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

Abstract

AbstractBackgroundSanfilippo 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.AimTo compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice.MethodsNeonatal 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.ResultsBoth 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.ConclusionsConfirmatory 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.