scholarly journals Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

2021 ◽  
Vol 22 (22) ◽  
pp. 12227
Author(s):  
Koji Matsuhisa ◽  
Kazunori Imaizumi
Keyword(s):  
Endoplasmic Reticulum ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Loss Of Function ◽  
Mucopolysaccharidosis Type Ii ◽  
Hematopoietic Stem ◽  
Mps Ii ◽  
Mechanism Of Degradation ◽  
Lysosomal Accumulation ◽  
Systemic Symptoms

Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the IDS gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.

scholarly journals Assessment of Activity of Daily Life in Mucopolysaccharidosis Type II Patients with Hematopoietic Stem Cell Transplantation

Diagnostics ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 46 ◽  
Author(s):  
Yasuyuki Suzuki ◽  
Madeleine Taylor ◽  
Kenji Orii ◽  
Toshiyuki Fukao ◽  
Tadao Orii ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Treated Group ◽  
Level Of Care ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Mucopolysaccharidosis Type Ii ◽  
Hematopoietic Stem ◽  
Mps Ii

The effectiveness of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis type II (MPS II, Hunter disease) remains controversial although recent studies have shown HSCT provides more clinical impact. This study aims to evaluate the long-term effectiveness of HSCT using the activity of daily living (ADL) scores in patients with MPS II. Sixty-nine severely affected MPS II patients (19 patients who received HSCT and 50 untreated patients) and 40 attenuated affected patients (five with HSCT and 35 untreated) were investigated by a simplified ADL questionnaire. The frequency of clinical findings and the scores of ADL (verbal, gross motor, and the level of care) were analyzed statistically. The mean age of onset of 19 severely affected patients who received HSCT was 1.40 years ± 1.06, which is not statistically different from that of 50 untreated patients (p = 0.11). Macroglossia, frequent airway infection, hepatosplenomegaly, joint contracture, and sleep apnea were less frequent in the HSCT-treated group of severe MPS II patients. The severe phenotype HSCT treated group reported a statistically significant higher score of verbal function and gross motor function between the ages of 10 and 15 years and a higher level of care score between 10 and 20 years. Patients with the attenuated phenotype showed high ADL scores, and all of five HSCT treated patients reported a lower frequency of frequent airway infection, coarse skin, umbilical/inguinal hernia, hepatosplenomegaly, heart valve disorders, and carpal tunnel. In conclusion, HSCT is effective, resulting in improvements in clinical features and ADL in patients with MPS II. HSCT should be re-reviewed as a therapeutic option for MPS II patients.

HMI-203: Gene therapy developmental candidate for mucopolysaccharidosis type II (MPS II), or Hunter syndrome

2021 ◽  
Vol 132 ◽  
pp. S147
Author(s):  
Kruti Patel ◽  
Laura Smith ◽  
Tania Seabrook ◽  
Alec Tzianabos ◽  
Lindsay Schulman ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hunter Syndrome ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Mucopolysaccharidosis Type Ii ◽  
Mps Ii

scholarly journals The Value of Case Reports in Systematic Reviews from Rare Diseases. The Example of Enzyme Replacement Therapy (ERT) in Patients with Mucopolysaccharidosis Type II (MPS-II)

2020 ◽  
Vol 17 (18) ◽  
pp. 6590
Author(s):  
Miguel Sampayo-Cordero ◽  
Bernat Miguel-Huguet ◽  
Andrea Malfettone ◽  
José Manuel Pérez-García ◽  
Antonio Llombart-Cussac ◽  
...  
Keyword(s):  
Enzyme Replacement Therapy ◽  
Systematic Reviews ◽  
Rare Diseases ◽  
Clinical Studies ◽  
Case Reports ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Mucopolysaccharidosis Type Ii ◽  
Enzyme Replacement ◽  
Mps Ii

Background: Case reports are usually excluded from systematic reviews. Patients with rare diseases are more dependent on novel individualized strategies than patients with common diseases. We reviewed and summarized the novelties reported by case reports in mucopolysaccharidosis type II (MPS-II) patients treated with enzyme replacement therapy (ERT). Methods: We selected the case reports included in a previous meta-analysis of patients with MPS-II treated with ERT. Later clinical studies evaluating the same topic of those case reports were reported. Our primary aim was to summarize novelties reported in previous case reports. Secondary objectives analyzed the number of novelties evaluated in subsequent clinical studies and the time elapsed between the publication of the case report to the publication of the clinical study. Results: We identified 11 innovative proposals in case reports that had not been previously considered in clinical studies. Only two (18.2%) were analyzed in subsequent nonrandomized cohort studies. The other nine novelties (81.8%) were analyzed in later case reports (five) or were not included in ulterior studies (four) after more than five years from their first publication. Conclusions: Case reports should be included in systematic reviews of rare disease to obtain a comprehensive summary of the state of research and offer valuable information for healthcare practitioners.

scholarly journals Modeling Mucopolysaccharidosis Type II in the Fruit Fly by Using the RNA Interference Approach

Life ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 263
Author(s):  
Laura Rigon ◽  
Nicole Kucharowski ◽  
Franka Eckardt ◽  
Reinhard Bauer
Keyword(s):  
Rna Interference ◽  
Enzymatic Activity ◽  
Dermatan Sulfate ◽  
Fruit Fly ◽  
Neurological Involvement ◽  
Mucopolysaccharidosis Type ◽  
Type Ii ◽  
Lysosomal Storage ◽  
Mucopolysaccharidosis Type Ii ◽  
Mps Ii

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder that occurs due to the deficit of the lysosomal enzyme iduronate 2-sulfatase (IDS) that leads to the storage of the glycosaminoglycan heparan- and dermatan-sulfate in all organs and tissues. It is characterized by important clinical features and the severe form presents with a heavy neurological involvement. However, almost nothing is known about the neuropathogenesis of MPS II. To address this issue, we developed a ubiquitous, neuronal, and glial-specific knockdown model in Drosophila melanogaster by using the RNA interference (RNAi) approach. Knockdown of the Ids/CG12014 gene resulted in a significant reduction of the Ids gene expression and enzymatic activity. However, glycosaminoglycan storage, survival, molecular markers (Atg8a, Lamp1, Rab11), and locomotion behavior were not affected. Even strongly reduced, IDS-activity was enough to prevent a pathological phenotype in a MPS II RNAi fruit fly. Thus, a Drosophila MPS II model requires complete abolishment of the enzymatic activity.

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