Recent scientific articles relevant to Sanfilippo Syndrome: October-December 2022, digest

January 5, 2023

Every week thousands of scientific articles on various topics are published. Here are some recent articles and abstracts that are relevant to understanding, managing, and/or treating Sanfilippo Syndrome (mucopolysaccharidosis III or MPS III) from October 2022 to December 2022.

“Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses”

Published: International Journal of Molecular Sciences, Oct. 3, 2022

Authors: Kohtaro Minami, Hideto Morimoto, Hiroki Morioka, Atsushi Imakiire, Masafumi Kinoshita, Ryuji Yamamoto, Tohru Hirato, Hiroyuki Sonoda

Abstract: “Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.”

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“Sanfilippo syndrome: consensus guidelines for clinical care”

Published: Orphanet Journal of Rare Diseases, Oct. 27, 2022

Authors: Nicole Muschol, Roberto Giugliani, Simon A Jones, Joseph Muenzer, Nicholas J C Smith, Chester B Whitley, Megan Donnell, Elise Drake, Kristina Elvidge, Lisa Melton, Cara O’Neill; MPS III Guideline Development Group

Abstract: “Sanfilippo syndrome is a group of rare, complex, and progressive neurodegenerative lysosomal storage disorders that is characterized by childhood dementia. The clinical management of patients with progressive neurological decline and multisystem involvement requires a multidisciplinary team with experience in the management of neurodegenerative disorders. Best practice guidelines for the clinical management of patients with these types of rare disorders are critical to ensure prompt diagnosis and initiation of appropriate care. However, there are no published standard global clinical care guidelines for patients with Sanfilippo syndrome. To address this, a literature review was conducted to evaluate the current evidence base and to identify evidence gaps. The findings were reviewed by an international steering committee composed of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. This review distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations for how to approach common management challenges and appropriate monitoring schedules in the care of patients with Sanfilippo syndrome.”

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“Brain transplantation of genetically corrected Sanfilippo type B neural stem cells induces partial cross-correction of the disease”

Published: Molecular Therapy Methods & Clinical Development, Oct. 27, 2022

Authors: Yewande Pearse, Don Clarke, Shih-hsin Kan, Steven Q. Le, Valentina Sanghez, Anna Luzzi, Ivy Pham, Lina R. Nih, Jonathan D. Cooper, Patricia I. Dickson, Michelina Iacovino

Abstract: “Sanfilippo syndrome type B (mucopolysaccharidosis type IIIB) is a recessive genetic disorder that severely affects the brain due to a deficiency in the enzyme α-N-acetylglucosaminidase (NAGLU), leading to intra-lysosomal accumulation of partially degraded heparan sulfate. There are no effective treatments for this disorder. In this project, we carried out an ex vivo correction of neural stem cells derived from Naglu−/− mice (iNSCs) induced pluripotent stem cells (iPSC) using a modified enzyme in which human NAGLU is fused to an insulin-like growth factor II receptor binding peptide in order to improve enzyme uptake. After brain transplantation of corrected iNSCs into Naglu−/− mice and long-term evaluation of their impact, we successfully detected NAGLU-IGFII activity in all transplanted animals. We found decreased lysosomal accumulation and reduced astrocytosis and microglial activation throughout transplanted brains. We also identified a novel neuropathological phenotype in untreated Naglu−/− brains with decreased levels of the neuronal marker Map2 and accumulation of synaptophysin-positive aggregates. Upon transplantation, we restored levels of Map2 expression and significantly reduced formation of synaptophysin-positive aggregates. Our findings suggest that genetically engineered iNSCs can be used to effectively deliver the missing enzyme to the brain and treat Sanfilippo type B-associated neuropathology.”

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“Activities of (Poly)phenolic Antioxidants and Other Natural Autophagy Modulators in the Treatment of Sanfilippo Disease: Remarkable Efficacy of Resveratrol in Cellular and Animal Models”

Published: Neurotherapeutics, Nov. 7, 2022

Authors: Estera Rintz, Magdalena Podlacha, Zuzanna Cyske, Karolina Pierzynowska, Grzegorz Węgrzyn, Lidia Gaffke

