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

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 101473265 Publication Model: Print Cited Medium: Internet ISSN: 1755-5949 (Electronic) Linking ISSN: 17555930 NLM ISO Abbreviation: CNS Neurosci Ther Subsets: MEDLINE

Original Publication: Oxford, UK : Wiley-Blackwell, c2008-

Mucopolysaccharidosis III*/therapy ; Mucopolysaccharidosis III*/genetics ; Genetic Therapy*/methods ; Dependovirus*/genetics ; Retina*/pathology; Animals ; Mice ; Disease Models, Animal ; Hydrolases/genetics ; Animals, Newborn ; Mice, Inbred C57BL ; Dementia/genetics ; Dementia/therapy ; Genetic Vectors/administration & dosage ; Injections, Intravenous

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.)

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University of Adelaide, PhD scholarship (A.S.); Lysosomal Diseases Research Unit, SAHMRI; 1121522 National Health and Medical Research Council

Keywords: AAV9; gene therapy; mouse; mucopolysaccharidosis type III; photoreceptor degeneration; pre‐clinical; sulfamidase

EC 3.10.1.1 (N-sulfoglucosamine sulfohydrolase)
EC 3.- (Hydrolases)

Date Created: 20240810 Date Completed: 20240810 Latest Revision: 20240812

20240813

PMC11315678

10.1111/cns.14919

39123298