Mucopolysaccharidosis Type VII Research Articles

Disease characteristics, effectiveness, and safety of vestronidase alfa for the treatment of patients with mucopolysaccharidosis VII in a novel, longitudinal, multicenter disease monitoring program

BackgroundMucopolysaccharidosis VII (MPS VII) is an ultra-rare, autosomal recessive, debilitating, progressive lysosomal storage disease caused by reduced activity of β-glucuronidase (GUS) enzyme. Vestronidase alfa (recombinant human GUS) intravenous enzyme replacement therapy is an approved treatment for patients with MPS VII.MethodsThis disease monitoring program (DMP) is an ongoing, multicenter observational study collecting standardized real-world data from patients with MPS VII (N ≈ 50 planned) treated with vestronidase alfa or any other management approach. Data are monitored and recorded in compliance with Good Clinical Practice guidelines and planned interim analyses of captured data are performed annually. Here we summarize the safety and efficacy outcomes as of 17 November 2022.ResultsAs of the data cutoff date, 35 patients were enrolled: 28 in the Treated Group and seven in the Untreated Group. Mean (SD) age at MPS VII diagnosis was 4.5 (4.0) years (range, 0.0 to 12.4 years), and mean (SD) age at DMP enrollment was 13.9 (11.1) years (range, 1.5 to 50.2 years). Ten patients (29%) had a history of nonimmune hydrops fetalis. In the 23 patients who initiated treatment prior to DMP enrollment, substantial changes in mean excretion from initial baseline to DMP enrollment were observed for the three urinary glycosaminoglycans (uGAGs): dermatan sulfate (DS), -84%; chondroitin sulfate (CS), -55%; heparan sulfate (HS), -42%. Also in this group, mean reduction from initial baseline to months 6, 12, and 24 were maintained for uGAG DS (-84%, -87%, -89%, respectively), CS (-70%, -71%, -76%, respectively), and HS (+ 3%, -32%, and − 41%, respectively). All adverse events (AEs) were consistent with the known vestronidase alfa safety profile. No patients discontinued vestronidase alfa. One patient died.ConclusionsTo date, the DMP has collected invaluable MPS VII disease characteristic data. The benefit-risk profile of vestronidase alfa remains unchanged and favorable for its use in the treatment of pediatric and adult patients with MPS VII. Reductions in DS and CS uGAG demonstrate effectiveness of vestronidase alfa to Month 24. Enrollment is ongoing.

Early clinical response and continued safety with vestronidase ALFA for the treatment of mucopolysaccharidosis VII (MPS VII)

Early clinical response and continued safety with vestronidase ALFA for the treatment of mucopolysaccharidosis VII (MPS VII)

Cellular Organelle-Related Transcriptomic Profile Abnormalities in Neuronopathic Types of Mucopolysaccharidosis: A Comparison with Other Neurodegenerative Diseases.

Mucopolysaccharidoses (MPS) are a group of diseases caused by mutations in genes encoding lysosomal enzymes that catalyze reactions of glycosaminoglycan (GAG) degradation. As a result, GAGs accumulate in lysosomes, impairing the proper functioning of entire cells and tissues. There are 14 types/subtypes of MPS, which are differentiated by the kind(s) of accumulated GAG(s) and the type of a non-functional lysosomal enzyme. Some of these types (severe forms of MPS types I and II, MPS III, and MPS VII) are characterized by extensive central nervous system disorders. The aim of this work was to identify, using transcriptomic methods, organelle-related genes whose expression levels are changed in neuronopathic types of MPS compared to healthy cells while remaining unchanged in non-neuronopathic types of MPS. The study was conducted with fibroblast lines derived from patients with neuronopathic and non-neuronopathic types of MPS and control (healthy) fibroblasts. Transcriptomic analysis has identified genes related to cellular organelles whose expression is altered. Then, using fluorescence and electron microscopy, we assessed the morphology of selected structures. Our analyses indicated that the genes whose expression is affected in neuronopathic MPS are often associated with the structures or functions of the cell nucleus, endoplasmic reticulum, or Golgi apparatus. Electron microscopic studies confirmed disruptions in the structures of these organelles. Special attention was paid to up-regulated genes, such as PDIA3 and MFGE8, and down-regulated genes, such as ARL6IP6, ABHD5, PDE4DIP, YIPF5, and CLDN11. Of particular interest is also the GM130 (GOLGA2) gene, which encodes golgin A2, which revealed an increased expression in neuronopathic MPS types. We propose to consider the levels of mRNAs of these genes as candidates for biomarkers of neurodegeneration in MPS. These genes may also become potential targets for therapies under development for neurological disorders associated with MPS and candidates for markers of the effectiveness of these therapies. Although fibroblasts rather than nerve cells were used in this study, it is worth noting that potential genetic markers characteristic solely of neurons would be impractical in testing patients, contrary to somatic cells that can be relatively easily obtained from assessed persons.

