%0 Journal Article
%T Evaluation of neuroretina following i.v. or intra-CSF AAV9 gene replacement in mice with MPS IIIA, a childhood dementia.
%A Beard H
%A Winner L
%A Shoubridge A
%A Parkinson-Lawrence E
%A Lau AA
%A Mubarokah SN
%A Lance TR
%A King B
%A Scott W
%A Snel MF
%A Trim PJ
%A Hemsley KM
%J CNS Neurosci Ther
%V 30
%N 8
%D 2024 Aug
%M 39123298
%F 7.035
%R 10.1111/cns.14919
%X <B>BACKGROUND: </B>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.<BR><B>OBJECTIVE: </B>To compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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.