Superior outcomes in neuroretina following IV versus intra-CSF AAV9 gene replacement in mice with MPS IIIA

Sanfilippo syndrome or mucopolysaccharidosis type IIIA (MPS IIIA) is a childhood dementia caused by inherited mutations in the SGSH gene, leading to accumulation of heparan sulfate. Brain and retina are particularly impacted. At present there is no treatment and children with classical disease generally die in their late teens. Intravenous or intra-cerebrospinal fluid injection of AAV9-gene replacement is being examined in human clinical trials and whilst the impact on brain disease is of current focus, Sanfilippo patients also experience profound, progressive photoreceptor loss, leading to night blindness. Therefore, we compared the efficacy of neonatal gene replacement via each route on retinal degeneration in Sanfilippo mice. Both treatments improved central retinal thickness in 20-week-old mice, however rhodopsin-stained sections revealed that in peripheral retina, outer nuclear layer thickness and photoreceptor cell length were only significantly improved in mice receiving intravenous gene replacement. Further, complete normalization of endo-lysosomal compartment size and microglial morphology was only observed following intravenous gene delivery. Should the two clinical trials demonstrate that AAV9-sulfamidase treatment improves cognitive measures, the impact on other disease sites may highlight a treatment of choice. Our data indicates that intravenous AAV9-sulfamidase leads to superior outcomes in mouse neuroretina, compared with cerebrospinal fluid-delivered viral vector.