Recent scientific articles relevant to Sanfilippo Syndrome: April – May 2023, digest

July 21, 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 April 2023 to May 2023.

“Histological characterization of retinal degeneration in mucopolysaccharidosis type IIIC”

Published: Experimental Eye Research, April 1, 2023

Authors: Jessica Ludwig, Onkar B Sawant, Jill Wood, Srikanth Singamsetty, Xuefang Pan, Vera L Bonilha, Sujata Rao, Alexey V Pshezhetsky

Abstract: “Heparan-α-glucosaminide N-acetyltransferase (HGSNAT) participates in lysosomal degradation of heparan sulfate. Mutations in the gene encoding this enzyme cause mucopolysaccharidosis IIIC (MPS IIIC) or Sanfilippo syndrome type C. MPS IIIC patients exhibit progressive neurodegeneration, leading to dementia and death in early adulthood. Currently there is no approved treatment for MPS IIIC. Incidences of non-syndromic retinitis pigmentosa and early signs of night blindness are reported in some MPS IIIC patients, however the majority of ocular phenotypes are not well characterized. The goal of this study was to investigate retinal degeneration phenotype in the Hgsnat knockout mouse model of MPS IIIC and a cadaveric human MPS IIIC eye. Cone and rod photoreceptors in the eyes of homozygous 6-month-old Hgsnat knockout mice and their wild-type counterparts were analyzed using cone arrestin, S-opsin, M-opsin and rhodopsin antibodies. Histological observation was performed on the eye from a 35-year-old MPS IIIC donor. We observed a nearly 50% reduction in the rod photoreceptors density in the Hgsnat knockout mice compared to the littermate wild-type controls. Cone photoreceptor density was unaltered at this age. Severe retinal degeneration was also observed in the MPS IIIC donor eye. To our knowledge, this is the first report characterizing ocular phenotypes arising from deleterious variants in the Hgsnat gene associated with MPS IIIC clinical phenotype. Our findings indicate retinal manifestations may be present even before behavioral manifestations. Thus, we speculate that ophthalmological evaluations could be used as diagnostic indicators of early disease, progression, and end-point evaluation for future MPS IIIC therapies.”

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“Effects of Trehalose Administration in Patients with Mucopolysaccharidosis Type III”

Published: Current Medicinal Chemistry, April 6, 2023

Authors: Moein Mobini, Shabnam Radbakhsh, Francyne Kubaski, Peyman Eshraghi, Saba Vakili, Rahim Vakili, Mitra Abbasifard, Tannaz Jamialahmadi, Omid Rajabi, Seyed Ahmad Emami, Zahra Tayarani-Najaran, Manfredi Rizzo, Ali H Eid, Maciej Banach, and Amirhossein Sahebkar

Results: “TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients, and the mean scores for quality of life were increased after the intervention. Serum GAG levels were reduced in all treated patients (however, the differences were not statistically significant). Alanine aminotransferase (ALT) levels were reduced in all patients post-treatment (p=0.0039). The mean levels of aspartate transaminase (AST) were also decreased after 12 weeks of treatment with Trehalose. Decreased serum pro-oxidant-antioxidant balance and increased GPX activity were observed at the end of the study. Decreases in mean splenic length were observed, whereas the liver volume did not change.”

Conclusion: Improvements in health-related quality of life and serum biomarkers (GAGs, liver aminotransferase levels, antioxidant status), as well as liver and spleen size, were found following 3 months of trehalose administration in patients with MPS IIIA and MPS IIIB.

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“IgG-cleavage protein allows therapeutic AAV gene delivery in passively immunized MPS IIIA mice”

Published: Gene Therapy, April 30, 2023

Authors: Tierra A Bobo, Preston N Samowitz, Michael I Robinson, Laura I Montes, Lawrence J Forsberg, Richard Feng, Nathan I Nicely, and Haiyan Fu

