RARE DISEASE
Mucopolysaccharidosis type 7
Mucopolysaccharidosis type 7
Mucopolysaccharidosis type 7
Synonyms: Beta-glucuronidase deficiency, MPS7, MPSVII, Mucopolysaccharidosis type VII, Sly disease
Synonyms: Beta-glucuronidase deficiency, MPS7, MPSVII, Mucopolysaccharidosis type VII, Sly disease
Synonyms: Beta-glucuronidase deficiency, MPS7, MPSVII, Mucopolysaccharidosis type VII, Sly disease
Drug discovery
2
drugs
With orphan designations
Overview
Mucopolysaccharidosis type VII (MPS VII) is an ultra-rare autosomal recessive lysosomal storage disorder caused by GUSB gene mutations, leading to β-glucuronidase deficiency and systemic glycosaminoglycan accumulation [1][2][4]. Clinical manifestations range from severe prenatal hydrops fetalis to milder childhood/adolescent forms, featuring skeletal dysplasia (dysostosis multiplex), hepatosplenomegaly, cognitive impairment, corneal clouding, and cardiorespiratory complications [1][4][19]. Diagnosis requires enzymatic assays and GUSB molecular analysis [1][6].
Burden
High morbidity from progressive multi-organ damage, with 50% mortality by age 42 months in NIHF-associated cases [15][19]. Survivors face lifelong disability, frequent hospitalizations (12.7/year), and caregiver strain (46% reduce work hours) [9][16]. Cognitive impairment occurs in 64% of postnatal cases [15].
Therapies
Enzyme replacement therapy (ERT) with vestronidase alfa improves mobility, respiratory function, and organomegaly [3][11][17].
Hematopoietic stem cell transplantation (HSCT) shows limited success, reserved for select cases [1][12].
Multidisciplinary supportive care addresses skeletal, respiratory, and cardiac complications [6][13].
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
306 drug discovery papers about Mucopolysaccharidosis type 7, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
306 drug discovery papers about Mucopolysaccharidosis type 7, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2025-11-11 | Trehalose-mediated activation of Mitf corrects autophagy defects and ameliorates neurodegeneration in MPS VII
Abstract Mucopolysaccharidosis type VII (MPS VII) is a progressive lysosomal storage disorder caused by β-glucuronidase (β-GUS) deficiency, featuring pronounced neurodegeneration. The Drosophila model of MPS VII, generated by deleting the fly β-GUS ortholog CG2135, exhibits hallmark neuropathological features, including dopaminergic neuron loss, brain vacuolisation, and impaired locomotor performance. Using this CG2135 −/− fly, we recently showed that impaired autophagosome formation and their turnover led to abnormal accumulation of damaged mitochondria and lipofuscins in the brain. In this study, we investigated the molecular basis of this autophagy defect and found that Mitf (the TFEB homolog), the transcriptional regulator of autophagy, is markedly downregulated in CG2135 −/− fly brains, accompanied by reduced expression of its target genes, including LAMP1, CLN3, and v-ATPase subunits. Guided by these observations, we assessed whether boosting Mitf activity could ameliorate neuropathology. Interestingly, oral trehalose treatment reactivated Mitf and its downstream autophagy gene network in CG2135 −/− fly brains, restoring autophagosome biogenesis, reducing lipofuscin accumulation, and alleviating apoptosis. Trehalose treatment also improved locomotor performance, indicating a clear mitigation of neurodegeneration. These findings demonstrate that Mitf dysregulation drives autophagy impairment in MPS VII fly brain and highlight Mitf activation as a promising therapeutic strategy to alleviate neurological pathology.
2025-02-06 | Unravelling a mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in Mucopolysaccharidosis VII.
Cognitive disability and neurodegeneration are prominent symptoms of Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. Yet, the mechanism of neurodegeneration in MPS VII remains unclear thereby limiting the scope of targeted therapy. We aimed to bridge this knowledge gap by employing the β-glucuronidase-deficient (CG2135-/-) Drosophila model of MPS VII. Taking cues from our initial observation that the adult CG2135-/- flies displayed enhanced susceptibility to starvation, we investigated potential impairments in the autophagy-lysosomal clearance machinery in their brain to dissect the underlying cause of neurodegeneration. We found that both autophagosome biogenesis and lysosome-mediated autophagosomal turnover were impaired in the CG2135-/- fly brain. This was evidenced by lower Atg8a-II levels, reduced Atg1 and Ref(2)P expression along with accumulation of lipofuscin-like inclusions and multilamellar bodies. Mitophagy was also found to be defective in their brain, resulting in buildup of enlarged mitochondria with distorted cristae and reduced membrane potential. This, in turn, compromised mitochondrial function, as reflected by drastically reduced brain ATP levels. Energy depletion triggered apoptosis in neuronal as well as non-neuronal cells of the CG2135-/- fly brain, where apoptotic dopaminergic neurons were also detected. Interestingly, resveratrol treatment corrected the mitophagy defect and prevented ATP depletion in the CG2135-/- fly brain, providing an explanation for its neuroprotective effects. Collectively, our study reveals a pharmacologically targetable mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII.