Abstract: “Sanfilippo disease, caused by mutations in the genes encoding heparan sulfate (HS) (a glycosaminoglycan; GAG) degradation enzymes, is a mucopolysaccharidosis (MPS), which is also known as MPS type III, and is characterized by subtypes A, B, C, and D, depending on identity of the dysfunctional enzyme. The lack of activity or low residual activity of an HS-degrading enzyme leads to excess HS in the cells, impairing the functions of different types of cells, including neurons. The disease usually leads to serious psychomotor dysfunction and death before adulthood. In this work, we show that the use of molecules known as dietary (poly)phenolic antioxidants and other natural compounds known as autophagy activators (genistein, capsaicin, curcumin, resveratrol, trehalose, and calcitriol) leads to accelerated degradation of accumulated HS in the fibroblasts of all subtypes of MPS III. Both the cytotoxicity tests we performed and the available literature data indicated that the use of selected autophagy inducers was safe. Since it showed the highest effectivity in cellular models, resveratrol efficacy was tested in experiments with a mouse model of MPS IIIB. Urinary GAG levels were normalized in MPS IIIB mice treated with 50 mg/kg/day resveratrol for 12 weeks or longer. Behavioral tests indicated complete correction of hyperactivity and anxiety in these animals. Biochemical analyses indicated that administration of resveratrol caused autophagy stimulation through an mTOR-independent pathway in the brains and livers of the MPS IIIB mice. These results indicate the potential use of resveratrol (and possibly other autophagy stimulators) in the treatment of Sanfilippo disease.”

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“Neurological, neurobehavioral, and radiological alterations in patients with mucopolysaccharidosis III (Sanfilippo’s syndrome) in Brazil”

Published: Frontiers in Neurology, Nov. 17, 2022

Authors: Daniel Almeida do Valle, Mara Lúcia Schmitz Ferreira Santos, Bruno Augusto Telles, Mara L Cordeiro

Abstract: “Mucopolysaccharidosis type III (MPS III) or Sanfilippo syndrome is the most common form of MPS, in which neurological involvement in all stages of the disease is prominent. The current study aimed to comprehensively describe the neurological profile of children and adolescents with MPS III who visited the largest pediatric hospital in South America. A prospective/retrospective cohort analysis was performed on 10 patients with MPS III from eight unrelated families. Most patients <12 months of age had achieved development milestones within the expected range for their age, with delay in walking independently and first single word acquisition. Behavioral symptoms were reported in seven patients. Eight patients (80%) developed profound intellectual disabilities. Six patients (60%) had epilepsy, among whom 75% had their first seizure between 2 and 4 years of age; the frequency of which increased with age. Monotherapy was effective in 60% of patients. Two patients, both aged <8 years, had normal baseline electroencephalographic activity. Epileptiform activity was observed in three patients. Cortical atrophy was visualized using magnetic resonance imaging in 71% patients; all but one of these patients were aged >6 years. Neurological abnormalities increased in prevalence and severity with age. Anti-seizure drug resistance was uncommon. Dysmorphological and systemic manifestations were uncommon and mild and did not correlate with neurological involvement. Despite high allelic heterogeneity, neurodegeneration was similar among all patients. Overall, these data contribute to the scarce literature from developing countries.”

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“A phase 1/2 study on intracerebroventricular tralesinidase alfa in patients with Sanfilippo syndrome type B”

Published: Journal of Clinical Investigation, Nov. 22, 2022

Authors: Nicole Muschol, Anja Koehn, Katharina von Cossel, Ilyas Okur, Fatih Ezgu, Paul Harmatz, Maria Jose de Castro Lopez, Maria Luz Couce, Shuan-Pei Lin, Spyros Batzios, Maureen Cleary, Martha Solano, Igor Nestrasil, Brian D Kaufman, Adam J Shaywitz, Stephen M Maricich, Bernice Kuca, Joseph Kovalchin, Eric H Zanelli

Results: “In the Part 1 dose escalation (30, 100, and 300 mg) phase, tralesinidase alfa 300 mg was necessary to achieve normalization of HS and HS-NRE in CSF and plasma. In Part 2, tralesinidase alfa 300 mg sustained HS and HS-NRE normalization in the CSF and stabilized cortical grey matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and reduction in spleen volume were observed in most subjects. Significant correlations were also established between change in cognitive AEq and plasma drug exposure, plasma HS-NRE level and change in CGMV.”

Conclusion: “ICV administration of tralesinidase alfa effectively normalized HS and HS-NRE as a prerequisite for clinical efficacy. Peripheral drug exposure data suggests a role for the glymphatic system in altering tralesinidase alfa efficacy.”

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Source: All information is sourced directly from the scientific abstracts and articles published by the researchers.

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