Affiliation:
1. Sidney Kimmel Comprehensive Cancer Center Johns Hopkins School of Medicine Baltimore MD USA
2. Engelhardt Institute of Molecular Biology Russian Academy of Sciences Moscow Russia
3. Department of Molecular and Cellular Pharmacology University of Miami Miller School of Medicine Miami FL USA
Abstract
AbstractSnyder–Robinson syndrome (SRS) results from mutations in spermine synthase (SMS), which converts the polyamine spermidine into spermine. Affecting primarily males, common manifestations of SRS include intellectual disability, osteoporosis, hypotonia, and seizures. Symptom management is the only treatment. Reduced SMS activity causes spermidine accumulation while spermine levels are reduced. The resulting exaggerated spermidine:spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity. Our studies aim to pharmacologically manipulate polyamine metabolism to correct this imbalance as a therapeutic strategy for SRS. Here we report the repurposing of 2‐difluoromethylornithine (DFMO), an FDA‐approved inhibitor of polyamine biosynthesis, in rebalancing spermidine:spermine ratios in SRS patient cells. Mechanistic in vitro studies demonstrate that, while reducing spermidine biosynthesis, DFMO also stimulates the conversion of spermidine into spermine in hypomorphic SMS cells and induces uptake of exogenous spermine, altogether reducing the aberrant ratios. In a Drosophila SRS model characterized by reduced lifespan, DFMO improves longevity. As nearly all SRS patient mutations are hypomorphic, these studies form a strong foundation for translational studies with significant therapeutic potential.
Funder
Chan Zuckerberg Initiative
Commonwealth Foundation for Cancer Research Foundation
National Institutes of Health
National Institute of Child Health and Human Development
National Cancer Institute
Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania
Russian Science Foundation
Publisher
Springer Science and Business Media LLC
Cited by
1 articles.
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