2022-06-02 | Flaxseed extract reduces tissue accumulation and enhances urinary excretion of chondroitin sulphate in the rat: a possible new path in substrate reduction therapy for mucopolysaccharidosis.
Chondroitin 6 sulphate (C6S) is a glycosaminoglycan (GAG) whose accumulation is notable in mucopolysaccharidosis type IVA and VII. Flaxseed, Linum usitatissimum L. (Linaceae) (FS), is reported to have comparable properties to those of soybean, a source of genistein, a potential new treatment for MPSs. We assess the effect of total ethanol flaxseed extract (EFSE) in an animal model of C6S accumulation. The study was performed in adult male Wistar rats (n = 24) for 15 successive days. The animals were divided into four groups: (1) control injected with physiological saline buffer, (2) intoxicated rats injected intraperitoneally with C6S, (3) intoxicated with C6S and treated with EFSE, and (4) treated with EFSE. All groups were subjected to histopathological and biochemical studies. The antioxidant and phytochemical properties of EFSE were examined. Dry EFSE contains total phenols (6.28 mg EAG/g), condensed tannins (2.98 mg ECAT/g) and flavonoids (0.44 mg ECAT/g) with high antioxidant potential [RPE (IC50 = 8.37 ± 0.176), DPPH (IC50 = 12.79 ± 0.273)]. The LD50 is higher than 5000 mg/kg. The histopathological examination showed an accumulation of C6S in the C6S intoxicated group, which disappeared in the C6S-EFSE treated group. GAGs assays showed an increased excretion in the C6S intoxicated group and increased excretion of 14% in the C6S-EFSE group compared to the C6S group. EFSE showed significant potential for chelation. Its use for the treatment of GAG accumulation could be suggested and generalized to a larger study population.
2022-04-19 | Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR.
Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or β-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135-/- fly), which also exhibited a significant loss of body fat. We report here that the lean phenotype of the CG2135-/- larvae is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135-/- larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135-/- larvae. Interestingly, treatment of the CG2135-/- larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII.
2021-09-05 | Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR
Abstract Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or β-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135 -/- fly), which also exhibited a significant loss of adiposity. We report here that the lean phenotype of the CG2135 -/- fly is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135 -/- larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135 -/- flies. Interestingly, treatment of the CG2135 -/- larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII.
gene therapies
2025-07-04 | CRISPR/Cas9-mediated promoterless gene targeting reduces lysosome storage in MPS VII mice.
Targeted gene integration mediated by CRISPR/Cas9 is a promising therapeutic strategy for monogenic autosomal recessive diseases. In this study, we established a novel all-in-one high-capacity adenovirus (HCAd) that can pack both CRISPR/Cas9 and donor DNA into the same vector and tested it on a mouse model of mucopolysaccharidosis type VII (MPS VII) caused by mutations in the β-glucuronidase (GUSB) gene. This system allowed targeted integration of promoterless GUSB in the mouse beta-actin gene (mActb) locus and the co-expression of GUSB with the self-cleaving peptide T2A (T2A) controlled by a strong endogenous mActb promoter. The in vivo results indicated that the serum GUSB level of MPS VII mice treated with a single intraperitoneal injection of the HCAd vector achieved 14% of that of wild-type mice, resulting in significant amelioration of lysosomal storage in the liver and spleen. Furthermore, the HCAd was injected intraventricularly in the brain of newborn MPS VII mice, leading to strongly positive GUSB enzyme staining in the choroid plexus and perivascular spaces of the periventricular regions and reduced lysosome storage. In summary, by using an all-in-one vector, the study provides a universal, one-for-all therapeutic for MPSVII, a disease caused by different mutations of the GUSB gene.
2024-04-27 | Self-complementary AAV vector therapy for treating corneal cloudiness of mucopolysaccharidosis type VII (MPS VII).
To design a novel efficacious scAAV-Gusb viral vector for treating Mucopolysaccharidosis Type VII (MPS VII) caused by a mutation in the β-Glu gene (Gusb allele). β-Glu expression of single-stranded AAV-Gusb (ssAAV-Gusb) and self-complementary AAV (scAAV-Gusb) vectors are tested with cultured murine Gusb fibroblasts. The scAAV-Gusb vector was chosen in further studies to prolong the life span and treat corneal pathology of Gusb mice via intrahepatic injection of neonates and intrastromal injection in adults, respectively. Corneal pathology was studied using HRT2 in vivo confocal microscope and histochemistry in mice corneas. Both ssAAV-Gusb and scAAV-Gusb vectors expressed murine β-Glu in cultured Gusb fibroblasts. The scAAV-Gusb vector had higher transduction efficiency than the ssAAV-Gusb vector. To prolong the life span of Gusb mice, neonates (3 days old) were administered with scAAV-Gusb virus via intrahepatic injection. The treatment improves the survival rate of Gusb mice, prolonging the median survival rate from 22.5 weeks (untreated) to 50 weeks (treated). Thereafter, we determined the efficacy of the scAAV-Gusb virus in ameliorating corneal cloudiness observed in aged Gusb mice. Both corneal cloudiness and stroma thickness decreased, and there was the presence of β-Glu enzyme activity in the Gusb corneas receiving scAAV-Gusb virus associated with morphology change of amoeboid stromal cells in untreated to characteristic dendritic keratocytes morphology after 4-12 weeks of scAAV-Gusb virus injection. Intrahepatic injection of scAAV-Gusb is efficacious in prolonging the life span of Gusb mice, and intrastromal injection can ameliorate corneal phenotypes. Both strategies can be adapted for treating other MPS.
