# Neonatal gene therapy effectively prevents disease manifestations in a murine model of Mucopolysaccharidosis type I

## TL;DR

Neonatal gene therapy in mice prevents disease symptoms of Mucopolysaccharidosis type I before they become irreversible.

## Contribution

Demonstrates the effectiveness of neonatal ex vivo gene therapy in preventing disease pathology in a murine model of MPS-I.

## Key findings

- Treated mice showed increased IDUA levels and reduced substrate accumulation in organs.
- Skeletal and neurological improvements were observed post-treatment.
- The study provides proof of principle for early intervention in MPS-I.

## Abstract

Mucopolysaccharidosis type I (MPS-I) is a rare pediatric disease caused by mutations in the α-L-iduronidase (IDUA) gene encoding for a lysosomal enzyme involved in glycosaminoglycan metabolism. While newborns with the severe Hurler variant are usually asymptomatic at birth, progressive disease manifestations emerge early in life. Since previous studies on lentiviral vector gene therapy (GT) in Hurler patients have demonstrated superior metabolic correction and early beneficial clinical effects, we investigated whether applying this GT approach during the neonatal period could be effective in preventing disease pathology before it becomes irreversible. Thus, newborn MPS-I mice were transplanted with affected bone marrow-derived progenitor cells transduced with an IDUA-encoding lentiviral vector. Treated animals displayed increased IDUA levels, significantly reducing substrate accumulation in analyzed organs, indicating metabolic correction. Skeletal manifestations, typically resistant to conventional therapies, showed improvements at radiographic and histological levels post-treatment. Additionally, a decrease in brain cortex vacuolization and inflammation suggested neurological amelioration. Overall, this study provides a proof of principle demonstrating the effectiveness of neonatal ex vivo GT in MPS-I mice and supports its potential for further optimization at the pre-clinical level.

This study provides a proof of principle for neonatal ex vivo gene therapy as a potential therapeutic strategy for mucopolysaccharidosis type I. It confirms the effectiveness of this early intervention in preventing disease pathology before it becomes irreversible and poses the base for further refinement and clinical translation.