scholarly journals Development of Substrate Degradation Enzyme Therapy for Mucopolysaccharidosis IVA Murine Model

2019 ◽  
Vol 20 (17) ◽  
pp. 4139 ◽  
Author(s):  
Kazuki Sawamoto ◽  
Shunji Tomatsu
Keyword(s):  
Positive Impact ◽  
Bone Lesion ◽  
Enzyme Therapy ◽  
Bone Pathology ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Substrate Degradation ◽  
Mps Iva ◽  
Ph Range ◽  
Optimal Ph

Mucopolysaccharidosis IVA (MPS IVA) is caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Conventional enzyme replacement therapy (ERT) is approved for MPS IVA. However, the fact that the infused enzyme cannot penetrate avascular lesions in cartilage leads to minimal impact on the bone lesion. Moreover, short half-life, high cost, instability, and narrow optimal pH range remain unmet challenges in ERT. Thermostable keratanase, endo-β-N-acetylglucosaminidase, has a unique character of a wide optimal pH range of pH 5.0–7.0. We hypothesized that this endoglycosidase degrades keratan sulfate (KS) polymer in circulating blood and, therefore, ameliorates the accumulation of KS in multiple tissues. We propose a novel approach, Substrate Degradation Enzyme Therapy (SDET), to treat bone lesion of MPS IVA. We assessed the effect of thermostable keratanase on blood KS level and bone pathology using Galns knock-out MPS IVA mice. After a single administration of 2 U/kg (= 0.2 mg/kg) of the enzyme at 8 weeks of age via intravenous injection, the level of serum KS was significantly decreased to normal range level, and this suppression was maintained for at least 4 weeks. We administered 2 U/kg of the enzyme to MPS IVA mice every fourth week for 12 weeks (total of 3 times) at newborns or 8 weeks of age. After a third injection, serum mono-sulfated KS levels were kept low for 4 weeks, similar to that in control mice, and at 12 weeks, bone pathology was markedly improved when SDET started at newborns, compared with untreated MPS IVA mice. Overall, thermostable keratanase reduces the level of KS in blood and provides a positive impact on cartilage lesions, demonstrating that SDET is a novel therapeutic approach to MPS IVA.

scholarly journals A 9-Month-Old with Skeletal Abnormalities and a Consanguineous Sibling with Mucopolysaccharidosis IVA: The Role of Urinary Glycosaminoglycan Testing in Disease Diagnosis and Treatment Monitoring

2021 ◽  
Vol 14 ◽  
pp. 117954762199940
Author(s):  
Eric Goldman ◽  
Angela Vu ◽  
Kelly Dietz ◽  
Stefani N Thomas
Keyword(s):  
Autosomal Recessive ◽  
Disease Diagnosis ◽  
Lysosomal Storage ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Mps Iva ◽  
Normal Urine

Mucopolysaccharidosis IVA (MPS IVA) is a rare autosomal recessive lysosomal storage disorder resulting from N-acetylgalactosamine-6-sulfatase (GALNS) deficiency that occurs in approximately 1 in 76 000 to 1 in 640 000 live births. Given that the diagnosis of MPS IVA relies heavily on the results of initial urine glycosaminoglycan (GAG) screening, cases that present with falsely normal urine GAG concentrations can delay the diagnosis and follow-up care for patients. This case study follows a patient diagnosed with MPS IVA at 9 months of age based on relation to a consanguineous 3-year-old sibling with MPS IVA and the use of direct enzyme activity analysis. Details regarding skeletal presentation and identification of genetic variants are presented along with data on follow-up urinary GAG monitoring during treatment with enzyme replacement therapy and treatment for a growth hormone disorder.

scholarly journals Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management

2020 ◽  
Vol 21 (4) ◽  
pp. 1517 ◽  
Author(s):  
Kazuki Sawamoto ◽  
José Álvarez González ◽  
Matthew Piechnik ◽  
Francisco Otero ◽  
Maria Couce ◽  
...  
Keyword(s):  
Skeletal Dysplasia ◽  
Keratan Sulfate ◽  
Life Time ◽  
Preclinical Study ◽  
Biochemical Tests ◽  
Lysosomal Disease ◽  
Hematopoietic Stem ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Mps Iva

