RARE DISEASE
Mucopolysaccharidosis type 10
Mucopolysaccharidosis type 10
Mucopolysaccharidosis type 10
Synonyms: Mucopolysaccharidosis type X, MSP type X,MPS10 Mucopolysaccharidosis due to ARSK deficiency
Synonyms: Mucopolysaccharidosis type X, MSP type X,MPS10 Mucopolysaccharidosis due to ARSK deficiency
Synonyms: Mucopolysaccharidosis type X, MSP type X,MPS10 Mucopolysaccharidosis due to ARSK deficiency
Drug discovery
0
drugs
With orphan designations
Overview
Mucopolysaccharidosis type 10 (MPS X) is an ultra-rare autosomal recessive lysosomal storage disorder caused by deficient arylsulfatase K (ARSK) activity, leading to glycosaminoglycan accumulation. Clinical features include disproportionate short stature, skeletal dysplasia, coarse facial features, hearing loss, and potential cardiac/liver involvement [1][19]. Cognitive impairment is typically absent. Diagnosis involves enzyme assays and genetic testing for ARSK mutations [19].
Therapies
Supportive care: Surgical correction of skeletal abnormalities, hearing aids, and cardiac monitoring [19]
No approved disease-modifying therapies; enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) remain investigational [16][20]
Preclinical studies exploring gene therapy approaches [20]
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
133 drug discovery papers about Mucopolysaccharidosis type 10, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
133 drug discovery papers about Mucopolysaccharidosis type 10, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2024-03-28 | Investigation of the Oxidative Process by Measuring Total Antioxidant Capacity and Total Oxidant Capacity in Patients with Mucopolysaccharidosis: Cross-Sectional Prospective Study
Objective: To compare the oxidative stress status between the patients with mucopolysaccharidosis who received and did not receive enzyme replacement therapy and healthy control group. Material and Methods: A retrospective study of mucopolysaccharidosis patients with analysis of the total oxidant and antioxidant capacity levels. Results: We included 29 mucopolysaccharidosis patients aged between 1-18 years and 50 healthy children. Total antioxidant capacity and total oxidant capacity parameters between this patients and healthy control group were compared. The median age of the patients who were included in the study was 9.0 years and the median age of the cases included in the control group was 8.0 years. Total antioxidant capacity, total oxidant capacity and Oxidative Stress Index (OSI) values did not differ significantly in patients receiving enzyme replacement therapy compared to patients who did not receive enzyme replacement therapy. A comparison of the oxidant and antioxidant system parameters between the patient and control groups revealed a distinct difference, with the control group exhibiting a considerably higher total antioxidant capacity than mucopolysaccharidosis patients, and the patient group showing a significantly higher total oxidant capacity and OSI. Conclusion: In this study, it was observed that the antioxidant defence system decreased in patients with mucopolysaccharidoses. It is thought that, in addition to standard treatments, the administration of antioxidant treatments and supporting nutrition in mucopolysaccharidosis patients will increase the quality of life of the patients. Regular sleep, eating healthy foods and doing regular exercise would also increase the effectiveness of these supplements.
2024-02-09 | REMOVER-PITCh: microhomology-assisted long-range gene replacement with highly multiplexed CRISPR-Cas9
A variety of CRISPR-Cas9-based gene editing technologies have been developed, including gene insertion and gene replacement, and applied to the study and treatment of diseases. While numerous studies have been conducted to improve the efficiency of gene insertion and to expand the system in various ways, there have been relatively few reports on gene replacement technology; therefore, further improvements are still needed in this context. Here, we developed the REMOVER-PITCh system to establish an efficient long-range gene replacement method and demonstrated its utility at two genomic loci in human cultured cells. REMOVER-PITCh depends on microhomology-assisted gene insertion technology called PITCh with highly multiplexed CRISPR-Cas9. First, we achieved gene replacement of about 20-kb GUSB locus using this system. Second, by applying the previously established knock-in-enhancing platform, the LoAD system, along with REMOVER-PITCh, we achieved the replacement of a longer gene region of about 200 kb at the ARSB locus. Our REMOVER-PITCh system will make it possible to remove and incorporate a variety of sequences from and into the genome, respectively, which will facilitate the generation of various disease and humanized models.
2023-11-17 | Gold nanoparticles decorated with monosaccharides and sulfated ligands as potential modulators of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase (GALNS).