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.
2019-09-12 | Intrathecal AAVrh10 corrects biochemical and histological hallmarks of mucopolysaccharidosis VII mice and improves behavior and survival
Abstract Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by ß-glucuronidase deficiency, prompting glycosaminoglycan accumulation in enlarged vesicles, leading to peripheral and neuronal dysfunction. Here, we present a gene therapy strategy using lumbar puncture of AAVrh10 encoding human β-glucuronidase (AAVrh10-GUSB) to adult MPS VII mice. This minimally invasive technique efficiently delivers the recombinant vector to the cerebrospinal fluid (CSF) with a single intrathecal injection. We show that AAVrh10 delivery to the CSF allows global, stable transduction of CNS structures. In addition, drainage of AAVrh10-GUSB from the CSF to the bloodstream resulted in the transduction of somatic organs such as liver, which provided a systemic β-glucuronidase source sufficient to achieve serum enzyme activity comparable to wild type mice. ß-glucuronidase levels were enough to correct biochemical and histopathological hallmarks of the disease in the CNS and somatic organs at short and long term. Moreover, the progression of the bone pathology was also reduced. Importantly, the biochemical correction led to a significant improvement in the physical, cognitive and emotional characteristics of MPS VII mice, and doubling their life span. Our strategy may have implications for gene therapy in patients with lysosomal storage diseases.
2018-11-09 | Treatment of brain disease in the mucopolysaccharidoses.
The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation, affecting various tissues throughout the body based on the specific enzyme deficiency. These disorders are characterized by their progressive nature and a variety of somatic manifestations and neurological symptoms. There are established treatments for some MPS disorders, but these mostly alleviate somatic and non-neurological symptoms and do not cure the disease. Patients with MPS I, II, III, and VII can present with neurological manifestations such as neurocognitive decline and behavioral problems. Treatment of these neurological manifestations remains challenging due to the blood-brain barrier (BBB) that limits delivery of therapeutic agents to the central nervous system (CNS). New therapies that circumvent this barrier and target brain disease in MPS are currently under development. They primarily focus on facilitating penetration of drugs through the BBB, delivery of recombinant enzyme to the brain by gene therapy, or direct CNS administration. This review summarizes existing and potential future treatment approaches that target brain disease in MPS. The information in this review is based on current literature and presentations and discussions during a closed meeting by an international group of experts with extensive experience in managing and treating MPS.
proteins
2025-12-15 | Mannose-6-phosphate functionalized liposomal nanocarrier for lysosome-specific delivery of β-glucuronidase in a Drosophila model of MPS VII
Mannose-6-phosphate (M6P) functionalised liposomal nanocarriers can achieve site-specific delivery of β-glucuronidase (β-GUS) to the targeted organelle lysosome of enzyme deficient cells in Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder. Created with BioRender.com.
2023-07-10 | Awake airway endoscopy in mucopolysaccharidosis: a case report.
Mucopolysaccharidosis (MPS) are a group of rare genetic inherited diseases with a progressive course due to the accumulation of glycosaminoglycans resulting in anatomic abnormalities and organ dysfunction, including the respiratory, cardiovascular, skeletal, and neurological systems that can increase the risk of anesthesia complications. Clinical manifestations are variable, multisystemic, and include severe morphological changes. The anesthetic management of these patients is complex, particularly airway management, which can be planned to include a fiberoptic airway investigation prior to surgery. We present two cases of patients with MPS type VI and VII who underwent fiberoptic airway mapping under conscious sedation, with no complications. Since MPS is a rare but challenging disease concerning the airway management, we propose a safe and effective anesthetic technique that could be used for fiberoptic bronchoscopy and allow fiberoptic-assisted tracheal intubation at the time of surgery.