Clinical manifestations and genetic mutation analysis of patients with mucopolysaccharidosis type VII in China

ObjectiveThis study aimed to explore the clinical and genetic features of Chinese patients with mucopolysaccharidosis type VII (MPS VII), thereby improving early detection, disease management, and patient outcomes. MethodsA retrospective review of medical records for five patients presenting with coarse facial features, rib protrusion, chest deformities, and scoliosis was conducted. Exome sequencing was employed to identify causative genetic mutations. ResultsThe study comprised five patients (four males, one female) with disease onset at six months of age (range: 0–1.5 years). Common symptoms included coarse facial features, skeletal abnormalities, delayed motor and language development, and intellectual disability. Approximately 80% of the patients exhibited multiple skeletal dysplasias, enlarged adenoids or tonsils, and snoring; 60% had hernias; 40% reported hearing loss and hepatosplenomegaly. Less frequent manifestations were short stature, valvular heart disease, non-immune hydrops fetalis, and corneal opacity. All patients demonstrated elevated urine glycosaminoglycans levels and absent β-glucuronidase activity in leukocytes. Exome sequencing identified compound heterozygous mutations in the GUSB gene in all four tested patients, uncovering seven mutations in total, three of which were novel (c.189G > A, c.869C > T, and c.1745 T > C). Furthermore, prenatal diagnosis through chorionic villus sampling in subsequent pregnancies of one patient's mother revealed both fetuses had normal β-glucuronidase activity and no disease-causing mutations in the GUSB gene. ConclusionThe study's patients all presented with classic symptoms of MPS VII due to β-glucuronidase deficiency, with three new pathogenic mutations identified in the GUSB gene. Genetic counseling and prenatal testing were highlighted as crucial for disease prevention.

#322 : A Rare Case Report of Successfull Live Twin Birth in a Couple Who are Carriers of Mucopolysaccharidoses VII-Sly Syndrome

Introduction: Mucopolysaccharidoses VII or sly syndrome is an autosomal recessive condition discovered in 1972 by William Sly, occurs due to mutation in the beta glucoronidase encoding gene, it is an ultra-rare neurometabolic disorder caused by inherited deficiency of the lysosomal enzyme [Formula: see text]eta-glucuronidase. Precise data regarding its epidemiology is scarce, but birth prevalence is estimated to vary from 0.02 to 0.24/100,000 live births with 54 types of recorded mutations. The clinical course and disease progression are widely heterogeneous. So far 9 pregnancies have been recorded in patients with sly syndrome of which the majority showed some deformity. Here we present a case of a couple with two different variants of GUSB gene who delivered live twin birth with normal development. Background: A couple aged 29 & 31 who were anxious to conceive came to the clinic with a previous history of two abortions for pre conceptual counselling. Both pregnancies had features suggestive of non-anemic type nonimmune hydrops with increased nuchal fold thickness in USG. Both her pregnancies were terminated mid trimester with the autopsy results conclusive of the findings. Method & Results: Whole exome sequencing showed that both were carriers of GUSB gene of two different variants encoding for Sly syndrome. Based on the WES and karyotyping reports genetic counselling was given, and PGT-M was suggested. The patient underwent antagonist protocol and 12MII were retrieved. ICSI was done and the embryos were cultured to day 5 and subjected to PGT-A, PGT-M. The resultant 2 carrier blastocysts were transferred. Post transfer Beta Hcg was positive. The patient had an uneventful obstetric course and delivered normal twin girl babies on 27/01/23. The twins showed no physical abnormality and their genetic profiling showed they were carriers of GUSB gene. Conclusion: This case demonstrates that with appropriate pre-conceptual evaluation, genetic counselling, constant maternal and fetal surveillance, carriers of sly syndrome can be given multidisciplinary care leading to successful outcome.