Mucopolysaccharidosis type IVA (MPS IVA, or Morquio syndrome type A) is an inherited metabolic lysosomal disease caused by the deficiency of the N-acetylglucosamine-6-sulfate sulfatase enzyme. The deficiency of this enzyme accumulates the specific glycosaminoglycans (GAG), keratan sulfate, and chondroitin-6-sulfate mainly in bone, cartilage, and its extracellular matrix. GAG accumulation in these lesions leads to unique skeletal dysplasia in MPS IVA patients. Clinical, radiographic, and biochemical tests are needed to complete the diagnosis of MPS IVA since some clinical characteristics in MPS IVA are overlapped with other disorders. Early and accurate diagnosis is vital to optimizing patient management, which provides a better quality of life and prolonged life-time in MPS IVA patients. Currently, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) are available for patients with MPS IVA. However, ERT and HSCT do not have enough impact on bone and cartilage lesions in patients with MPS IVA. Penetrating the deficient enzyme into an avascular lesion remains an unmet challenge, and several innovative therapies are under development in a preclinical study. In this review article, we comprehensively describe the current diagnosis, treatment, and management for MPS IVA. We also illustrate developing future therapies focused on the improvement of skeletal dysplasia in MPS IVA.

Characterization of disease-specific chondroitin sulfate nonreducing end accumulation in mucopolysaccharidosis IVA

Glycobiology ◽  
2020 ◽  
Vol 30 (7) ◽  
pp. 433-445
Author(s):  
Roger Lawrence ◽  
Heather Prill ◽  
Preejith P Vachali ◽  
Evan G Adintori ◽  
Greg de Hart ◽  
...  
Keyword(s):  
Chondroitin Sulfate ◽  
Keratan Sulfate ◽  
Autosomal Recessive Disorder ◽  
Pilot Studies ◽  
Mucopolysaccharidosis Iva ◽  
Enzyme Replacement ◽  
Mps Iva ◽  
Morquio Syndrome ◽  
Disease Specific

Abstract Morquio syndrome type A, also known as MPS IVA, is a rare autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, a lysosomal hydrolase critical in the degradation of keratan sulfate (KS) and chondroitin sulfate (CS). The CS that accumulates in MPS IVA patients has a disease-specific nonreducing end (NRE) terminating with N-acetyl-D-galactosamine 6-sulfate, which can be specifically quantified after enzymatic depolymerization of CS polysaccharide chains. The abundance of N-acetyl-D-galactosamine 6-sulfate over other possible NRE structures is diagnostic for MPS IVA. Here, we describe an assay for the liberation and measurement of N-acetyl-D-galactosamine 6-sulfate and explore its application to MPS IVA patient samples in pilot studies examining disease detection, effects of age and treatment with enzyme-replacement therapy. This assay complements the existing urinary KS assay by quantifying CS-derived substrates, which represent a distinct biochemical aspect of MPS IVA. A more complete understanding of the disease could help to more definitively detect disease across age ranges and more completely measure the pharmacodynamic efficacy of therapies. Larger studies will be needed to clarify the potential value of this CS-derived substrate to manage disease in MPS IVA patients.

scholarly journals Impact of long-term elosulfase alfa treatment on clinical and patient-reported outcomes in patients with mucopolysaccharidosis type IVA: results from a Managed Access Agreement in England

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Maureen Cleary ◽  
James Davison ◽  
Rachel Gould ◽  
Tarekegn Geberhiwot ◽  
Derralynn Hughes ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Patient Reported Outcomes ◽  
Positive Impact ◽  
Duration Of Treatment ◽  
Enzyme Replacement ◽  
Patient Reported ◽  
Mps Iva ◽  
Elosulfase Alfa

Abstract Background We present baseline characteristics and follow-up data of a Managed Access Agreement (MAA), including patients with mucopolysaccharidosis IVA (MPS IVA) receiving elosulfase alfa enzyme replacement therapy (ERT) in England on a conditional basis. Patients enrolled in the MAA programme are reviewed on an annual basis. Therapy can be continued if patients are compliant, able to tolerate infusions, and meet four out of five pre-defined clinical and patient-reported outcomes (PRO) criteria. Baseline and follow-up clinical and PRO data are presented for all participants who completed ≥ 1 year of assessments in the MAA. Results The analysis included data from 55 patients, including 26 patients previously enrolled in clinical trials and 29 who started ERT after enrolling in the MAA. In patients with both baseline and follow-up data, mean 6-min walk test distance increased from 217 m at baseline to 244 m after a mean follow-up of 4.9 years. Improvement or stabilisation was seen regardless of age at treatment initiation or duration of treatment. Mean forced vital capacity and forced expiratory volume in 1 s were 0.87 L and 0.78 L, respectively at baseline and 1.05 L and 0.88 L after a mean follow-up of 5.5 years. PRO data showed overall improvements over time in Mobility, Self-care, and Caregiver assistance scores of the MPS-Health Assessment Questionnaire, relatively stable quality of life, and some improvements in pain scores. Conclusions The MAA data confirm the effects of elosulfase alfa on clinical and PRO results observed in the clinical trials and provide real-world evidence for long-term stabilisation in these measures, suggesting a positive impact on the natural history of MPS IVA.