2023-06-03 | Transplacental delivery of therapeutic proteins by engineered immunoglobulin G: a step toward perinatal replacement therapy
Background Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to replace missing enzymes in the fetus, as shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires during fetal development and induce tolerance to self-antigens or immunogenic therapeutic molecules. Objectives To investigate whether proteins that are administered to pregnant mice or endogenously present in their circulation may be delivered through the placenta. Methods We engineered monovalent immunoglobulin G (FabFc) specific for different domains of human factor VIII (FVIII), a therapeutically relevant model antigen. FabFc was injected with exogenous FVIII into pregnant severe hemophilia A mice or pregnant mice expressing human FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant mice and/or fetuses by enzyme-linked immunosorbent assay and immunohistochemistry. Results Administration of FabFc to pregnant mice allowed the maternofetal delivery of FVIII in a FcRn-dependent manner. FVIII antigen levels achieved in the fetuses represented 10% of normal plasma levels in the human. We identified antigen/FabFc complex stability, antigen size, and shielding of promiscuous protein patches as key parameters to foster optimal antigen delivery. Conclusion Our results pave the way toward the development of novel strategies for the in utero delivery of endogenous maternal proteins to replace genetically deficient fetal proteins or to educate the immune system and favor active immune tolerance upon protein encounter later in life.
2020-07-15 | C-Type Natriuretic Peptide Restores Growth Impairment Under Enzyme Replacement in Mice With Mucopolysaccharidosis VII.
Growth impairment in mucopolysaccharidoses (MPSs) is an unresolved issue as it is resistant to enzyme replacement therapy (ERT) and growth hormone therapy. C-type natriuretic peptide (CNP) is a promising agent that has growth-promoting effects. Here we investigate the effects of CNP on growth impairment of MPSs using Gusbmps-2J mice, a model for MPS type VII, with combination therapy of CNP and ERT by hydrodynamic gene delivery. Although monotherapies were not sufficient to restore short statures of treated mice, combination therapy resulted in successful restoration. The synergistic effects of CNP and ERT were not only observed in skeletal growth but also in growth plates. ERT reduced cell swelling in the resting zone and increased cell number by accelerating proliferation or inhibiting apoptosis. CNP thickened the proliferative and hypertrophic zones. Regarding changes in the bone, ERT restored bone sclerosis through decreased bone formation and increased bone resorption, and CNP did not adversely affect this process. In addition, improvement of joint deformation by ERT was suggested by analyses of joint spaces and articular cartilage. CNP additively provided restoration of the short stature of MPS VII mice in combination with ERT, which improved abnormalities of growth plates and bone metabolism.
2019-02-22 | Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone
The biological basis for documented in vivo bone-protective effects of turmeric-derived curcumin is unclear since curcumin is barely detectable in serum, being rapidly conjugated to form what is thought to be an inactive glucuronide. Studies were therefore undertaken to test the postulate that antiresorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone and that β-glucuronidase (GUSB), a deconjugating enzyme expressed by hematopoietic marrow cells, facilitates this site-specific transformation. Consistent with this postulate, aglycone, but not glucuronidated, curcumin inhibited RANKL-stimulated osteoclastogenesis, a key curcumin target in bone. Aglycone curcumin, expressed relative to total curcumin, was higher in bone marrow than in serum of curcumin-treated C57BL/6J mice, while remaining a minor component. Ex vivo, under conditions preventing further metabolism of the unstable aglycone, the majority of curcumin-glucuronide delivered to marrow in vivo was hydrolyzed to the aglycone, a process that was inhibited by treatment with saccharolactone, a GUSB inhibitor, or in mice having reduced (C3H/HeJ) or absent (mps/mps) GUSB activity. These findings suggest that curcumin, despite low systemic bioavailability, may be enzymatically activated (deconjugated) within GUSB-enriched bone to exert protective effects, a metabolic process that could also contribute to bone-protective effects of other highly glucuronidated dietary polyphenols.
antibodies
2023-12-16 | Glycosaminoglycan-induced proinflammatory cytokine levels as disease marker in mucopolysaccharidosis.
Recently, it has been shown disturbances in oxidant/antioxidant system and increases in some inflammatory markers in animal studies and in some Mucopolysaccharidoses (MPSs) patients. In this study, we aimed to determine the oxidative stress/antioxidant parameters and pro-inflammatory cytokine levels in the serum of MPS patients, in order to evaluate the possible role of inflammation in these patient groups regarding to accumulated metabolites. MPS I (n = 3), MPS II (n = 8), MPS III (n = 4), MPS IVA (n = 3), MPS VI (n = 3), and VII (n = 1) patients and 20 age-matched healthy subjects were included into the study. There was no statistically significant change in activities of SOD, Catalase, GSH-Px and lipid peroxidation levels in erythrocytes between the MPS patients and healthy controls. While IL-1alpha (p = 0.054), IL-6 (p = 0.008) levels, and chitotriosidase activity (p = 0.003) elevated in MPS3 patients, IL1α (p = 0.006), IL-1β (p = 0.006), IL-6 (p = 0.006), IFNγ (p = 0.006), and NFκB (p = 0.006) levels increased in MPS-6 patients. Elevated levels of IL-6, IL1α and chitotriosidase activity demonstrated macrophage activation in MPSIII untreated with enzyme replacement. Our study showed for the first time that high levels of IL1α, IL-6, IL1β and NFκB were present in MPSVI patients, demonstrating the induction of inflammation by dermatan sulphate. The low level of paraoxonase in MPSVI patients may be a good marker for cardiac involvement. Overall, this study provides important insights into the relationship between lysosomal storage of glycosaminoglycan and inflammation in MPS patients. It highlights possible pathways for the increased release of inflammatory molecules and suggests new targets for the development of treatments.
