Determination of the role of injection site on the efficacy of intra-CSF enzyme replacement therapy in MPS IIIA mice

Molecular Genetics and Metabolism
Helen BeardKim M Hemsley

Abstract

MPS IIIA is an inherited neurodegenerative lysosomal storage disorder characterized by cognitive impairment, sleep-wake cycle disturbance, speech difficulties, eventual mental regression and early death. Neuropathological changes include accumulation of heparan sulfate and glycolipids, neuroinflammation and degeneration. Pre-clinical animal studies indicate that replacement of the deficient enzyme, sulfamidase, via intra-cerebrospinal fluid (CSF) injection is a clinically-relevant treatment approach, reducing neuropathological changes and improving symptoms. Given that there are several routes of administration of enzyme into the CSF (intrathecal lumbar, cisternal and ventricular), determining the effectiveness of each injection strategy is crucial in order to provide the best outcome for patients. We delivered recombinant human sulfamidase (rhSGSH) to a congenic mouse model of MPS IIIA via each of the three routes. Mice were euthanized 24h or one-week post-injection; the distribution of enzyme within the brain and spinal cord parenchyma was investigated, and the impact on primary substrate levels and other pathological lesions determined. Both ventricular and cisternal injection of rhSGSH enable enzyme delivery to brain and sp...Continue Reading

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Citations

Mar 16, 2016·Neurobiology of Disease·Litsa KarageorgosJohn J Hopwood
Aug 8, 2015·Experimental Neurology·Reynold SpectorConrad E Johanson
Mar 29, 2016·The Journal of Clinical Investigation·Keisuke KitakazeKohji Itoh
Dec 3, 2016·Scientific Reports·Gerald V RaymondTroy C Lund
Sep 19, 2020·Journal of Inherited Metabolic Disease·Berna Seker YilmazJulien Baruteau
Sep 19, 2017·Metabolic Brain Disease·Lidia GaffkeGrzegorz Węgrzyn
Nov 18, 2018·Italian Journal of Pediatrics·Simona FecarottaGiancarlo Parenti
Sep 2, 2020·International Journal of Molecular Sciences·Andrés Felipe LealAngela Johana Espejo-Mojica
Mar 12, 2021·Advanced Drug Delivery Reviews·Ghazal Naseri KouzehgaraniDidier R Lefebvre

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