Keywords

Snyder-Robinson syndrome, novel spermine Prodrug, polyamine deficiency, X-linked disorder, SmsG56S mouse model

Abstract

Snyder-Robinson syndrome (SRS) is an X-linked neurodegenerative disorder affecting males. The disease appears early in childhood with symptoms like bone abnormalities, reduced muscle mass, and mobility issues. It results from disrupted polyamine biosynthesis, which is due to a mutation in spermine synthase (Sms). This causes an abnormally elevated Spermidine: Spermine ratios. There is no approved SRS treatment, rather only management of symptoms. A genetic mouse model for the SmsG56S mutation found in some SRS patients was characterized, and a novel spermine Prodrug treatment was tested. The hypothesis is that male SmsG56S mutant mice exhibit polyamine dysregulation and SRS traits, while Prodrug intervention may rebalance abnormal ratios and facilitate a normalized phenotype. Mice were phenotyped in pure C57BL/6J, mixed C3H, and backcrossed C57BL/6J x C3H backgrounds. Lethality of the mutation, especially in C57BL/6J mice, was an obstacle. Viable mutant mice exhibited reduced body weight, typically smaller size, and lower bone densities compared to age-matched wild-type mice. Prodrug treatment was performed using different dosing strategies and in all backgrounds. Upon histological examination, testes and bone exhibited subtle defects in affected mutant male mice, while no detectable differences were found in skeletal muscle, liver, or kidney compared to wild-type mice. Acute prodrug treatment using oral gavage 5 times per week over 2 weeks was found to rebalance the Spermidine: Spermine ratio. Repeated efforts to dose Prodrug over a longer 6-8 week duration in mice required lower intraperitoneal doses but outcomes may have been moderated by the mice background. Overall, the SmsG56S phenotype in the testes and bone are consistent with other mutant Sms models, although C57BL/6J mice seemed to be more sensitive to the SmsG56S mutation. Further testing of Prodrug is needed, including in younger mice and for a longer duration of treatment, to evaluate Prodrug effectiveness in improving traits in SmsG56S mice.

Completion Date

2023

Semester

Fall

Committee Chair

Altomare, Deborah

Degree

Master of Science (M.S.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Degree Program

Biotechnology

Format

application/pdf

Identifier

DP0028069

URL

https://purls.library.ucf.edu/go/DP0028069

Language

English

Release Date

December 2028

Length of Campus-only Access

5 years

Access Status

Masters Thesis (Campus-only Access)

Campus Location

Health Sciences Campus

Download

Restricted to the UCF community until December 2028; it will then be open access.

Share

COinS