Identification of genetic variants associated with a wide spectrum of phenotypes clinically diagnosed as Sanfilippo and Morquio syndromes using whole genome sequencing.

Mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders (LSDs). MPSs are caused by excessive accumulation of mucopolysaccharides due to missing or deficiency of enzymes required for the degradation of specific macromolecules. MPS I-IV, MPS VI, MPS VII, and MPS IX are sub-types of mucopolysaccharidoses. Among these, MPS III (also known as Sanfilippo) and MPS IV (Morquio) syndromes are lethal and prevalent sub-types. This study aimed to identify causal genetic variants in cases of MPS III and MPS IV and characterize genotype-phenotype relations in Pakistan. We performed clinical, biochemical and genetic analysis using Whole Genome Sequencing (WGS) in 14 Pakistani families affected with MPS III or MPS IV. Patients were classified into MPS III by history of aggressive behaviors, dementia, clear cornea and into MPS IV by short trunk, short stature, reversed ratio of upper segment to lower segment with a short upper segment. Data analysis and variant selections were made based on segregation analysis, examination of known MPS III and MPS IV genes, gene function, gene expression, the pathogenicity of variants based on ACMG guidelines and in silico analysis. In total, 58 individuals from 14 families were included in the present study. Six families were clinically diagnosed with MPS III and eight families with MPS IV. WGS revealed variants in MPS-associated genes including NAGLU, SGSH, GALNS, GNPTG as well as the genes VWA3B, BTD, and GNPTG which have not previously associated with MPS. One family had causal variants in both GALNS and BTD. Accurate and early diagnosis of MPS in children represents a helpful step for designing therapeutic strategies to protect different organs from permanent damage. In addition, pre-natal screening and identification of genetic etiology will facilitate genetic counselling of the affected families. Identification of novel causal MPS genes might help identifying new targeted therapies to treat LSDs.

Mucopolysaccharidosis: An overview and new treatment modalities

Mucopolysaccharidosis is a lysosomal storage disorder, caused due to deficiency of enzymes required for the breakdown of Mucopolysaccharides. These undegraded Mucopolysaccharides accumulate in various tissues and cause characteristic features like neurological deficit, impaired motor function, developmental delay, hearing loss, behavioral problems, corneal clouding, glaucoma, respiratory distress, coarse facial features, skeletal deformities, and organomegaly. Based on deficient enzymes they have divided into subtypes Mucopolysaccharidosis I (MPS I) Hunter syndrome (I H / I HS / I S), Mucopolysaccharidosis II(MPS II) Hunter syndrome (severe and mild form), Mucopolysaccharidosis III (MPS III) Sanfilippo syndrome, Mucopolysaccharidosis IV(MPS IV) Morquio syndrome, Mucopolysaccharidosis VI(MPS VI) Maroteaux Lamy syndrome, Mucopolysaccharidosis VI (MPS VII) Sly syndrome. Diagnosis is classically based on clinical examination and urine analysis. Enzyme assay can also aid in diagnosis. Chorionic villi sampling and amniocentesis are also becoming popular. The main objective of treatment is to improve the quality of life. Symptomatic management includes daily exercise, physiotherapy, tonsillectomy, shunting surgery, and corneal transplantation. There are various recent concepts utilized for the treatment of Mucopolysaccharidosis. This review article emphasizes such treatment aspects as Hematopoietic stem cell therapy, Enzyme replacement therapy, Gene therapy, Nano-enabled therapy, and Substrate reduction therapy.

