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Establishment of the effectiveness of early versus late stem cell gene therapy in Mucopolysaccharidosis II for treating central versus peripheral disease

Mandolfo, Oriana; Liao, Aiyin; Singh, Esha; O'Leary, Claire; Holley, Rebecca Jane; Bigger, Brian; (2023) Establishment of the effectiveness of early versus late stem cell gene therapy in Mucopolysaccharidosis II for treating central versus peripheral disease. Human Gene Therapy 10.1089/hum.2023.002. (In press). Green open access

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Abstract

Mucopolysaccharidosis type II (MPSII) is a rare paediatric X-linked lysosomal storage disease, caused by heterogeneous mutations in the IDS gene, which result in accumulation of heparan sulphate and dermatan sulphate within cells. This leads to severe skeletal abnormalities, hepatosplenomegaly and cognitive deterioration. The progressive nature of the disease is a huge obstacle to achieve full neurological correction. Although current therapies can only treat somatic symptoms, a lentivirus-based hematopoietic stem cell gene therapy (HSCGT) approach has recently achieved improved central nervous system neuropathology in the MPSII mouse model following transplant at 2-months of age. Here we evaluate neuropathology progression in 2-month, 4-month and 9-month-old MPSII mice and using the same HSCGT strategy we investigated somatic and neurological disease attenuation following treatment at 4-months of age. Our results showed gradual accumulation of heparan sulphate between 2 and 4 months of age, but full manifestation of microgliosis/astrogliosis as early as 2 months. Late HSCGT fully reversed the somatic symptoms, thus achieving the same degree of peripheral correction as early therapy. However, late treatment resulted in slightly decreased efficacy in the CNS, with poorer brain enzymatic activity, together with reduced normalisation of heparan sulphate over-sulphation. Overall, our findings confirm significant lysosomal burden and neuropathology in 2-month-old MPSII mice. Peripheral disease is readily reversible by LV.IDS-HSCGT regardless of age of transplant, suggesting a viable treatment for somatic disease. However, in the brain, higher IDS enzyme levels are achievable with early HSCGT treatment, and later transplant seems to be less effective, supporting the view that the earlier patients are diagnosed and treated, the better the therapy outcome.

Type: Article
Title: Establishment of the effectiveness of early versus late stem cell gene therapy in Mucopolysaccharidosis II for treating central versus peripheral disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1089/hum.2023.002
Publisher version: https://doi.org/10.1089/hum.2023.002
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/10173616
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