Document Type

Article

Publication Date

1-27-2025

Publication Title

Commun Med (Lond)

Keywords

JMG, SS1

JAX Source

Commun Med (Lond). 2025;5(1):29.

Volume

5

Issue

1

First Page

29

Last Page

29

ISSN

2730-664X

PMID

39870870

DOI

https://doi.org/10.1038/s43856-025-00734-9

Grant

This work was supported by The Center for Precision Genetics at The Jackson Laboratory (NIH grant, U54 OD020351, and U54 OD030187) (to C.L.) and the Mouse Mutant Resource and Research Center (NIH grant U42 OD010921) (to C.L.). The authors wish to acknowledge the Scientific Services at The Jackson Laboratory for assistance in behavioral phenotyping and histology. These services are supported by NIH grant CA034196.

Abstract

BACKGROUND: Multiple Sulfatase Deficiency (MSD) is a rare inherited lysosomal storage disorder characterized by loss of function mutations in the SUMF1 gene that manifests as a severe pediatric neurological disease. There are no available targeted therapies for MSD.

METHODS: We engineered a viral vector (AAV9/SUMF1) to deliver working copies of the SUMF1 gene and tested the vector in Sumf1 knock out mice that generally display a median lifespan of 10 days. Mice were injected as pre-symptomatic neonates via intracerebroventricular administration, or as post-symptomatic juveniles via intrathecal alone or combination intrathecal and intravenous delivery. Cohorts were assessed for survival, behavioral outcomes, and post-mortem for sulfatase activity.

RESULTS: We show that treatment of neonates extends survival up to 1-year post-injection. Importantly, delivery of SUMF1 through cerebral spinal fluid at 7 days of age alleviates MSD symptoms. The treated mice show wide distribution of the SUMF1 gene, no signs of toxicity or neuropathy, improved vision and cardiac function, and no behavioral deficits. One-year post treatment, tissues show increased sulfatase activity, indicating functional SUMF1. Further, a GLP toxicology study conducted in rats demonstrates favorable overall safety of this approach.

CONCLUSIONS: These preclinical studies highlight the potential of our AAV9/SUMF1 vector, the design of which is directly translatable for clinical use, as a gene replacement therapy for MSD patients.

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