Evaluation of neuroretina following i.v. or intra-CSF AAV9 gene replacement in mice with MPS IIIA, a childhood dementia.

Autor: Beard H; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia., Winner L; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia., Shoubridge A; Healthy Microbiome and Chronic Disease, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia., Parkinson-Lawrence E; Mechanisms in Cell Biology and Disease Research Group, Clinical Health Sciences, UniSA, Adelaide, South Australia, Australia., Lau AA; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia., Mubarokah SN; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia., Lance TR; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia., King B; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia., Scott W; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia., Snel MF; Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia., Trim PJ; Proteomics, Metabolomics and MS-Imaging Facility, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia., Hemsley KM; Childhood Dementia Research Group, Flinders Health and Medical Research Institute College of Medicine and Public Health Flinders University, Bedford Park, South Australia, Australia.
Jazyk: angličtina
Zdroj: CNS neuroscience & therapeutics [CNS Neurosci Ther] 2024 Aug; Vol. 30 (8), pp. e14919.
DOI: 10.1111/cns.14919
Abstrakt: Background: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is a childhood dementia caused by inherited mutations in the sulfamidase gene. At present, there is no treatment and children with classical disease generally die in their late teens. Intravenous or intra-cerebrospinal fluid (CSF) injection of AAV9-gene replacement is being examined in human clinical trials; evaluation of the impact on brain disease is an intense focus; however, MPS IIIA patients also experience profound, progressive photoreceptor loss, leading to night blindness.
Aim: To compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice.
Methods: Neonatal mice received i.v. or intra-CSF AAV9-sulfamidase or vehicle and after 20 weeks, biochemical and histological evaluation of neuroretina integrity was carried out.
Results: Both treatments improved central retinal thickness; however, in peripheral retina, outer nuclear layer thickness and photoreceptor cell length were only significantly improved by i.v. gene replacement. Further, normalization of endo-lysosomal compartment size and microglial morphology was only observed following intravenous gene delivery.
Conclusions: Confirmatory studies are needed in adult mice; however, these data indicate that i.v. AAV9-sulfamidase infusion leads to superior outcomes in neuroretina, and cerebrospinal fluid-delivered AAV9 may need to be supplemented with another therapeutic approach for optimal patient quality of life.
(© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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