Growth patterns in patients with mucopolysaccharidosis VII

ObjectiveThis study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy. MethodsHeight, weight, and body mass index (BMI) measurements and Z-scores from patients from three clinical studies were compared with those from CDC healthy population growth charts. Relationships with age/sex and history of non-immune hydrops fetalis (NIHF) were assessed by linear regression and ANOVA, respectively. ResultsAmong 20 enrolled patients with MPS VII, height Z-scores were near normal until 1 year of age but declined thereafter, particularly among males. There was no consistent pattern in weight Z-score. BMI Z-scores were above normal and increased slightly with age among males and were slightly below normal among females. Male patients with a history of NIHF had greater declines in height and weight Z-scores over time versus males without history of NIHF. There was no clear effect of NIHF history on height and weight Z-scores in female patients. ConclusionsIn patients with MPS VII, declines in height Z-score began early in life, particularly among males, while changes in BMI varied by sex. Patients with MPS VII and a history of NIHF had greater declines in height Z-score with age than did patients without a history of NIHF.Clinical trial registration: This retrospective analysis included patients enrolled in an open-label phase 2 study (UX003-CL203; ClinicalTrials.gov, NCT02418455), a randomized, placebo-controlled, blind-start phase 3 study (UX003-CL301; ClinicalTrials.gov, NCT02230566), or its open-label, long-term extension (UX003-CL202; ClinicalTrials.gov, NCT02432144). Requests for individual de-identified participant data and the clinical study report from this study are available to researchers providing a methodologically sound proposal that is in accordance with the Ultragenyx data sharing commitment. To gain access, data requestors will need to sign a data access and use agreement. Data will be shared via secured portal. The study protocol and statistical analysis plan for this study are available on the relevant clinical trial registry websites with the tabulated results.