small molecules
2025-11-11 | Trehalose-mediated activation of Mitf corrects autophagy defects and ameliorates neurodegeneration in MPS VII
Abstract Mucopolysaccharidosis type VII (MPS VII) is a progressive lysosomal storage disorder caused by β-glucuronidase (β-GUS) deficiency, featuring pronounced neurodegeneration. The Drosophila model of MPS VII, generated by deleting the fly β-GUS ortholog CG2135, exhibits hallmark neuropathological features, including dopaminergic neuron loss, brain vacuolisation, and impaired locomotor performance. Using this CG2135 −/− fly, we recently showed that impaired autophagosome formation and their turnover led to abnormal accumulation of damaged mitochondria and lipofuscins in the brain. In this study, we investigated the molecular basis of this autophagy defect and found that Mitf (the TFEB homolog), the transcriptional regulator of autophagy, is markedly downregulated in CG2135 −/− fly brains, accompanied by reduced expression of its target genes, including LAMP1, CLN3, and v-ATPase subunits. Guided by these observations, we assessed whether boosting Mitf activity could ameliorate neuropathology. Interestingly, oral trehalose treatment reactivated Mitf and its downstream autophagy gene network in CG2135 −/− fly brains, restoring autophagosome biogenesis, reducing lipofuscin accumulation, and alleviating apoptosis. Trehalose treatment also improved locomotor performance, indicating a clear mitigation of neurodegeneration. These findings demonstrate that Mitf dysregulation drives autophagy impairment in MPS VII fly brain and highlight Mitf activation as a promising therapeutic strategy to alleviate neurological pathology.
2025-02-06 | Unravelling a mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in Mucopolysaccharidosis VII.
Cognitive disability and neurodegeneration are prominent symptoms of Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder caused by β-glucuronidase enzyme deficiency. Yet, the mechanism of neurodegeneration in MPS VII remains unclear thereby limiting the scope of targeted therapy. We aimed to bridge this knowledge gap by employing the β-glucuronidase-deficient (CG2135-/-) Drosophila model of MPS VII. Taking cues from our initial observation that the adult CG2135-/- flies displayed enhanced susceptibility to starvation, we investigated potential impairments in the autophagy-lysosomal clearance machinery in their brain to dissect the underlying cause of neurodegeneration. We found that both autophagosome biogenesis and lysosome-mediated autophagosomal turnover were impaired in the CG2135-/- fly brain. This was evidenced by lower Atg8a-II levels, reduced Atg1 and Ref(2)P expression along with accumulation of lipofuscin-like inclusions and multilamellar bodies. Mitophagy was also found to be defective in their brain, resulting in buildup of enlarged mitochondria with distorted cristae and reduced membrane potential. This, in turn, compromised mitochondrial function, as reflected by drastically reduced brain ATP levels. Energy depletion triggered apoptosis in neuronal as well as non-neuronal cells of the CG2135-/- fly brain, where apoptotic dopaminergic neurons were also detected. Interestingly, resveratrol treatment corrected the mitophagy defect and prevented ATP depletion in the CG2135-/- fly brain, providing an explanation for its neuroprotective effects. Collectively, our study reveals a pharmacologically targetable mechanistic link between mitophagy defect, mitochondrial malfunction, and apoptotic neurodegeneration in MPS VII.
2022-06-02 | Flaxseed extract reduces tissue accumulation and enhances urinary excretion of chondroitin sulphate in the rat: a possible new path in substrate reduction therapy for mucopolysaccharidosis.
Chondroitin 6 sulphate (C6S) is a glycosaminoglycan (GAG) whose accumulation is notable in mucopolysaccharidosis type IVA and VII. Flaxseed, Linum usitatissimum L. (Linaceae) (FS), is reported to have comparable properties to those of soybean, a source of genistein, a potential new treatment for MPSs. We assess the effect of total ethanol flaxseed extract (EFSE) in an animal model of C6S accumulation. The study was performed in adult male Wistar rats (n = 24) for 15 successive days. The animals were divided into four groups: (1) control injected with physiological saline buffer, (2) intoxicated rats injected intraperitoneally with C6S, (3) intoxicated with C6S and treated with EFSE, and (4) treated with EFSE. All groups were subjected to histopathological and biochemical studies. The antioxidant and phytochemical properties of EFSE were examined. Dry EFSE contains total phenols (6.28 mg EAG/g), condensed tannins (2.98 mg ECAT/g) and flavonoids (0.44 mg ECAT/g) with high antioxidant potential [RPE (IC50 = 8.37 ± 0.176), DPPH (IC50 = 12.79 ± 0.273)]. The LD50 is higher than 5000 mg/kg. The histopathological examination showed an accumulation of C6S in the C6S intoxicated group, which disappeared in the C6S-EFSE treated group. GAGs assays showed an increased excretion in the C6S intoxicated group and increased excretion of 14% in the C6S-EFSE group compared to the C6S group. EFSE showed significant potential for chelation. Its use for the treatment of GAG accumulation could be suggested and generalized to a larger study population.