N-Acetylgalactosamine-6-sulfatase (GALNS) is an enzyme whose deficiency is related to the lysosomal storage disease Morquio A. For the development of effective therapeutic approaches against this disease, the design of suitable enzyme enhancers (i.e. pharmacological chaperones) is fundamental. The natural substrates of GALNS are the glycosaminoglycans keratan sulfate and chondroitin 6-sulfate, which mainly display repeating units of sulfated carbohydrates. With a biomimetic approach, gold nanoparticles (AuNPs) decorated with simple monosaccharides, sulfated ligands (homoligand AuNPs), or both monosaccharides and sulfated ligands (mixed-ligand AuNPs) were designed here as multivalent inhibitors of GALNS. Among the homoligand AuNPs, the most effective inhibitors of GALNS activity are the β-D-galactoside-coated AuNPs. In the case of mixed-ligand AuNPs, β-D-galactosides/sulfated ligands do not show better inhibition than the β-D-galactoside-coated AuNPs. However, a synergistic effect is observed for α-D-mannosides in a mixed-ligand coating with sulfated ligands that reduced IC50 by one order of magnitude with respect to the homoligand α-D-mannoside-coated AuNPs. SAXS experiments corroborated the association of GALNS with β-D-galactoside AuNPs. These AuNPs are able to restore the enzyme activity by almost 2-fold after thermal denaturation, indicating a potential chaperoning activity towards GALNS. This information could be exploited for future development of nanomedicines for Morquio A. The recent implications of GALNS in cancer and neuropathic pain make these kinds of multivalent bionanomaterials of great interest towards multiple therapies.
2023-10-29 | The Experiences and Challenges of Mothers of Adult Patients with Mucopolysaccharidosis; Mothers of Adults with Severe Mucopolysaccharidosis
Although many studies have examined the treatment and symptoms of children with MPS, very few studies have focused on adults with MPS. This study aimed to clarify the experiences and challenges of mothers of adult patients with severe mucopolysaccharidosis (MPS) who live at home. The data from semi-structured interviews with twelve mothers (patients’ ages ranged 19-44 years) were analyzed. The following six categories were extracted: fear that the disease will continue to progress despite treatment, tired of shifting gears in care and healing, fatigue due to multi-department visits to control the progression of the disease, the pain of not being able to see a bright future, desperate for new treatment methods for MPS, and developing care and a place to stay after parental support is gone. A unique issue of patients with MPS is that enzyme replacement therapy must be continued throughout life, and there is an urgent need to create a system that allows patients with severe MPS to receive enzyme replacement therapy for the rest of their lives, even after their parents pass away.
2023-08-31 | Synthesis and Evaluation of Novel Triaryl Derivatives with Readthrough-Inducing Activity
The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay. In Q70X mutant IDUA transgenic cells, KY-516 significantly increased enzyme activity at 0.1 µM. After the oral administration of KY-516 (10 mg/kg), the highest plasma concentration of KY-516 was above 5 µM in rats. These results indicate that KY-516, a novel triaryl derivative, exhibits potent readthrough-inducing activity and has potential as a therapeutic agent for Hurler syndrome.
2024-03-28 | Investigation of the Oxidative Process by Measuring Total Antioxidant Capacity and Total Oxidant Capacity in Patients with Mucopolysaccharidosis: Cross-Sectional Prospective Study
Objective: To compare the oxidative stress status between the patients with mucopolysaccharidosis who received and did not receive enzyme replacement therapy and healthy control group. Material and Methods: A retrospective study of mucopolysaccharidosis patients with analysis of the total oxidant and antioxidant capacity levels. Results: We included 29 mucopolysaccharidosis patients aged between 1-18 years and 50 healthy children. Total antioxidant capacity and total oxidant capacity parameters between this patients and healthy control group were compared. The median age of the patients who were included in the study was 9.0 years and the median age of the cases included in the control group was 8.0 years. Total antioxidant capacity, total oxidant capacity and Oxidative Stress Index (OSI) values did not differ significantly in patients receiving enzyme replacement therapy compared to patients who did not receive enzyme replacement therapy. A comparison of the oxidant and antioxidant system parameters between the patient and control groups revealed a distinct difference, with the control group exhibiting a considerably higher total antioxidant capacity than mucopolysaccharidosis patients, and the patient group showing a significantly higher total oxidant capacity and OSI. Conclusion: In this study, it was observed that the antioxidant defence system decreased in patients with mucopolysaccharidoses. It is thought that, in addition to standard treatments, the administration of antioxidant treatments and supporting nutrition in mucopolysaccharidosis patients will increase the quality of life of the patients. Regular sleep, eating healthy foods and doing regular exercise would also increase the effectiveness of these supplements.