How to Develop a Rare Disease Treatment

GEN BiotechnologyVol. 2, No. 1 Book ReviewsFree AccessHow to Develop a Rare Disease TreatmentSean EkinsSean Ekins*Address correspondence to: Sean Ekins, Collaborations Pharmaceuticals, 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA, E-mail Address: sean@collaborationspharma.comCollaborations Pharmaceuticals, Raleigh, North Carolina, USA.Search for more papers by this authorPublished Online:15 Feb 2023https://doi.org/10.1089/genbio.2023.29075.sekAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Saving Ryan: The 30-Year Journey into Saving the Life of a Childby Emil D. Kakkis (Impositivity Media, LLC, 2022).There are several excellent books about patients diagnosed with a rare disease [e.g., Gina Kolata's Mercies in Disguise (St Martins Press, 2017)] or about building a rare disease biotech, such as A Rare Breed by Daniel Levine and Daniel Maher (Biomarin, 2017) and Conscience and Courage by John Hawkins (Cold Spring Harbor Laboratory Press, 2019). Published in 2022, Saving Ryan by physician/scientist and entrepreneur Emil Kakkis successfully merges the story of a rare disease patient chasing a life-saving treatment with the clinician scientist's perspective of developing it.(My company has benefitted from Emil's generosity in providing a letter of support for a rare disease grant.) The author's compassion and willingness to help others who are developing rare disease treatments shine in every page. He even started a publishing company to self-publish the book to provide a story of hope.Inspiration and FrustrationThe book blends autobiography, inspirational read, and instructions on how to make an enzyme replacement therapy (ERT) for a rare disease. Kakkis tells the story of Ryan Dant, who was diagnosed as a young child with a lysosomal storage disease, mucopolysaccharidoses type I (MPS I). His parents are determined to fund a treatment to save his life.MPS I is caused by a mutation in an enzyme iduronidase, which clears glycosaminoglycans. In patients lacking this enzyme, these build up in the joints and various organs and may lead to life-threatening complications. Emil and the Dants cross paths in 1995, raising significant funds that helps Emil and his laboratory develop the treatment. A start-up biotech (Biomarin) and then a bigger biotech (Genzyme) provide additional funding and expertise, resulting in clinical trials and ultimately, in 2003, approval by the FDA.That is the abbreviated story. What is remarkable is the “warts and all” telling of it, especially the numerous hurdles that must be surmounted and unexpected setbacks that reminded me of a game of snakes and ladders. We hear a perspective from a clinician/principal investigator in an academic laboratory who must balance the ups and downs of hiring staff, the challenges of raising funds, and ultimately the dual pressures of publishing vs continuing research to develop a treatment.Kakkis spares no details in the ups and downs of working with the FDA. Over 2 years, the relationship went from very supportive to delaying the treatment reaching the market, necessitating an additional clinical trial and millions of dollars of further investment to be raised. Kakkis surprisingly names those people at the FDA, whom he alleges cost several children's lives by delaying treatment availability. Working on such rare diseases is heartbreaking and Kakkis took those losses personally.In the epilogue, Kakkis provides an update on the participants in the first clinical trial. Sadly, 6 of the 10 are no longer alive, likely because they were treated relatively late, and the effects of the disease were already advanced. The remaining four are living productive independent lives, which previously would have been unimaginable.TranslationAs someone developing an ERT for a rare disease (Batten disease), the timing of this book could not have been better. We learn every step in the process of how an ERT is made and tested before translation to the clinic. The book is a well-written “how to” manual. Not that everyone will be able to follow in his footsteps, but Kakkis provides a roadmap for other families and scientists.An index would have added to the book's value. The scientific explanations of lysosomal diseases are clear and the author pays tribute to the pioneers such as Elizabeth Neufeld working on rare genetic diseases who discovered the mutation that causes MPS I and laid the foundation for eventual treatments. Kakkis started working on MPS I not in some swanky modern laboratory but in a bungalow laboratory from the 1940s at Harbor-UCLA Medical Center in Torrance, CA, which ultimately had to be retrofitted to be able to provide Good manufacturing practice conditions to make clinical material.The detailing of the “shoestring science” and agonizing efforts to make tiny quantities of enzyme for the initial preclinical studies in dogs is revealing for how little it cost to get this far in 1993, likely tens of thousands of dollars and many very long days. Kakkis made it work with part-time staff and second-hand equipment, but he was clearly very demanding.As Kakkis raises more money, the team grows and so does the protein production scale. You get the sense that if more academics were like him and not continually chasing publications, grant funding, and tenure, we would have more treatments available for patients. Kakkis ultimately sacrificed his academic career to bring hope to the families of MPS I patients, but his route in biotech also positioned him well to become an entrepreneur, starting his own company.ImpactThe monumental effort to get the ERT treatment approved ultimately led to the product Aldurazyme being used by >1000 people around the world, leading to newborn screening for the disease. Kakkis intertwines this story with the more personal story of the Dants' fundraising efforts and their hopes and fears for their son. There is a happy ending for Ryan and plentiful photos to chart his life from young child through to married adult. Kakkis has been at Ryan's side for many of his milestones. He spent 11 years at Biomarin bringing six more treatments to market (which he mentions in passing), rising to chief medical officer. He then started a foundation to work with the FDA, congress, and companies to help improve the process of bringing treatments to patients.In 2010, Kakkis founded Ultragenyx to work on rare and ultrarare diseases, developing an ERT for MPS VII, for which the FDA provided compassionate access. Perhaps more importantly, Kakkis serves as an inspiration for families, and he provides much useful advice throughout this book. For example, The Ryan Foundation had a massive impact on his laboratory and ability to develop the ERT, something other families should heed. They could focus their funds and resources on supporting young scientists without NIH funding.Some diseases will be tough to address with ERTs, but Emil makes a strong case for their potential (at the outset he wanted to work on gene therapies but was nudged toward ERT). Kakkis' biggest impact may be to inspire the hundreds if not thousands of other families and scientists who are also looking for a cure or a purpose, respectively.Providing HopeSaving Ryan is an important historical document. Will we look back on the early 2000s as a turning point with companies including Biomarin and Genzyme developing ERTs? Like many other companies, they have also invested heavily in gene therapy, with no treatments to show for it. What have we lost by not continuing to develop the technologies for producing more ERTs that might also enable them to be made more cost-effectively?I would have liked Kakkis to talk more about the future, what technologies could be used to enable developing ERTs to scale. Nevertheless, Kakkis has shown what is possible and perhaps others will pick up the baton. Saving Ryan shines a light on how a family foundation can have a dramatic effect on funding cutting-edge science. The next time you are asked to sponsor someone or participate in a charity golf tournament for a rare disease, remember that your generosity could help the next breakthrough therapy, leading to a story of hope that will one day be told just like this one.FiguresReferencesRelatedDetails Volume 2Issue 1Feb 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Sean Ekins.How to Develop a Rare Disease Treatment.GEN Biotechnology.Feb 2023.27-28.http://doi.org/10.1089/genbio.2023.29075.sekPublished in Volume: 2 Issue 1: February 15, 2023PDF download

Personal perspectives of international caregivers and a clinician of the impact of a lack of newborn screening for MPS VII

Personal perspectives of international caregivers and a clinician of the impact of a lack of newborn screening for MPS VII

