> Publications > Preclinical use of a clinically-relevant scAAV9/SUMF1 vector for the treatment of multiple sulfatase deficiency

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March 11, 2025 • ✎ STRIA TECH

Preclinical use of a clinically-relevant scAAV9/SUMF1 vector for the treatment of multiple sulfatase deficiency

Topics:

Blindness

Gene Therapy

Maintaining and Restoring Vision

Rare and Inherited CNS and Eye Disorders

Rare Disease

Retinal Degeneration

Publication

Communications Medicine (Jan 27, 2025) Preclinical use of a clinically-relevant scAAV9/SUMF1 vector for the treatment of multiple sulfatase deficiency

Presa M, Bailey RM, Ray S, Bailey L, Tata S, Murphy T, Piec PA, Combs H, Gray SJ, Lutz C

DOI: 10.1038/s43856-025-00734-9 >>

Journal Club

Multiple Sulfatase Deficiency (MSD) is a rare genetic disorder caused by mutations in the SUMF1 gene, leading to severe problems with the brain and other organs in children. Currently, there is no available treatment. This study explores a potential gene therapy in a mouse model of MSD in which the deficient Sumf1 gene is replaced with the normal gene. Treatment of newborn mice extended their lifespan up to one year, while treating 7-day-old mice alleviated MSD symptoms. The therapy improved vision, as assessed with the OptoDrum, and heart function, and increased sulfatase activity without toxicity or behavioral deficits. A safety study in rats yielded promising results, suggesting potential clinical application for MSD patients.

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.