Recent scientific articles relevant to Sanfilippo Syndrome: June – July 2023, digest

August 25, 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 June 2023 to July 2023.

“Focal lesions following intracerebral gene therapy for mucopolysaccharidosis IIIA”

Published: Annals of Clinical and Translational Neurology, June 10, 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, Marjo S van der Knaap


“Objective: Mucopolysaccharidosis type IIIA (MPSIIIA) caused by recessive SGSH variants results in sulfamidase deficiency, leading to neurocognitive decline and death. No disease-modifying therapy is available. The AAVance gene therapy trial investigates AAVrh.10 overexpressing human sulfamidase (LYS-SAF302) delivered by intracerebral injection in children with MPSIIIA. Post-treatment MRI monitoring revealed lesions around injection sites. Investigations were initiated in one patient to determine the cause.

Methods: Clinical and MRI details were reviewed. Stereotactic needle biopsies of a lesion were performed; blood and CSF were sampled. All samples were used for viral studies. Immunohistochemistry, electron microscopy, and transcriptome analysis were performed on brain tissue of the patient and various controls.

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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“Endogenous, non-reducing end glycosaminoglycan biomarkers are superior to internal disaccharide glycosaminoglycan biomarkers for newborn screening of mucopolysaccharidoses and GM1 gangliosidosis”

Published: Molecular Genetics and Metabolism, June 24, 2023

Authors: Zackary M. Herbst, Xinying Hong, Leslie Urdaneta, Terri Klein, Christine Waggoner, Hsuan-Chieh Liao, Francyne Kubaski, Roberto Giugliani, Maria Fuller, Michael H. Gelb

Abstract: “Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidoses (MPSs). Our previous publications on glycosaminoglycan (GAG) biomarker levels in DBS for mucopolysaccharidosis type 1 (MPS-I) and MPS-II demonstrated that second-tier GAG biomarker analysis can dramatically reduce the false positive rate in NBS. In the present study, we evaluate two methods for measuring GAG biomarkers in seven MPS types and GM1 gangliosidosis. We obtained newborn DBS from patients with MPS-IIIA-D, -IVA, -VI, -VII, and GM1 gangliosidosis. These samples were analyzed via two GAG mass spectrometry methods: (1) The internal disaccharide biomarker method; (2) The endogenous non-reducing end (NRE) biomarker method. This study supports the use of second-tier GAG analysis of newborn DBS by the endogenous NRE biomarker method, as part of NBS to reduce the false positive rate.”

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“Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia”

Published: Journal of Neurochemistry, June 26, 2023

Authors: Leanne K. Winner, Mary-Louise Rogers, Marten F. Snel, Kim M. Hemsley

Abstract: “Sanfilippo syndrome (MPS III) is an autosomal recessive inherited disorder causing dementia in children, following an essentially normal early developmental period. First symptoms typically include delayed language development, hyperactivity and/or insomnia from 2 years of age, followed by unremitting and overt loss of previously acquired skills. There are no approved treatments, and the median age of death is 18 years. Treatments under clinical trial demonstrate therapeutic benefit when applied pre-symptomatically in children diagnosed early through known familial inheritance risk. Newborn screening for Sanfilippo syndrome would enable pre-symptomatic diagnosis and optimal therapeutic benefit, however, many fold more patients with Sanfilippo syndrome are expected to be identified in the population than present with childhood dementia. Therefore, the capacity to stratify which Sanfilippo infants will need treatment in toddlerhood is necessary. While diagnostic methods have been developed, and continue to be refined, currently there are no tools or laboratory-based biomarkers available to provide pre-symptomatic prognosis. There is also a lack of progression and neurocognitive response-to-treatment biomarkers; disease stage and rate of progression are currently determined by age at symptom onset, loss of cerebral grey matter volume by magnetic resonance imaging and developmental quotient score for age. Robust blood-based biomarkers are an urgent unmet need. In this review, we discuss the development of biomarker assays for Sanfilippo based on the neuropathological pathways known to change leading into symptom onset and progression, and their performance as biomarkers in other neurodegenerative diseases. We propose that neural-derived exosomes extracted from blood may provide an ideal liquid biopsy to detect reductions in synaptic protein availability, and mitochondrial function. Furthermore, given the prominent role of neuroinflammation in symptom expression, glial fibrillary acidic protein detection in plasma/serum, alongside measurement of active brain atrophy by neurofilament light chain, warrant increased investigation for prognostic, progression and neurocognitive response-to-treatment biomarker potential in Sanfilippo syndrome and potentially other childhood dementias.”