scholarly journals Characterization of New Proteomic Biomarker Candidates in Mucopolysaccharidosis Type IVA

2020 ◽  
Vol 22 (1) ◽  
pp. 226
Author(s):  
Víctor J. Álvarez ◽  
Susana B. Bravo ◽  
Maria Pilar Chantada-Vazquez ◽  
Cristóbal Colón ◽  
María J. De Castro ◽  
...  
Keyword(s):  
Keratan Sulfate ◽  
Bone Lesions ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Protein Biomarkers ◽  
Enzyme Replacement ◽  
Endurance Tests ◽  
Mps Iva ◽  
Mucopolysaccharidosis Type Iva ◽  
Potential Biomarkers

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. Skeletal dysplasia and the related clinical features of MPS IVA are caused by disruption of the cartilage and its extracellular matrix, leading to a growth imbalance. Enzyme replacement therapy (ERT) with recombinant human GALNS has yielded positive results in activity of daily living and endurance tests. However, no data have demonstrated improvements in bone lesions and bone grow thin MPS IVA after ERT, and there is no correlation between therapeutic efficacy and urine levels of keratan sulfate, which accumulates in MPS IVA patients. Using qualitative and quantitative proteomics approaches, we analyzed leukocyte samples from healthy controls (n = 6) and from untreated (n = 5) and ERT-treated (n = 8, sampled before and after treatment) MPS IVA patients to identify potential biomarkers of disease. Out of 690 proteins identified in leukocytes, we selected a group of proteins that were dysregulated in MPS IVA patients with ERT. From these, we identified four potential protein biomarkers, all of which may influence bone and cartilage metabolism: lactotransferrin, coronin 1A, neutral alpha-glucosidase AB, and vitronectin. Further studies of cartilage and bone alterations in MPS IVA will be required to verify the validity of these proteins as potential biomarkers of MPS IVA.

Substrate degradation enzyme therapy (SDET) for mucopolysaccharidosis type IVA

2018 ◽  
Vol 123 (2) ◽  
pp. S140
Author(s):  
Shunji Tomatsu ◽  
Kazuki Sawamoto ◽  
Tokiko Sakai ◽  
Ikue Kitazawa ◽  
Hideyuki Futatsumori ◽  
...  
Keyword(s):  
Mucopolysaccharidosis Type ◽  
Enzyme Therapy ◽  
Substrate Degradation ◽  
Mucopolysaccharidosis Type Iva

scholarly journals Optimal pH in chlorinated swimming pools – balancing formation of by-products

2013 ◽  
Vol 11 (3) ◽  
pp. 465-472 ◽  
Author(s):  
Kamilla M. S. Hansen ◽  
Hans-Jørgen Albrechtsen ◽  
Henrik R. Andersen
Keyword(s):  
Body Fluid ◽  
Product Formation ◽  
Swimming Pools ◽  
Batch Experiments ◽  
Ph Values ◽  
Precursor Ratio ◽  
Decreasing Ph ◽  
Ph Range ◽  
By Products ◽  
Optimal Ph

In order to identify the optimal pH range for chlorinated swimming pools, the formation of trihalomethanes, haloacetonitriles and trichloramine was investigated in the pH-range 6.5–7.5 in batch experiments. An artificial body fluid analogue was used to simulate bather load as the precursor for by-products. The chlorine-to-precursor ratio used in the batch experiments influenced the amounts of by-products formed, but regardless of the ratio the same trends in the effect of pH were observed. Trihalomethane formation was reduced by decreasing pH, but haloacetonitrile and trichloramine formation increased. To evaluate the significance of the increase and decrease of the investigated organic by-products at the different pH values, the genotoxicity was calculated based on literature values. The calculated genotoxicity was approximately at the same level in the pH range 6.8–7.5 and increased when pH was 6.7 or lower. An optimal pH range for by-products formation in swimming pools was identified at pH 7.0–7.2. In the wider pH range (pH 6.8–7.5), the effect on by-product formation was negligible. Swimming pools should never be maintained at lower pH than 6.8 since formation of both haloacetonitriles and trichloramine increase significantly below this value.