Abstract: “The widespread pre-existing αAAV-Abs in humans pose a critical challenge in translation of AAV gene therapy. The IgG degrading enzyme of Streptococci (IdeS) is demonstrated to specifically cleave IgG of humans and other species (not mouse). This study developed a modified new modified IdeS protein product (IdeSop). When incubated in vitro, IdeSop was shown to completely cleave human and rabbit IgGs within 6 h. To test IdeSop in a disease setting, we established a rabbitized αAAV9-Ab+ mouse by an IV infusion of purified acute αAAV9-Ab+ rabbit IgG into MPS IIIA mice, resulting in serum αAAV9-IgG at 1:6,400 and αAAV9-nAbs at 1:800. IdeSop-Ab-cleavage was shown to be dose-dependent. An IV IdeSop infusion at the effective doses resulted in rapid IgG depletion and clearance of pre-existing αAAV9-IgG and αAAV9-nAbs in rabbitized αAAV9-Abs+ MPS IIIA mice. Importantly, an IV injection of a high dose AAV9-hSGSHop vector (5 × 1013vg/kg) at 24 h post IdeSop treatment led to transduction as effective in αAAV9-Abs+ MPS IIIA mice, as in αAAV9-Abs-negative controls. We believe that transient IdeSop administration may offer a great tool to address the pre-existing-αAAV-Abs for the translation of rAAV gene therapy to treat diseases in humans, making effective rAAV gene therapy available to all patients in need..”

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“Focal lesions following intracerebral gene therapy for mucopolysaccharidosis IIIA”

Published: Annals of Clinical and Translational Neurology, May 11, 2023

Authors: Marianna Bugiani, Truus E M Abbink, Arthur W D Edridge, Lia van der Hoek, Anne E J Hillen, Niek P van Til, Gino V Hu-A-Ng, Marjolein Breur, Karen Aiach, Philippe Drevot, Michaël Hocquemiller, Ralph Laufer, Frits A Wijburg, and Marjo S van der Knaap

Results: “MRI revealed focal lesions around injection sites with onset from 3 months after therapy, progression until 7 months post therapy with subsequent stabilization and some regression. The patient had transient slight neurological signs and is following near-normal development. No evidence of viral or immunological/inflammatory cause was found. Immunohistochemistry showed immature oligodendrocytes and astrocytes, oligodendrocyte apoptosis, strong intracellular and extracellular sulfamidase expression and hardly detectable intracellular or extracellular heparan sulfate. No activation of the unfolded protein response was found.”

Interpretation: Results suggest that intracerebral gene therapy with local sulfamidase overexpression leads to dysfunction of transduced cells close to injection sites, with extracellular spilling of lysosomal enzymes. This alters extracellular matrix composition, depletes heparan sulfate, impairs astrocyte and oligodendrocyte function, and causes cystic white matter degeneration at the site of highest gene expression. The AAVance trial results will reveal the potential benefit-risk ratio of this therapy.

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“Dysregulation of genes coding for proteins involved in metabolic processes in mucopolysaccharidoses, evidenced by a transcriptomic approach”

Published: Metabolic Brain Disease, May 17, 2023

Authors: Karolina Pierzynowska, Patrycja Deresz, Grzegorz Węgrzyn, and Lidia Gaffke

Abstract: “Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSD) caused by mutations in genes coding for enzymes responsible for degradation of glycosaminoglycans (GAGs). Most types of these severe disorders are characterized by neuronopathic phenotypes. Although lysosomal accumulation of GAGs is the primary metabolic defect in MPS, secondary alterations in biochemical processes are considerable and influence the course of the disease. Early hypothesis suggested that these secondary changes might be due to lysosomal storage-mediated impairment of activities of other enzymes, and subsequent accumulation of various compounds in cells. However, recent studies indicated that expression of hundreds of genes is changed in MPS cells. Therefore, we asked whether metabolic effects observed in MPS are caused primarily by GAG-mediated inhibition of specific biochemical reactions or appear as results of dysregulation of expression of genes coding for proteins involved in metabolic processes. Transcriptomic analyses of 11 types of MPS (using RNA isolated from patient-derived fibroblasts), performed in this study, showed that a battery of the above mentioned genes is dysregulated in MPS cells. Some biochemical pathways might be especially affected by changes in expression of many genes, including GAG metabolism and sphingolipid metabolism which is especially interesting as secondary accumulation of various sphingolipids is one of the best known additional (while significantly enhancing neuropathological effects) metabolic defects in MPS. We conclude that severe metabolic disturbances, observed in MPS cells, can partially arise from changes in the expression of many genes coding for proteins involved in metabolic processes.”

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

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