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“Intraparenchymal convection enhanced delivery of AAV in sheep to treat Mucopolysaccharidosis IIIC”

Published: Journal of Translational Medicine, July 5, 2023

Authors: Claire O’Leary, Gabriella Forte, Nadia L Mitchell, Amir Saam Youshani, Adam Dyer, Martin P Wellby, Katharina N Russell, Samantha J Murray, Nelly Jolinon, Simon A Jones, Kevin Stacey, Daniel M Davis, Els Henckaerts, David N Palmer, Ian Kamaly-Asl, Brian W Bigger


“Background: Mucopolysaccharidosis IIIC (MPSIIIC) is one of four Sanfilippo diseases sharing clinical symptoms of severe cognitive decline and shortened lifespan. The missing enzyme, heparan sulfate acetyl-CoA: α-glucosaminide-N-acetyltransferase (HGSNAT), is bound to the lysosomal membrane, therefore cannot cross the blood-brain barrier or diffuse between cells. We previously demonstrated disease correction in MPSIIIC mice using an Adeno-Associated Vector (AAV) delivering HGSNAT via intraparenchymal brain injections using an AAV2 derived AAV-truetype (AAV-TT) serotype with improved distribution over AAV9.

Methods: Here, intraparenchymal AAV was delivered in sheep using catheters or Hamilton syringes, placed using Brainlab cranial navigation for convection enhanced delivery, to reduce proximal vector expression and improve spread.

Results: Hamilton syringes gave improved AAV-GFP distribution, despite lower vector doses and titres. AAV-TT-GFP displayed moderately better transduction compared to AAV9-GFP but both serotypes almost exclusively transduced neurons. Functional HGSNAT enzyme was detected in 24-37% of a 140g gyrencephalic sheep brain using AAV9-HGSNAT with three injections in one hemisphere.

Conclusions: Despite variabilities in volume and titre, catheter design may be critical for efficient brain delivery. These data help inform a clinical trial for MPSIIIC.”

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“Child Neurology: Mucopolysaccharidosis IIID: Evidence From Ultrastructural and Genomic Study”

Published: Neurology, July 24, 2023

Authors: Rashmi Santhoshkumar, Rohan R Mahale, Pakina Krishna Kishore, Yasha T Chickabasaviah

Abstract: “Mucopolysaccharidosis IIID (MPS IIID/ Sanfilippo syndrome D, OMIM # 252940), is an autosomal recessive lysosomal storage disorder (LSD) and the rarest form of the mucopolysaccharidosis (MPS) III subtypes. It is caused by mutations in the gene encoding lysosomal enzyme N-acetyl glucosamine-6-sulphatase (GNS). Deficiency of GNS impairs catabolism of glycosaminoglycans causing accumulation of heparan sulphate within lysosomes of various tissues which is visualized as membranous cytoplasmic bodies (MCBs) on electron microscopy. The recognition of this ultrastructural feature in a muscle biopsy instigated genetic evaluation for LSD in our case resulting in the detection of a novel pathogenic GNS gene mutation. The patient also exhibited intellectual disability since childhood, reduced vision due to pigmentary retinopathy, and behavioural abnormalities without other systemic features of MPS. Here, we report a patient of Indian origin with MPS IIID based on a novel pathogenic variant c.1078 G>T (p.G360C) in the GNS gene and the presence of MCBs in muscle biopsy, characterized by several novel findings including the occurrence of pigmentary retinopathy which extends the clinical spectrum of MPS IIID.”

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“Mucopolysaccharidosis type IIIB: a current review and exploration of the AAV therapy landscape”

Published: Neural Regeneration Research

Authors: Courtney J Rouse, Victoria N Jensen, Coy D Heldermon

Abstract: “Mucopolysaccharidoses type IIIB is a rare genetic disorder caused by mutations in the gene that encodes for N-acetyl-alpha-glucosaminidase. This results in the aggregation of heparan sulfate polysaccharides within cell lysosomes that leads to progressive and severe debilitating neurological dysfunction. Current treatment options are expensive, limited, and presently there are no approved cures for mucopolysaccharidoses type IIIB. Adeno-associated virus gene therapy has significantly advanced the field forward, allowing researchers to successfully design, enhance, and improve potential cures. Our group recently published an effective treatment using a codon-optimized triple mutant adeno-associated virus 8 vector that restores N-acetyl-alpha-glucosaminidase levels, auditory function, and lifespan in the murine model for mucopolysaccharidoses type IIIB to that seen in healthy mice. Here, we review the current state of the field in relation to the capsid landscape, adeno-associated virus gene therapy and its successes and challenges in the clinic, and how novel adeno-associated virus capsid designs have evolved research in the mucopolysaccharidoses type IIIB field.”

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

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