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Fusion of RVG or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II

Wood, Shaun Roger; Chaudrhy, Ahsan; Ellison, Stuart; Searle, Rachel; Burgod, Constance; Tehseen, Ghazala; Forte, Gabriella; ... Bigger, Brian; + view all (2023) Fusion of RVG or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II. Human Gene Therapy 10.1089/hum.2023.025. (In press). Green open access

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Abstract

Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disease caused by a mutation in the IDS gene, resulting in deficiency of the enzyme iduronate-2-sulfatase (IDS) causing heparan sulfate (HS) and dermatan sulfate (DS) accumulation in all cells. This leads to skeletal and cardiorespiratory disease with severe neurodegeneration in two thirds of sufferers. Enzyme replacement therapy is ineffective at treating neurological disease, as intravenously-delivered IDS is unable to cross the blood-brain barrier (BBB). Haematopoietic stem cell transplant is also unsuccessful, presumably due to insufficient IDS enzyme production from transplanted cells engrafting in the brain. We used two different peptide sequences (RVG and gh625), both previously published as BBB-crossing peptides, fused to IDS and delivered via haematopoietic stem cell gene therapy (HSCGT). HSCGT with LV.IDS.RVG and LV.IDS.gh625 was compared to LV.IDS.ApoEII and LV.IDS in MPSII mice at 6-months post-transplant. Levels of IDS enzyme activity in the brain and peripheral tissues were lower in LV.IDS.RVG and LV.IDS.gh625 treated mice than in LV.IDS.ApoEII and LV.IDS treated mice, despite comparable vector copy numbers. Microgliosis, astrocytosis and lysosomal swelling were partially normalised in MPSII mice treated with LV.IDS.RVG and LV.IDS.gh625. Skeletal thickening was normalised by both treatments to wild-type levels. Although reductions in skeletal abnormalities and neuropathology are encouraging, given the low levels of enzyme activity compared to control tissue from LV.IDS and LV.IDS.ApoEII transplanted mice, the RVG and gh625 peptides are unlikely to be ideal candidates for HSCGT in MPSII, and are inferior to the ApoEII peptide that we have previously demonstrated to be more effective at correcting MPSII disease than IDS alone.

Type: Article
Title: Fusion of RVG or gh625 to Iduronate-2-Sulfatase for the Treatment of Mucopolysaccharidosis Type II
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/hum.2023.025
Publisher version: https://doi.org/10.1089/hum.2023.025
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10171346
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