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

## TL;DR

This study compares two gene therapy methods in mice with a childhood dementia, finding that intravenous delivery improves retinal health better than cerebrospinal fluid delivery.

## Contribution

The study reveals that intravenous AAV9 gene replacement is more effective than CSF delivery in preserving retinal structure in a mouse model of Sanfilippo syndrome.

## Key findings

- Intravenous AAV9 gene replacement significantly improved peripheral retinal thickness and photoreceptor cell length.
- Normalization of endo-lysosomal compartment size and microglial morphology was observed only with intravenous delivery.
- Intra-CSF gene replacement showed limited efficacy in peripheral retinal degeneration.

## Abstract

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.

To compare the relative efficacy of the two therapeutic approaches on retinal degeneration in MPS IIIA mice.

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.

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.

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.

Beard, Hemsley and colleagues compared the efficacy of neonatal AAV9‐based gene replacement via intravenous or cerebrospinal fluid injection routes, on retinal degeneration in a mouse model of childhood dementia caused by Sanfilippo syndrome. Intravenous AAV9‐CMV‐human sulfamidase resulted in superior therapeutic efficacy, compared with cerebrospinal fluid infusions of the same viral vector. Created with BioRender.com.