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.
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by Stewart,T. R... a las www.biorxiv.org 03-30-2023
https://www.biorxiv.org/content/10.1101/2023.03.30.534977v2Consultas más profundas