A Neonate with Mucopolysaccharidosis Type VII with Intractable Ascites

We report a case of a patient with severe fetal hydrops and refractory ascites, diagnosed as mucopolysaccharidosis type VII (MPS VII) by whole-exome sequencing, and discharged at 5 months of age after long-term ventilatory management. A male neonate was born by emergency cesarean section due to fetal distress at 30 1/7 weeks' gestation. Physical examination and X-rays revealed pleural effusion, ascites, and generalized edema, indicating severe fetal hydrops. He underwent tracheal intubation because of respiratory distress that was attributed to massive ascites, pulmonary hypoplasia, and pulmonary hypertension. He received mechanical ventilation and inhaled nitric oxide therapy. Prednisone, octreotide, and a factor XIII preparation were used as the treatment for ascites, and the ascites gradually decreased. He was extubated within 2 months of age. At 4 months of age, the results of whole-exome sequencing of the cord blood showed a compound heterozygous mutation in the GUSB gene, the gene responsible for MPS VII. Enzyme replacement therapy was initiated, and the ascites was resolved. Careful systemic management, including lung-protective respiratory management and the early establishment of nutrition, is important for the long-term survival of infants with fetal hydrops, and early aggressive workup, including whole-genome sequencing for the cause, should be performed in the case of refractory ascites.

P189: Vestronidase alfa for the treatment of mucopolysaccharidosis VII (MPS VII): Updated results from a novel, longitudinal, multicenter disease monitoring program

P189: Vestronidase alfa for the treatment of mucopolysaccharidosis VII (MPS VII): Updated results from a novel, longitudinal, multicenter disease monitoring program

Diagnosis and Emerging Treatment Strategies for Mucopolysaccharidosis VII (Sly Syndrome).

Mucopolysaccharidosis VII (MPS VII, Sly syndrome) is an ultra-rare lysosomal disease caused by a deficiency of the enzyme β-glucuronidase (GUS). The diagnosis is suspected based on a range of symptoms that are common to many other MPS types, and it is confirmed through biochemical and molecular studies. Besides supportive treatment, current and emerging treatments include enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy. This review summarizes the clinical manifestations, diagnosis, and emerging treatments for MPS VII.

Dose-dependent effects of enzyme replacement therapy on skeletal disease progression in mucopolysaccharidosis VII dogs

Mucopolysaccharidosis (MPS) VII is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme β-glucuronidase. Skeletal abnormalities are common in patients and result in diminished quality of life. Enzyme replacement therapy (ERT) for MPS VII using recombinant human β-glucuronidase (vestronidase alfa) was recently approved for use in patients; however, to date there have been no studies evaluating therapeutic efficacy in a large animal model of MPS VII. The objective of this study was to establish the effects of intravenous ERT, administered at either the standard clinical dose (4mg/kg) or a high dose (20mg/kg), on skeletal disease progression in MPS VII using the naturally occurring canine model. Untreated MPS VII animals exhibited progressive synovial joint and vertebral bone disease and were no longer ambulatory by age 6months. Standard-dose ERT-treated animals exhibited modest attenuation of joint disease, but by age 6months were no longer ambulatory. High-dose ERT-treated animals exhibited marked attenuation of joint disease, and all were still ambulatory by age 6months. Vertebral bone disease was recalcitrant to ERT irrespective of dose. Overall, our findings indicate that ERT administered at higher doses results in significantly improved skeletal disease outcomes in MPS VII dogs.

Circulatory C-type natriuretic peptide reduces mucopolysaccharidosis-associated craniofacial hypoplasia in vivo.

Skeletal alterations in the head and neck region, such as midfacial hypoplasia, foramen magnum stenosis and spinal canal stenosis, are commonly observed in patients with mucopolysaccharidosis (MPS). However, enzyme replacement therapy (ERT), one of the major treatment approaches for MPS, shows limited efficacy for skeletal conditions. In this study, we analysed the craniofacial morphology of mice with MPS type VII, and investigated the underlying mechanisms promoting jaw deformities in these animals. Furthermore, we investigated the effects of C-type natriuretic peptide (CNP), a potent endochondral ossification promoter, on growth impairment of the craniofacial region in MPS VII mice when administered alone or in combination with ERT. MPS VII mice exhibited midfacial hypoplasia caused by impaired endochondral ossification, and histological analysis revealed increased number of swelling cells in the resting zone of the spheno-occipital synchondrosis (SOS), an important growth centre for craniomaxillofacial skeletogenesis. We crossed MPS VII mice with transgenic mice in which CNP was expressed in the liver under the control of the human serum amyloid-P component promoter, resulting in elevated levels of circulatory CNP. The maxillofacial morphological abnormalities associated with MPS VII were ameliorated by CNP expression, and further prevented by a combination of CNP and ERT. Histological analysis showed that ERT decreased the swelling cell number, and CNP treatment increased the width of the proliferative and hypertrophic zones of the SOS. Furthermore, the foramen magnum and spinal stenoses observed in MPS VII mice were significantly alleviated by CNP and ERT combination. These results demonstrate the therapeutic potential of CNP, which can be used to enhance ERT outcome for MPS VII-associated head and neck abnormalities.

