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The molecular determinant of IGF-1(Mecasermin)action in Rett Syndrome Patients
SHOVLIN, STEPHEN
Abstract This is a preliminary investigation of effects of insulin-like growth factor-1 (IGF-1) treatment on differential gene expression (DGE) of whole blood samples from Rett syndrome (RTT) patients. Samples were obtained from two independent open label clinical trials testing the safety and efficacy of recombinant human IGF-1 (mecasermin). We used patient matched samples to compare DGE for different time intervals across these trials. Due to heterogeneic design the only time interval that could be compared across the studies was the untreated samples. Our initial findings showed a clear down regulation of two genes that encode core subunits in the mitochondrial complex enzymes after treatment with mecasermin. Mitochondrial dysfunctions have been shown in RTT patients in the past and recent lines of evidence suggests that mitochondrial dysfunction causes increased oxidative stress in RTT. We also found a number of immune response functioning genes to be differentially expressed, including genes related to antigen presenting cells and dendritic cells. Immune responses have been identified in RTT, including autoimmune inflammation and glial cell activity. Our analysis identified a set of significantly differentiated genes that were found in untreated RTT patient blood samples that showed clinical improvements when treated relative to those patients without improvements. These genes warrant further assessment to analyse as potential blood biomarkers for positively responding RTT patients treated with mecasermin. As a clinical tool blood biomarkers may aid clinicians in treatment of RTT in the future. Considering the variability of mecasermin as a treatment, blood biomarkers for RTT may provide a better criteria for inclusion in clinical trials or guide treatment options. Despite the need for further validation of these genes S100A8 and S100A12 in particular have been identified as biomarkers in other neurological conditions including stroke and traumatic brain injury. In summary this analysis revealed that ribonucleic acid (RNA) from extracted whole blood was of sufficient quality for further application in high-throughput sequencing. It also provided a number of targets for further investigation in their potential roles in the RTT molecular mechanism.
Keyword(s): Rett syndrome; IGF-1; Mecasermin; Differential Gene Expression
Publication Date:
2018
Type: Master thesis (research)
Peer-Reviewed: Yes
Institution: Trinity College Dublin
Citation(s): SHOVLIN, STEPHEN, The molecular determinant of IGF-1(Mecasermin)action in Rett Syndrome Patients, Trinity College Dublin.School of Medicine, 2018
Publisher(s): Trinity College Dublin. School of Medicine. Discipline of Psychiatry
Supervisor(s): Tropea, Daniela
First Indexed: 2018-12-02 06:12:16 Last Updated: 2018-12-02 06:12:16