cardiac, renal, cerebrovascular systems. The current treatment is comprised of enzyme replacement therapy (ERT), oral pharmacological chaperone therapy and adjunctive supportive therapy. ERT has been introduced 20 years ago, changing the outcome of FD patients with proven effectiveness. However, FD patients have many unmet needs. ERT needs a life-long intravenous therapy, inefficient bio-distribution, and generation of anti-drug antibodies. Migalastat, a pharmacological chaperone, augmenting α-Gal A enzyme activity only in patients with mutations amenable to the therapy, is now available for clinical practice. Furthermore, these therapies should be initiated before the organ damage becomes irreversible. Development of novel drugs aim at improving the clinical effectiveness and convenience of therapy. Clinical trial of next generation ERT is underway. Polyethylene glycolylated enzyme has a longer half-life and potentially reduced antigenicity, compared with standard preparations with longer dosing interval. Moss-derived enzyme has a higher affinity for mannose receptors, and seems to have more efficient access to podocytes of kidney which is relatively resistant to reach by conventional ERT. Substrate reduction therapy is currently under clinical trial. Gene therapy has now been started in several clinical trials using in vivo and ex vivo technologies. Early results are emerging. Other strategic approaches at preclinical research level are stem cell-based therapy with genome editing and systemic mRNA therapy.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.16 no.3
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• pp.117-122
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• 2016

제1형 고셔병(Gaucher disease type 1)은 리소좀 효소인 산성 ${\beta}$-글루코시다아제(acid ${\beta}-glucosidase$)의 결핍으로 인한 리소솜 축적 질환이다. 효소 활성도가 감소되어 기질이 축적되어, 간비종대, 빈혈, 혈소판감소증 및 골질환을 포함한 전신 증상이 발생한다. 재조합 효소 단백을 정맥 주입하는 효소 대체요법(Enzyme replacement therapy)는 지난 20년 넘게 고셔병의 표준 치료법이었다. 그러나 성공적인 효소 대체요법에도 불구하고, 심각한 폐증상과 골격 증상 등 고셔병 치료에 여전히 해결되지 않는 문제들이 남아 있다. 기질 감소 치료(Substrate reduction therapy)는 기질의 생합성을 억제하여 축적을 감소시킨다. 최근 새로운 경구용 기질감소 치료제인 엘리글루스타트(eliglustat)가 적합한 CYP2D6 대사 표현형을 가진 고셔병 성인 환자를 위한 1차 치료제로 미국과 유럽에서 승인되었다. 엘리글루스타트가 아직 한국에서는 쓰이지 않고 있지만, 본 종설에서는 문헌 검토를 통해 고셔병의 새로운 치료로서의 효소 대체요법을 소개하고자 한다. 아직 확고한 결론을 도출하기에는 연구 결과가 제한적이기는 하지만, 현재까지의 데이터에 따르면 엘리글루스타트는 임상 효능에 있어서 효소 보충 요법에 비열등성을 보인다. 장기 결과에 대한 추가 연구가 필요하지만, 엘리글루스타트의 승인은 해당 1형 고셔병 성인 환자들에게 경구 치료제라는 새로운 선택을 가능하게 하였다. 향후 국내에서 엘리글루스타트가 처방 가능해 지면, 각 환자 마다 철저한 평가를 통해 치료법을 선택할 수 있도록 해야 할 것이다. 나아가, 국내 1형 고셔병 환자들을 위해 엘리글루스타트의 사용에 관한 임상적 지침 또한 조만간 개발될 필요가 있다.

• Journal of Genetic Medicine
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• v.17 no.2
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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.

• 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 Genetic Medicine
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• v.13 no.2
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• pp.72-77
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• 2016

Purpose: Gaucher disease (GD) is the most common lysosomal storage disease caused by beta-glucocerebrosidase (GBA) deficiency. Oral substrate reduction therapy with miglustat ($Zavesca^{(R)}$) was approved for the treatment of adults with GD type 1, for whom enzyme replacement therapy (ERT) is unsuitable or not a therapeutic option. In this study, we report the effect of miglustat ($Zavesca^{(R)}$) in three Korean GD patients. Materials and Methods: Clinical findings comprising age at diagnosis, presenting signs, laboratory findings at diagnosis, GBA activity and mutations, and clinical courses of the three patients were reviewed. Results: Miglustat was administered to three patients who reported allergic reactions during intravenous imiglucerase infusions. One patient withdrew after 15 months of miglustat administration owing to continuous elevation of disease biomarker levels (chitotriosidase, acid phosphatase, and angiotensin-converting enzyme). Poor adherence to medication was suspected but was denied by the patient. In the other two patients, platelet count and levels of hemoglobin and other biomarkers remained stable during miglustat administration. However, they suffered from severe diarrhea and weight loss, which led to miglustat discontinuation after 1 and 12 months of administration. Conclusion: Our study shows that although miglustat is suggested to GD patients as an alternative treatment to ERT, significant adverse reactions may lead to discontinuation of miglustat. In addition, it is difficult to monitor the drug adherence.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.14 no.1
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• pp.29-36
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• 2014

Mucopolysaccharidoses (MPSs) are a group of rare inherited metabolic diseases caused by deficiency of lysosomal enzymes. MPSs are clinically heterogeneous and characterized by progressive deterioration in visceral, skeletal and neurological functions. The aim of this article is to review the treatment of MPSs, the unmet needs of current treatments and vision for the future including recent clinical trials. Until recently, supportive care was the only option available for the management of MPSs. Hematopoietic stem cell transplantation (HSCT), another potentially curative treatment, is not routinely advocated in clinical practice due to its high risk profile and lack of evidence for efficacy. From the early 2000s, enzyme replacement therapy (ERT) was approved and available for the treatment of MPS I, II and VI. ERT is effective for the treatment of many somatic symptoms, particularly walking ability and respiratory function, and remains the mainstay of MPS treatment. However, no benefit was found in the neurological symptoms because the enzymes do not readily cross the blood-brain barrier (BBB). In recent years, intrathecal (IT) ERT, substrate reduction therapy (SRT) and gene therapy have been rapidly gaining greater recognition as potential therapeutic avenues. Although still under investigation, IT ERT, SRT and gene therapy are promising MPS treatments that may prevent the neurodegeneration not improved by ERT.

• Journal of mucopolysaccharidosis and rare diseases
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• v.3 no.2
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• pp.37-40
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• 2017

Mucopolysaccharidosis (MPS) is caused by accumulation of the glycosaminoglycans in all tissues due to decreased activity of the lysosomal enzyme. Patients exhibit multisystemic signs and symptoms in a chronic and progressive manner, especially with changes in the skeleton, cardiopulmonary system, central nervous system, cornea, skin, liver, and spleen. In the past, treatment of MPS was limited to enzyme replacement therapy (ERT). The outcome for affected patients improved with the introduction of new technologies as hematopoietic stem cell transplantation, relegated to specific situations after ERT became available. Intrathecal ERT may be considered in situations of high neurosurgical risk but still it is experimental in humans. New insights on the pathophysiology of MPS disorders are leading to alternative therapeutic approaches, as gene therapy, inflammatory response modulators and substrate reduction therapy. In this paper, we will highlight the recent novel treatment and clinical trials for MPS and discuss with the goal of fostering an understanding of this field.