2022-04-19 | Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR.
Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or β-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135-/- fly), which also exhibited a significant loss of body fat. We report here that the lean phenotype of the CG2135-/- larvae is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135-/- larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135-/- larvae. Interestingly, treatment of the CG2135-/- larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII.
2021-09-05 | Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR
Abstract Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or β-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135 -/- fly), which also exhibited a significant loss of adiposity. We report here that the lean phenotype of the CG2135 -/- fly is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135 -/- larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135 -/- flies. Interestingly, treatment of the CG2135 -/- larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII.
gene therapies
2025-07-04 | CRISPR/Cas9-mediated promoterless gene targeting reduces lysosome storage in MPS VII mice.
Targeted gene integration mediated by CRISPR/Cas9 is a promising therapeutic strategy for monogenic autosomal recessive diseases. In this study, we established a novel all-in-one high-capacity adenovirus (HCAd) that can pack both CRISPR/Cas9 and donor DNA into the same vector and tested it on a mouse model of mucopolysaccharidosis type VII (MPS VII) caused by mutations in the β-glucuronidase (GUSB) gene. This system allowed targeted integration of promoterless GUSB in the mouse beta-actin gene (mActb) locus and the co-expression of GUSB with the self-cleaving peptide T2A (T2A) controlled by a strong endogenous mActb promoter. The in vivo results indicated that the serum GUSB level of MPS VII mice treated with a single intraperitoneal injection of the HCAd vector achieved 14% of that of wild-type mice, resulting in significant amelioration of lysosomal storage in the liver and spleen. Furthermore, the HCAd was injected intraventricularly in the brain of newborn MPS VII mice, leading to strongly positive GUSB enzyme staining in the choroid plexus and perivascular spaces of the periventricular regions and reduced lysosome storage. In summary, by using an all-in-one vector, the study provides a universal, one-for-all therapeutic for MPSVII, a disease caused by different mutations of the GUSB gene.
2024-04-27 | Self-complementary AAV vector therapy for treating corneal cloudiness of mucopolysaccharidosis type VII (MPS VII).
To design a novel efficacious scAAV-Gusb viral vector for treating Mucopolysaccharidosis Type VII (MPS VII) caused by a mutation in the β-Glu gene (Gusb allele). β-Glu expression of single-stranded AAV-Gusb (ssAAV-Gusb) and self-complementary AAV (scAAV-Gusb) vectors are tested with cultured murine Gusb fibroblasts. The scAAV-Gusb vector was chosen in further studies to prolong the life span and treat corneal pathology of Gusb mice via intrahepatic injection of neonates and intrastromal injection in adults, respectively. Corneal pathology was studied using HRT2 in vivo confocal microscope and histochemistry in mice corneas. Both ssAAV-Gusb and scAAV-Gusb vectors expressed murine β-Glu in cultured Gusb fibroblasts. The scAAV-Gusb vector had higher transduction efficiency than the ssAAV-Gusb vector. To prolong the life span of Gusb mice, neonates (3 days old) were administered with scAAV-Gusb virus via intrahepatic injection. The treatment improves the survival rate of Gusb mice, prolonging the median survival rate from 22.5 weeks (untreated) to 50 weeks (treated). Thereafter, we determined the efficacy of the scAAV-Gusb virus in ameliorating corneal cloudiness observed in aged Gusb mice. Both corneal cloudiness and stroma thickness decreased, and there was the presence of β-Glu enzyme activity in the Gusb corneas receiving scAAV-Gusb virus associated with morphology change of amoeboid stromal cells in untreated to characteristic dendritic keratocytes morphology after 4-12 weeks of scAAV-Gusb virus injection. Intrahepatic injection of scAAV-Gusb is efficacious in prolonging the life span of Gusb mice, and intrastromal injection can ameliorate corneal phenotypes. Both strategies can be adapted for treating other MPS.
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.
