Snyder-Robinson Syndrome (SRS) is caused by mutations in the
spermine synthase (SMS) gene, the
enzyme product of which converts the
polyamine spermidine into
spermine. Affecting primarily males, common manifestations of SRS include
intellectual disability,
osteoporosis, hypotonic musculature, and
seizures, along with other more variable symptoms. Currently, medical management focuses on treating these symptoms without addressing the underlying molecular cause of the disease. Reduced SMS catalytic activity in cells of SRS patients causes the accumulation of
spermidine, while
spermine levels are reduced. The resulting exaggeration in
spermidine-to-
spermine ratio is a biochemical hallmark of SRS that tends to correlate with symptom severity in the patient. Our studies aim to pharmacologically manipulate
polyamine metabolism to correct this
polyamine imbalance and investigate the potential of this approach as a therapeutic strategy for affected individuals. Here we report the use of
difluoromethylornithine (DFMO;
eflornithine), an FDA-approved inhibitor of
polyamine biosynthesis, in re-establishing normal
spermidine-to-
spermine ratios in SRS patient cells. Through mechanistic studies, we demonstrate that, while reducing
spermidine biosynthesis, DFMO also stimulates the conversion of existing
spermidine into
spermine in cell lines with hypomorphic variants of SMS. Further, DFMO treatment induces a compensatory uptake of exogenous
polyamines, including
spermine and
spermine mimetics, cooperatively reducing
spermidine and increasing
spermine levels. In a Drosophila SRS model characterized by reduced lifespan, adding DFMO to the feed extended lifespan. As nearly all known SRS patient mutations are hypomorphic, these studies form a foundation for future translational studies with significant therapeutic potential.