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 language | English |
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Article number | e14919 |
Journal | CNS Neuroscience and Therapeutics |
Volume | 30 |
Issue number | 8 |
DOIs | |
Publication status | Published 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)