2019-09-12 | Intrathecal AAVrh10 corrects biochemical and histological hallmarks of mucopolysaccharidosis VII mice and improves behavior and survival
Abstract Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by ß-glucuronidase deficiency, prompting glycosaminoglycan accumulation in enlarged vesicles, leading to peripheral and neuronal dysfunction. Here, we present a gene therapy strategy using lumbar puncture of AAVrh10 encoding human β-glucuronidase (AAVrh10-GUSB) to adult MPS VII mice. This minimally invasive technique efficiently delivers the recombinant vector to the cerebrospinal fluid (CSF) with a single intrathecal injection. We show that AAVrh10 delivery to the CSF allows global, stable transduction of CNS structures. In addition, drainage of AAVrh10-GUSB from the CSF to the bloodstream resulted in the transduction of somatic organs such as liver, which provided a systemic β-glucuronidase source sufficient to achieve serum enzyme activity comparable to wild type mice. ß-glucuronidase levels were enough to correct biochemical and histopathological hallmarks of the disease in the CNS and somatic organs at short and long term. Moreover, the progression of the bone pathology was also reduced. Importantly, the biochemical correction led to a significant improvement in the physical, cognitive and emotional characteristics of MPS VII mice, and doubling their life span. Our strategy may have implications for gene therapy in patients with lysosomal storage diseases.
2018-11-09 | Treatment of brain disease in the mucopolysaccharidoses.
The mucopolysaccharidosis (MPS) disorders are a group of lysosomal storage diseases caused by lysosomal enzyme deficits that lead to glycosaminoglycan accumulation, affecting various tissues throughout the body based on the specific enzyme deficiency. These disorders are characterized by their progressive nature and a variety of somatic manifestations and neurological symptoms. There are established treatments for some MPS disorders, but these mostly alleviate somatic and non-neurological symptoms and do not cure the disease. Patients with MPS I, II, III, and VII can present with neurological manifestations such as neurocognitive decline and behavioral problems. Treatment of these neurological manifestations remains challenging due to the blood-brain barrier (BBB) that limits delivery of therapeutic agents to the central nervous system (CNS). New therapies that circumvent this barrier and target brain disease in MPS are currently under development. They primarily focus on facilitating penetration of drugs through the BBB, delivery of recombinant enzyme to the brain by gene therapy, or direct CNS administration. This review summarizes existing and potential future treatment approaches that target brain disease in MPS. The information in this review is based on current literature and presentations and discussions during a closed meeting by an international group of experts with extensive experience in managing and treating MPS.
proteins
2025-12-15 | Mannose-6-phosphate functionalized liposomal nanocarrier for lysosome-specific delivery of β-glucuronidase in a Drosophila model of MPS VII
Mannose-6-phosphate (M6P) functionalised liposomal nanocarriers can achieve site-specific delivery of β-glucuronidase (β-GUS) to the targeted organelle lysosome of enzyme deficient cells in Mucopolysaccharidosis VII (MPS VII), a lysosomal storage disorder. Created with BioRender.com.
2023-07-10 | Awake airway endoscopy in mucopolysaccharidosis: a case report.
Mucopolysaccharidosis (MPS) are a group of rare genetic inherited diseases with a progressive course due to the accumulation of glycosaminoglycans resulting in anatomic abnormalities and organ dysfunction, including the respiratory, cardiovascular, skeletal, and neurological systems that can increase the risk of anesthesia complications. Clinical manifestations are variable, multisystemic, and include severe morphological changes. The anesthetic management of these patients is complex, particularly airway management, which can be planned to include a fiberoptic airway investigation prior to surgery. We present two cases of patients with MPS type VI and VII who underwent fiberoptic airway mapping under conscious sedation, with no complications. Since MPS is a rare but challenging disease concerning the airway management, we propose a safe and effective anesthetic technique that could be used for fiberoptic bronchoscopy and allow fiberoptic-assisted tracheal intubation at the time of surgery.
2023-06-03 | Transplacental delivery of therapeutic proteins by engineered immunoglobulin G: a step toward perinatal replacement therapy
Background Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to replace missing enzymes in the fetus, as shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires during fetal development and induce tolerance to self-antigens or immunogenic therapeutic molecules. Objectives To investigate whether proteins that are administered to pregnant mice or endogenously present in their circulation may be delivered through the placenta. Methods We engineered monovalent immunoglobulin G (FabFc) specific for different domains of human factor VIII (FVIII), a therapeutically relevant model antigen. FabFc was injected with exogenous FVIII into pregnant severe hemophilia A mice or pregnant mice expressing human FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant mice and/or fetuses by enzyme-linked immunosorbent assay and immunohistochemistry. Results Administration of FabFc to pregnant mice allowed the maternofetal delivery of FVIII in a FcRn-dependent manner. FVIII antigen levels achieved in the fetuses represented 10% of normal plasma levels in the human. We identified antigen/FabFc complex stability, antigen size, and shielding of promiscuous protein patches as key parameters to foster optimal antigen delivery. Conclusion Our results pave the way toward the development of novel strategies for the in utero delivery of endogenous maternal proteins to replace genetically deficient fetal proteins or to educate the immune system and favor active immune tolerance upon protein encounter later in life.
2020-07-15 | C-Type Natriuretic Peptide Restores Growth Impairment Under Enzyme Replacement in Mice With Mucopolysaccharidosis VII.
