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Title: Early phase disease modification trials with selisistat & optical coherence tomography as a biomarker in Huntington's disease
Author: Haider, Salman
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Huntington's disease (HD) is a monogenic neurodegenerative disorder with no known cure. Selisistat is a novel, highly potent Sirt1 inhibitor with supportive pre-clinical data. Facilitation of autophagy and amelioration of transcriptional dysregulation are proposed as mechanisms of action. A first in disease Phase 1B study showed safety and tolerability. The peripheral immune dysfunction in HD could be modulated by Sirtuins which have both pro and anti-inflammatory activities. However selisistat did not alter the cytokine profile in this study. Phase 2 data over a longer duration was also well tolerated however potential hepatotoxicity is a concern. Sub-analysis of clinical assessments did not reveal any significant effect. Confirmation of proposed mechanisms of action is lacking and no Phase III studies are planned. Significant clinical heterogeneity exists in HD phenotypes which must reflect differing neuronal susceptibilities. A novel total motor score based sub-division of HD phenotypes failed to demonstrate any changes in a whole brain voxel-based morphometry (VBM) analysis. Clinical assessment alone lacks sensitivity over shorter time-spans in HD, and thus reliable, tolerable and sensitive biomarkers are required. Optical coherence tomography is a potential novel biomarker. The hypothesis that neuroretinal structures may be surrogate marker of intracranial disease was tested in a pilot biomarker study, the first of its kind in HD. Evidence of a statistically significant (p < 0.01) reduction in macular volume in HD subjects versus age and sex-matched controls is seen. No change in RFNL measures was seen. A correlation with increasing disease severity on ordinal regression was also noted. No correlation of macular volume and RNFL thickness with change in whole brain and caudate volumes. Furthermore, OCT was well tolerated by the majority of participants. Retinal abnormalities in HD have been confirmed in three subsequent independent OCT studies.
Supervisor: Tabrizi, S. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available