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by Grant L. Austin, Feng Wang, Steven Q. Le, Alexander Sorensen, Shan Li, Lai C. Foong, Srikanth Singamsetty, Jill Wood, Tsui-Fen Chou, Patricia I. Dickson
Mucopolysaccharidosis type IIID (MPS IIID; Sanfilippo D) is caused by biallelic pathogenic variants in N-acetylglucosamine-6-sulfatase (GNS), which participates in catabolism of heparan sulfate (HS) glycosaminoglycans. Characterization of MPS IIID disease at a cellular level has not been robustly achieved. We used unbiased quantitative proteomics to establish a cellular phenotype for MPS IIID mice. Recombinant human GNS (rhGNS), a variant of which previously demonstrated single dose efficacy in MPS IIID human fibroblasts and in MPS IIID neonatal mice, was used to establish a repeat dosing schedule to treat MPS IIID mice. Adult Gns KO mice or heterozygous carriers were treated via intracerebroventricular (ICV) injections and received 3, 30, or 200 μg rhGNS in 4 doses over 2 weeks or vehicle. Twenty-four hours after the final dose, HS in brain and CSF showed dose-dependent reductions, reaching carrier levels in the higher dose groups. Furthermore, the proteomic perturbations that we described were corrected by rhGNS treatment. Next, Gns KO or carrier adult mice were treated via ICV and received 3, 30 or 200 μg rhGNS or vehicle once every two weeks (Day 1, 15, 29, 43, 57, 71, 85) and were euthanized on day 91. Following treatment, total HS and MPS IIID-specific HS (GlcNAc6S) showed dose-dependent reductions in brain and CSF and markers of neuroinflammation were substantially reduced. ICV enzyme replacement therapy with rhGNS restores CNS pathology of adult MPS IIID mice even with treatment at 14-day intervals, demonstrating preclinical efficacy for MPS IIID.Type 1 diabetes (T1D) is associated with changes in brain structure, cognition, mental health, and functional outcomes. While these changes have been linked to dysregulated glycaemic control, findings are inconsistent, and their long-term impact remains unclear. Most evidence comes from cross-sectional or short-term longitudinal studies, limiting insights into causal associations. To address this, we aim to study individuals with T1D approximately 30 years after onset to assess how early dysglycaemic insults during neurodevelopment influence cognitive and functional outcomes in mid-adulthood.
This protocol paper outlines an observational, case/control, cross-sectional/longitudinal and descriptive study that follows up the original Royal Children’s Hospital (RCH) Diabetes Cohort Study. The initial study recruited children in Australia diagnosed with T1D between 1990 and 1992, conducting five waves of data collection. We now introduce the Cognition and Longitudinal Assessments of Risk Factors over 30 Years (CLARiFY) Diabetes Complications Study to assess brain, cognition and functional outcomes in mid-adulthood, approximately 30 years post-T1D onset. Both T1D participants from the original cohort and healthy controls will participate in semistructured interviews, neuroimaging and cognitive testing. T1D participants will also undergo complications screening. Data from this study and previous waves will be used to (Aim 1) explore cross-sectional and longitudinal impacts of T1D on brain health over 30 years. Linear regression will analyse cross-sectional outcomes, and multivariate analysis will assess cognitive variables jointly. Longitudinal outcomes will be examined using linear mixed-effects regression for IQ patterns, with secondary outcomes analysed via generalised linear models. Additionally, linear mixed-effects regression (Aim 2) will identify T1D-related metabolic factors affecting brain outcomes, with covariate selection informed by the construction of directed acyclic graphs (DAGs).
The study was approved by the Royal Children’s Hospital Human Research Ethics Committee (HREC 35 240F and 2019.065). The research findings will be disseminated through peer-reviewed publications, conference presentations, and print and social media. Participants will receive a summary of the study findings on its completion.
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