Fabry disease: current treatment and future perspective

Han-Wook Yoo 대한의학유전학회 2023 대한의학유전학회지 Vol.20 No.1

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 halflife 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.

Fabry nephropathy before and after enzyme replacement therapy: important role of renal biopsy in patients with Fabry disease

( Il Young Kim ),( Hyun Jung Lee ),( Chong Kun Cheon ) 대한신장학회 2021 Kidney Research and Clinical Practice Vol.40 No.4

Background: In Fabry disease, the presence of globotriaosylceramide (GL3) deposits in various kidney cells leads to progressive renal dysfunction. However, kidney biopsy studies in patients with Fabry disease are limited. In the present study, the pathologic findings of patients with Fabry nephropathy receiving enzyme replacement therapy (ERT) and untreated patients without albuminuria were investigated. Methods: The present study included 15 patients with Fabry disease who underwent renal biopsy while receiving ERT (group 1: n = 9, age 19-58 years, two males and seven females) or before ERT initiation (group 2: n = 6, age 11-66 years, one male and five females). All patients in group 2 were normoalbuminuric. Results: Group 1 showed improved clinical symptoms, such as acroparesthesia. The ERT duration was 1.2 to 8 years and seven of the nine patients showed GL3 deposits in various kidney cells and segmental foot process effacement (FPE) of podocytes. GL3 deposits and FPE were not observed in the two remaining patients in group 1. Group 2 showed segmental FPE and podocyte GL3 deposits. Most patients in group 2 also showed GL3 deposits in the mesangium, endothelium, or tubular epithelium. Conclusion: The study results showed that segmental FPE and GL3 deposits can persist in Fabry nephropathy despite ERT. In addition, segmental FPE and GL3 deposits were observed in various kidney cells in normoalbuminuric patients with Fabry disease. These findings indicated that kidney biopsies at baseline and follow-up evaluation of Fabry nephropathy are essential for timely ERT initiation and ERT response assessment.

Single enzyme nanoparticle, an effective tool for enzyme replacement therapy

Dong Hyun Kim,Han Sol Lee,Tae-Wan Kwon,Young-Min Han,Naewon Kang,이미연,Dae-Duk Kim,김명규,이재영 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.1

The term “single enzyme nanoparticle” (SEN)refers to a chemically or biologically engineered singleenzyme molecule. SENs are distinguished from conventionalprotein nanoparticles in that they can maintain theirindividual structure and enzymatic activity following modification. Furthermore, SENs exhibit enhanced propertiesas biopharmaceuticals, such as reduced antigenicity, andincreased stability and targetability, which are attributed tothe introduction of specifi c moieties, such as poly(ethyleneglycol), carbohydrates, and antibodies. Enzyme replacementtherapy (ERT) is a crucial therapeutic option for controllingenzyme-defi ciency-related disorders. However, the unfavorableproperties of enzymes, including immunogenicity, lackof targetability, and instability, can undermine the clinicalsignifi cance of ERT. As shown in the cases of Adagen®,Revcovi®, Palynziq®, and Strensiq®, SEN can be an eff ectivetechnology for overcoming these obstacles. Based onthese four licensed products, we expect that additional SENs will be introduced for ERT in the near future. In this article,we review the concepts and features of SENs, as well as theirpreparation methods. Additionally, we summarize diff erenttypes of enzyme defi ciency disorders and the correspondingtherapeutic enzymes. Finally, we focus on the current statusof SENs in ERT by reviewing FDA-approved products.

