Pharmacologic modulation of the polyamine metabolic pathway to restore normal spermidine/spermine ratios and ameliorate symptoms in Snyder-Robinson Syndrome models
Awardee: Robert Casero
Co-PI: Tracy Murray Stewart
Institution: Johns Hopkins University
Award Amount: $68,840
Funding Period: February 1, 2021 - January 31, 2022
Summary:
Snyder-Robinson syndrome (SRS) is caused by mutation of the spermine synthase (SMS) gene that reduces the enzyme activity responsible for converting spermidine to spermine in the polyamine biosynthesis pathway. Cells of patients affected by SRS have very low levels of spermine, while spermidine levels are excessive, resulting in elevated spermidine/spermine ratios that tend to correlate with severity of disease. SRS symptoms commonly include intellectual disability, osteoporosis, low muscle mass, and seizures. There is no cure or treatment for SRS beyond symptom management. The goal of our research is to pharmacologically exploit inherent cellular polyamine control mechanisms to redistribute spermidine and spermine levels to more normal ratios. We have identified an established therapeutic with FDA-approval for other indications that has the potential to rebalance these abnormal polyamine pools in cell lines derived from SRS patients. This drug is orally bioavailable and has a proven safety record in human clinical trials, including those in children. Mechanistically, this drug is effective in reducing the biosynthesis of spermidine as well as stimulating the conversion of spermidine to spermine in patient cell lines with hypomorphic SMS activity. With the exception of a single patient, all others identified to date exhibit partial rather than complete loss of SMS function. Our continuing studies include elucidation of the specific mechanism-of-action of this drug in SRS patient cells, the potential for combination therapies with our previously described spermine mimetic, and investigation of the safety and efficacy of the drug in an SRS mouse model. By reducing the spermidine/spermine ratio observed in SRS patients, it is possible that syndrome-associated symptoms may be ameliorated. Therefore, this agent, as a monotherapy and in combination, holds promise for not only alleviating symptoms of SRS, but doing so through targeting the underlying mechanism of the disease.
Final Report Lay Summary:
Snyder-Robinson Syndrome (SRS) is an X-linked disability syndrome that primarily affects males and manifests as a range of debilitating pathologies including osteoporosis, hypotonia, seizures, cognitive impairment, and developmental delay. Symptom severity is variable among patients and appears to correlate with the degree of increase in the SPD/SPM ratio, reflecting the reduction in SMS activity caused by the specific mutation. According to the Snyder-Robinson Foundation, approximately 80 individuals have now been identified with SRS worldwide, a number likely to increase with expanded awareness and sequencing accessibility. There is currently no treatment or cure for SRS beyond symptom management, generaly including prevention of seizures and osteoporosis progression. The Casero/Murray Stewart laboratory first reported functional polyamine transport in SRS patient ce ls, a discovery that clarified early misconceptions and revealed potential treatment strategies using polyamine-related agents, the research focus of this award. Our preliminary and published studies resulting from this award indicate the potential to rebalance polyamine pools using these agents, including DFMO, in SRS patient ce ls and animals. These results represent the first potential treatment strategy aimed at correcting the fundamental biochemical cause of SRS.