A rare lysosomal storage disorder: Feline mucopolysaccharidosis VII

AbstractA 9‐week‐old, male domestic shorthair presented with a 2‐week history of progressive hindlimb weakness and reduction in normal play behaviour. At 17 weeks of age, the patient exhibited progressive hindlimb paresis and ataxia and had developed facial dysmorphia and bilateral corneal clouding, prompting investigation into a mucopolysaccharidosis disorder. Peripheral blood cytology, increased urinary glycosaminoglycan excretion and radiographic findings (generalised epiphyseal dysplasia, coxofemoral luxation and vertebral fusion) suggested mucopolysaccharidosis. Definitive diagnosis was obtained through serum enzymatic testing, which yielded a complete deficiency in β‐glucuronidase and increased compensatory activity in α‐L‐iduronidase and B‐arylsulfatase. This pattern was consistent with a diagnosis of feline mucopolysaccharidosis VII, and palliative therapy was initially implemented. The patient ultimately died at 21 months of age.

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

Context 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. Objective We assess the effect of total ethanol flaxseed extract (EFSE) in an animal model of C6S accumulation. Materials and methods 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. Results 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. Discussion and conclusions EFSE showed significant potential for chelation. Its use for the treatment of GAG accumulation could be suggested and generalized to a larger study population.

Lysosomal storage diseases. Mucopolysaccharidosis types IV, VI, and VII – Morquio, Maroto–Lamy and Sly syndrome

The review is devoted to the clinical, biochemical, and molecular genetic characteristics of autosomal recessive mucopolysaccharidoses (MPS) types IV, VI, and VII. MPS IV type, or Morquios syndrome, is represented by 2 types A and B. The cause of the most frequent MPS IVA is hereditary deficiency of galactose-6-sulfatase, due to the presence of inactivating mutations in the GALNS gene. The pathogenetic basis of the disease is associated with excessive accumulation in lysosomes, mainly of cartilage tissue of keratan sulfate and chondroitin-6-sulfate. Main clinical manifestations of MPS IVA are dwarfism and progressive deformity of the spine, sternum, and knees. The milder MPS IVB is due to hereditary -galactosidase deficiency and is an allelic variant of GM1 gangliosidosis. The cause of MPS VI, or MarotoLamy syndrome, and MPS VII, or Sly syndrome, is hereditary deficiency of arylsulfatase B and -glucuronidase, respectively. The pathogenesis of these diseases is due to the excessive accumulation of dermatan sulfate and, in the second case, additionally, heparan sulfate. Patients with type VI and VII MPS have a Hurler-like phenotype, but in the first case, intellectual deficiency are usually absent, while in Sly syndrome, moderate mental retardation is observed. The possibility of neonatal screening and early diagnosis of these MPS in order to increase the effectiveness of their prevention and treatment is discussed. The importance of experimental models for studying the molecular basis of the pathogenesis of these severe hereditary diseases and the development of various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy and substrate-reducing therapy, is emphasized. Descriptions of clinical cases of MPS IVA and VI types are presented.

Viral Vectors in Transgenic Research: Prospects for the Treatment of CNS Diseases and Gene Therapy

Viral vectors are of great clinical interest due to their high efficiency, which allows them to find practical applications in gene therapy. The review presents current research data on various fish species as potential models for the use of viral vectors. During the study of high-performance adenoviral vectors data on the stable expression of transgenes in the body of Danio rerio and other fish species was obtained. The features of the use of adeno-associated vectors in the study of transneuronal transfer of the glucuronidase protein in the projection neurons of the ventral tegmental area and striatum to treat metabolic insufficiency in case of mucopolysaccharidosis VII are considered. Taking into consideration the wide set of genetically modified Danio rerio strains, ethical aspects, and the acceptability of applying this model in neurogenic studies, it is clear that Danio rerio, as well as other fish species, can be used as an alternative for early preclinical evaluation of the efficiency of viral vectors.

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.