2024-02-09 | REMOVER-PITCh: microhomology-assisted long-range gene replacement with highly multiplexed CRISPR-Cas9
A variety of CRISPR-Cas9-based gene editing technologies have been developed, including gene insertion and gene replacement, and applied to the study and treatment of diseases. While numerous studies have been conducted to improve the efficiency of gene insertion and to expand the system in various ways, there have been relatively few reports on gene replacement technology; therefore, further improvements are still needed in this context. Here, we developed the REMOVER-PITCh system to establish an efficient long-range gene replacement method and demonstrated its utility at two genomic loci in human cultured cells. REMOVER-PITCh depends on microhomology-assisted gene insertion technology called PITCh with highly multiplexed CRISPR-Cas9. First, we achieved gene replacement of about 20-kb GUSB locus using this system. Second, by applying the previously established knock-in-enhancing platform, the LoAD system, along with REMOVER-PITCh, we achieved the replacement of a longer gene region of about 200 kb at the ARSB locus. Our REMOVER-PITCh system will make it possible to remove and incorporate a variety of sequences from and into the genome, respectively, which will facilitate the generation of various disease and humanized models.
2023-11-17 | Gold nanoparticles decorated with monosaccharides and sulfated ligands as potential modulators of the lysosomal enzyme N-acetylgalactosamine-6-sulfatase (GALNS).
N-Acetylgalactosamine-6-sulfatase (GALNS) is an enzyme whose deficiency is related to the lysosomal storage disease Morquio A. For the development of effective therapeutic approaches against this disease, the design of suitable enzyme enhancers (i.e. pharmacological chaperones) is fundamental. The natural substrates of GALNS are the glycosaminoglycans keratan sulfate and chondroitin 6-sulfate, which mainly display repeating units of sulfated carbohydrates. With a biomimetic approach, gold nanoparticles (AuNPs) decorated with simple monosaccharides, sulfated ligands (homoligand AuNPs), or both monosaccharides and sulfated ligands (mixed-ligand AuNPs) were designed here as multivalent inhibitors of GALNS. Among the homoligand AuNPs, the most effective inhibitors of GALNS activity are the β-D-galactoside-coated AuNPs. In the case of mixed-ligand AuNPs, β-D-galactosides/sulfated ligands do not show better inhibition than the β-D-galactoside-coated AuNPs. However, a synergistic effect is observed for α-D-mannosides in a mixed-ligand coating with sulfated ligands that reduced IC50 by one order of magnitude with respect to the homoligand α-D-mannoside-coated AuNPs. SAXS experiments corroborated the association of GALNS with β-D-galactoside AuNPs. These AuNPs are able to restore the enzyme activity by almost 2-fold after thermal denaturation, indicating a potential chaperoning activity towards GALNS. This information could be exploited for future development of nanomedicines for Morquio A. The recent implications of GALNS in cancer and neuropathic pain make these kinds of multivalent bionanomaterials of great interest towards multiple therapies.
2023-10-29 | The Experiences and Challenges of Mothers of Adult Patients with Mucopolysaccharidosis; Mothers of Adults with Severe Mucopolysaccharidosis
Although many studies have examined the treatment and symptoms of children with MPS, very few studies have focused on adults with MPS. This study aimed to clarify the experiences and challenges of mothers of adult patients with severe mucopolysaccharidosis (MPS) who live at home. The data from semi-structured interviews with twelve mothers (patients’ ages ranged 19-44 years) were analyzed. The following six categories were extracted: fear that the disease will continue to progress despite treatment, tired of shifting gears in care and healing, fatigue due to multi-department visits to control the progression of the disease, the pain of not being able to see a bright future, desperate for new treatment methods for MPS, and developing care and a place to stay after parental support is gone. A unique issue of patients with MPS is that enzyme replacement therapy must be continued throughout life, and there is an urgent need to create a system that allows patients with severe MPS to receive enzyme replacement therapy for the rest of their lives, even after their parents pass away.
2023-08-31 | Synthesis and Evaluation of Novel Triaryl Derivatives with Readthrough-Inducing Activity
The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay. In Q70X mutant IDUA transgenic cells, KY-516 significantly increased enzyme activity at 0.1 µM. After the oral administration of KY-516 (10 mg/kg), the highest plasma concentration of KY-516 was above 5 µM in rats. These results indicate that KY-516, a novel triaryl derivative, exhibits potent readthrough-inducing activity and has potential as a therapeutic agent for Hurler syndrome.
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