Growth impairment in mucopolysaccharidoses (MPSs) is an unresolved issue as it is resistant to enzyme replacement therapy (ERT) and growth hormone therapy. C-type natriuretic peptide (CNP) is a promising agent that has growth-promoting effects. Here we investigate the effects of CNP on growth impairment of MPSs using Gusbmps-2J mice, a model for MPS type VII, with combination therapy of CNP and ERT by hydrodynamic gene delivery. Although monotherapies were not sufficient to restore short statures of treated mice, combination therapy resulted in successful restoration. The synergistic effects of CNP and ERT were not only observed in skeletal growth but also in growth plates. ERT reduced cell swelling in the resting zone and increased cell number by accelerating proliferation or inhibiting apoptosis. CNP thickened the proliferative and hypertrophic zones. Regarding changes in the bone, ERT restored bone sclerosis through decreased bone formation and increased bone resorption, and CNP did not adversely affect this process. In addition, improvement of joint deformation by ERT was suggested by analyses of joint spaces and articular cartilage. CNP additively provided restoration of the short stature of MPS VII mice in combination with ERT, which improved abnormalities of growth plates and bone metabolism.
2019-02-22 | Beta-Glucuronidase Catalyzes Deconjugation and Activation of Curcumin-Glucuronide in Bone
The biological basis for documented in vivo bone-protective effects of turmeric-derived curcumin is unclear since curcumin is barely detectable in serum, being rapidly conjugated to form what is thought to be an inactive glucuronide. Studies were therefore undertaken to test the postulate that antiresorptive effects of curcumin require deconjugation within bone to form the bioactive aglycone and that β-glucuronidase (GUSB), a deconjugating enzyme expressed by hematopoietic marrow cells, facilitates this site-specific transformation. Consistent with this postulate, aglycone, but not glucuronidated, curcumin inhibited RANKL-stimulated osteoclastogenesis, a key curcumin target in bone. Aglycone curcumin, expressed relative to total curcumin, was higher in bone marrow than in serum of curcumin-treated C57BL/6J mice, while remaining a minor component. Ex vivo, under conditions preventing further metabolism of the unstable aglycone, the majority of curcumin-glucuronide delivered to marrow in vivo was hydrolyzed to the aglycone, a process that was inhibited by treatment with saccharolactone, a GUSB inhibitor, or in mice having reduced (C3H/HeJ) or absent (mps/mps) GUSB activity. These findings suggest that curcumin, despite low systemic bioavailability, may be enzymatically activated (deconjugated) within GUSB-enriched bone to exert protective effects, a metabolic process that could also contribute to bone-protective effects of other highly glucuronidated dietary polyphenols.
antibodies
2023-12-16 | Glycosaminoglycan-induced proinflammatory cytokine levels as disease marker in mucopolysaccharidosis.
Recently, it has been shown disturbances in oxidant/antioxidant system and increases in some inflammatory markers in animal studies and in some Mucopolysaccharidoses (MPSs) patients. In this study, we aimed to determine the oxidative stress/antioxidant parameters and pro-inflammatory cytokine levels in the serum of MPS patients, in order to evaluate the possible role of inflammation in these patient groups regarding to accumulated metabolites. MPS I (n = 3), MPS II (n = 8), MPS III (n = 4), MPS IVA (n = 3), MPS VI (n = 3), and VII (n = 1) patients and 20 age-matched healthy subjects were included into the study. There was no statistically significant change in activities of SOD, Catalase, GSH-Px and lipid peroxidation levels in erythrocytes between the MPS patients and healthy controls. While IL-1alpha (p = 0.054), IL-6 (p = 0.008) levels, and chitotriosidase activity (p = 0.003) elevated in MPS3 patients, IL1α (p = 0.006), IL-1β (p = 0.006), IL-6 (p = 0.006), IFNγ (p = 0.006), and NFκB (p = 0.006) levels increased in MPS-6 patients. Elevated levels of IL-6, IL1α and chitotriosidase activity demonstrated macrophage activation in MPSIII untreated with enzyme replacement. Our study showed for the first time that high levels of IL1α, IL-6, IL1β and NFκB were present in MPSVI patients, demonstrating the induction of inflammation by dermatan sulphate. The low level of paraoxonase in MPSVI patients may be a good marker for cardiac involvement. Overall, this study provides important insights into the relationship between lysosomal storage of glycosaminoglycan and inflammation in MPS patients. It highlights possible pathways for the increased release of inflammatory molecules and suggests new targets for the development of treatments.
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Drug Discovery Landscape
2 orphan drug designations for Mucopolysaccharidosis type 7, including 2 approved therapies.
2 orphan drug designations for Mucopolysaccharidosis type 7, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human beta-glucuronidase [Mepsevii] | proteins | EMA | 2012-03-21 | 2018-08-27 | Ultragenyx Germany GmbH |
vestronidase alfa-vjbk [Mepsevii] | proteins | FDA | 2012-02-16 | 2017-11-15 | Ultragenyx Pharmaceutical, Inc. |
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