scholarly journals Pathophysiology of Hip Disorders in Patients with Mucopolysaccharidosis IVA

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 264
Author(s):  
Zhigang Wang ◽  
Yunlan Xu ◽  
Enze Jiang ◽  
Jianmin Wang ◽  
Shunji Tomatsu ◽  
...  
Keyword(s):  
Femoral Head ◽  
Bone Mineralization ◽  
Plain Film ◽  
Hip Joints ◽  
Related Factors ◽  
Mucopolysaccharidosis Iva ◽  
Neck Shaft Angle ◽  
Femoral Head Osteonecrosis ◽  
Hip Morphology ◽  
Mps Iva

Patients with mucopolysaccharidoses IVA (MPS IVA) have a progressive accumulation of the specific glycosaminoglycans (GAGs): chondroitin-6-sulfate (C6S) and keratan sulfate (KS), leading to the degeneration of the cartilage matrix and its connective tissue perturbing the regular microarchitecture of cartilage and successively distorting bone ossification and growth. Impaired cartilage quality and poor bone mineralization lead to serious hip disorders in MPS IVA patients. Although hip dysplasia is seen widely in musculoskeletal abnormality of this disorder, the pathophysiology of the hip bone and cartilage morphology in these patients remains unclear. Until now, no systemic study of the hip joints in MPS IVA has been reported by using the combined images of plain film radiographs (PFR) and Magnetic Resonance Imaging (MRI). This study aimed to assess the bony and cartilaginous features of hip joints and to explore the potentially related factors of femoral head osteonecrosis (FHN) and hip subluxation/dislocation in patients with MPS IVA. Hip joints in MPS IVA patients were retrospectively reviewed, based on the findings of PFR and MRI data from 2014 to 2019. Demographic information was also collected and analyzed with imaging measurements. A total of 19 patients (eight boys and 11 girls) were recruited, and 38 hip joints in these patients were examined. Eleven patients (57.9%) had FHN. FHN patients were statistically compared with those without FHN. Correlations between cartilaginous femoral head coverage (CFHC) and acetabular index (AI), cartilaginous AI (CAI), or neck-shaft angle (NSA) were investigated in patients with hip subluxation or dislocation. The greater cartilaginous coverage of the hips than their osseous inherency was observed. Significant correlation was observed between CFHC and AI (r =−0.351, p = 0.049) or CAI (r =−0.381, p = 0.032). Severe subluxations or dislocations were more likely to be present in those with more dysplastic bony and cartilaginous hips. In conclusion, our study provides the first systemic description of bony and cartilaginous characteristics in the hip morphology of MPS IVA patients. We have demonstrated that plain radiography alone leads to a misunderstanding of hip morphology and that MRI measurements with PFR are an essential tool to evaluate the ‘true’ characterization of hips for MPS IVA patients.

scholarly journals Hearing Loss in Mucopolysaccharidoses: Current Knowledge and Future Directions

Diagnostics ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 554
Author(s):  
Jeremy Wolfberg ◽  
Keerthana Chintalapati ◽  
Shunji Tomatsu ◽  
Kyoko Nagao
Keyword(s):  
Hearing Loss ◽  
Current Knowledge ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mixed Hearing Loss ◽  
Hearing Function ◽  
Common Clinical Presentation ◽  
Mps Iva ◽  
Mps Vii ◽  
Mps I

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency of one of the enzymes involved in the degradation of glycosaminoglycans. Hearing loss is a common clinical presentation in MPS. This paper reviews the literature on hearing loss for each of the seven recognized subtypes of MPS. Hearing loss was found to be common in MPS I, II, III, IVA, VI, and VII, and absent from MPS IVB and MPS IX. MPS VI presents primarily with conductive hearing loss, while the other subtypes (MPS I, MPS II, MPS III, MPS IVA, and MPS VII) can present with any type of hearing loss (conductive, sensorineural, or mixed hearing loss). The sensorineural component develops as the disease progresses, but there is no consensus on the etiology of the sensorineural component. Enzyme replacement therapy (ERT) is the most common therapy utilized for MPS, but the effects of ERT on hearing function have been inconclusive. This review highlights a need for more comprehensive and multidisciplinary research on hearing function that includes behavioral testing, objective testing, and temporal bone imaging. This information would allow for better understanding of the progression and etiology of hearing loss. Owing to the prevalence of hearing loss in MPS, early diagnosis of hearing loss and annual comprehensive audiological evaluations are recommended.

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