효소 보충 치료로 호전을 보인 Pompe병 1례

전유훈,은백린,이동환,Jeon, You Hoon,Eun, Baik Lin,Lee, Dong Hwan 대한유전성대사질환학회 2005 대한유전성대사질환학회지 Vol.5 No.1

저자들은 Pompe 병으로 진단된 3세 남아에 recombinant human GAA 정주를 통한 효소 보충 치료를 시행하여 운동 능력과 심기능이 호전되며 간비대도 호전된 1례를 경험하였기에 보고하는 바이다. Pompe disease is a genetic disorder caused by a deficiency of acid ${\alpha}$-glucosidase (GAA). This enzyme defect results in lysosomal glycogen accumulation in multiple tissues and cell types, with cardiac, skeletal, and smooth muscle cells the most seriously affected. Infantile-onset Pompe disease is uniformly lethal. Affected infants present in the first few months of life with hypotonia, generalized muscle weakness, and a hypertrophic cardiomyopathy, followed by death from cardiorespiratory failure or respiratory infection, usually by 1 year of age. Late-onset forms is characterized by a lack of severe cardiac involvement and a less severe short-term prognosis. Enzyme replacement therapy for Pompe disease is intended to address directly the underlying metabolic defect via intravenous infusions of recombinant human GAA to provide the missing enzyme. We experienced one case of Pompe disease in 3-years old boy that has improved his exercise ability and cardiac function after GAA enzyme replacement therapy.

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

( Ji-yeon Kang ),( Hong-yeol Choi ),( Dong-il Kim ),( Ohsuk Kwon ),( Doo-byoung Oh ) 한국미생물생명공학회(구 한국산업미생물학회) 2021 Journal of microbiology and biotechnology Vol.31 No.1

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, rMnn14_77-935 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 rMnn14_77-935 were determined through enzyme assays with a high-mannose type N-glycan (Man₈GlcNAc₂) as a substrate. In addition, rMnn14_77-935 was shown to mannosyl-phosphorylate high-mannose type Nglycans (Man_7-9GlcNAc₂) 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 rMnn14_77-935 will provide a flexible and straightforward method to increase the M6P glycan content for the generation of “Biobetter” therapeutic enzymes.

5세 미만 뮤코다당체침착증 환자에서의 효소 대체 요법

박성원,손영배,김세화,조성윤,지선태,진동규,Park, Seong-Won,Son, Yeong-Bae,Kim, Se-Hwa,Jo, Seong-Yun,Ji, Seon-Tae,Jin, Dong-Gyu 대한유전성대사질환학회 2010 대한유전성대사질환학회지 Vol.10 No.1

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.

뮤코다당증의 장기 치료 효과와 한계점 극복을 위한 노력

손영배,Son, Yeong-Bae 대한유전성대사질환학회 2014 대한유전성대사질환학회지 Vol.14 No.1

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.

A Review of Recent Research in Treatment Approaches of Mucopolysaccharidosis (MPS)

Yang, Aram,Kim, Jinsup,Cho, Sung Yoon,Jin, Dong-Kyu Association for Research of MPS and Rare Diseases 2017 Journal of mucopolysaccharidosis and rare disease Vol.3 No.2

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.

Caucher 환자의 효소 대치요법에 따른 Chititriosidase 활성도 변화

유한욱,임대성,양송현,YOO, Han Wook,IM, Dae Seong,YANG, Song Hyun 대한유전성대사질환학회 2006 대한유전성대사질환학회지 Vol.6 No.1

Gaucher disease is an inherited disorder due to a deficiency in the activity of glucocerebrosidase (EC. 3.2.1.45) by genetic mutation which resulted from missense, nonsense, frameshift, deletion in long arm 21 of chromosome 1 (1q21). Gaucher disease is classified into the main three types as type 1 (nonneuronopathic), type 2 (acute neuronopathic) and type 3 (subacute neuronopathic) according to the progressive phase of manifestations and nervous system involvement. Gaucher disease patients had been treated by using the method as splenectomy and bone marrow transplantation. But enzyme replacement therapy as a more effective treatment has been available since the early 1990's. In order to treat Gaucher disease efficiently by using ERT, it is necessary to chase the progress of the therapy. In this study, therefore, we tried to chase the progress of the ERT by using the measurement of chitotriosidase activity in Gaucher disease patients.

A Review of Gaucher Disease in Korea

Sohn, Young Bae Association for Research of MPS and Rare Diseases 2021 Journal of mucopolysaccharidosis and rare disease Vol.5 No.1

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.