Core Concepts
Difluoromethylornithine (DFMO) can effectively rebalance the aberrant spermidine-to-spermine ratio in Snyder-Robinson syndrome by reducing spermidine biosynthesis and enhancing spermine production through induction of S-adenosylmethionine decarboxylase.
Abstract
Snyder-Robinson Syndrome (SRS) is a rare, recessive X-linked intellectual disability disorder caused by mutations in the spermine synthase (SMS) gene. SRS is characterized by an accumulation of spermidine and reduced spermine levels, leading to an exaggerated spermidine-to-spermine ratio.
The authors investigated the use of 2-difluoromethylornithine (DFMO), an FDA-approved inhibitor of polyamine biosynthesis, as a potential treatment strategy for SRS. Key findings:
DFMO treatment reduced the elevated spermidine levels and increased spermine concentrations in SRS patient-derived cell lines, effectively restoring the spermidine-to-spermine ratio to normal levels.
The mechanism of action involves DFMO-induced upregulation of S-adenosylmethionine decarboxylase (AMD1) activity, which increases the availability of the aminopropyl donor required for spermine synthesis by the hypomorphic SMS enzyme variants.
SRS cell lines with hypomorphic SMS mutations exhibited increased resistance to the growth-inhibitory effects of DFMO compared to wild-type cells, but this could be overcome by co-treatment with exogenous spermine or a spermine mimetic.
In a Drosophila model of SRS, adding DFMO to the feed extended the shortened lifespan in a dose-dependent manner, demonstrating the potential for in vivo efficacy.
These results support the further clinical development of DFMO as a targeted therapy for Snyder-Robinson syndrome, as it addresses the underlying biochemical imbalance driving the disease pathology.
Stats
DFMO treatment reduced the SPD/SPM ratio in SRS patient-derived lymphoblastoid and fibroblast cell lines to levels observed in cells with wild-type SMS.
DFMO treatment induced a 2-3 fold increase in AMD1 activity and intracellular dcSAM levels in SRS cell lines.
Hypomorphic SRS cell lines exhibited 10-27% maximum growth inhibition by DFMO, compared to 46% in wild-type cells.
DFMO extended the lifespan of male dSms-/- Drosophila in a dose-dependent manner, increasing median survival from 21 days to 35 days at the highest dose.
Quotes
"DFMO represents a potential treatment for SRS patients that targets the underlying biochemical aspects of the pathology."
"As DFMO is an FDA-approved drug with a history of safe administration, our results strongly support its further clinical development in the context of SRS."