{Reference Type}: Journal Article
{Title}: Evaluation of neuroretina following i.v. or intra-CSF AAV9 gene replacement in mice with MPS IIIA, a childhood dementia.
{Author}: Beard H;Winner L;Shoubridge A;Parkinson-Lawrence E;Lau AA;Mubarokah SN;Lance TR;King B;Scott W;Snel MF;Trim PJ;Hemsley KM;
{Journal}: CNS Neurosci Ther
{Volume}: 30
{Issue}: 8
{Year}: 2024 Aug
{Factor}: 7.035
{DOI}: 10.1111/cns.14919
{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.
OBJECTIVE: 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.