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

Helen Beard, Leanne Winner, Andrew Shoubridge, Emma Parkinson-Lawrence, Adeline A. Lau, Siti N. Mubarokah, Tabitha Rose Lance, Barbara King, William Scott, Marten F. Snel, Paul J. Trim, Kim M. Hemsley

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere14919
JournalCNS Neuroscience and Therapeutics
Volume30
Issue number8
DOIs
Publication statusPublished or Issued - 9 Aug 2024

Keywords

  • AAV9
  • gene therapy
  • mouse
  • mucopolysaccharidosis type III
  • photoreceptor degeneration
  • pre-clinical
  • sulfamidase

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)

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