Huntington's disease is a progressive neurodegenerative disease caused by an abnormally expanded (>36) CAG repeat within the ITI5 gene encoding a widely expressed 349‐kd protein, huntingtin. The medium spiny neurons of the caudate preferentially degenerate in Huntington's disease, with the presence of neuronal intranuclear inclusions. Excitotoxicity is thought to be important in the pathogenesis of Huntington's disease; the recently described mitochondrial respiratory chain and aconitase defects in Huntington's disease brain are consistent with this hypothesis. A transgenic mouse model (R6/2) of Huntington's disease develops a movement disorder, muscle wasting, and premature death at about 14 to 16 weeks. Selective neuronal death in these mice is not seen until 14 weeks. Biochemical analysis of R6/2 mouse brain at 12 weeks demonstrated a significant reduction in aconitase and mitochondrial complex IV activities in the striatum and a decrease in complex IV activity in the cerebral cortex. Increased immunostaining for inducible nitric oxide synthase and nitrotyrosine was seen in the transgenic mouse model but not control mouse brains. These results extend the parallels between Huntington's disease and the transgenic mouse model to biochemical events and suggest complex IV deficiency and elevated nitric oxide and superoxide radical generation precede neuronal death in the R6/2 mouse and contribute to pathogenesis. Ann Neurol 2000; 47:80–86

Huntington’s disease (HD) causes a combination of motor, cognitive, and psychiatric changes; of these, the behavioral and cognitive aspects cause the greatest disability and have the highest impact on quality of life. The most common and troublesome behavioral problems are depression, suicidal thinking, irritability, apathy, and perseveration. Apathy and perseveration become more common as the disease progresses and correlate with other markers of disease progression, including cognitive impairment, whereas mood changes do not. The most prominent cognitive changes are psychomotor slowing and problems in executive skills and memory. Emotional processing and odor recognition difficulties also occur early. Simple psychomotor measures provide sensitive markers of change, even in premanifest HD, and therefore are crucial in evaluating efficacy of therapeutic interventions. The causes of problem behaviors in HD are complex and reflect an interaction of biologic, social, and environmental factors.

BackgroundSiena Biotech SpA is developing selisistat (SEN0014196) as a potentially disease-modifying therapy for HD. Selsistat is a potent and selective SirT1 inhibitor (IC50 98 nM) that has shown benefit across a range of preclinical models for HD, from cells and neurons transfected with mutant huntingtin to transgenic Drosophila and R6/2 mice. The compound has shown to be safe and well tolerated in healthy volunteers and has a favourable pharmacokinetic profile.AimThe current study was designed to provide biophase samples for analysis of a series of potential target engagement and disease-modification read-outs, helping to establish a proof-of-principle and aid in dose selection for future safety and efficacy studies.MethodsA total of 63 HD patients with a wide range of CAG repeats and disease burden scores were screened across six sites in Germany (Bochum, Ulm), Poland (Krakow, Warsaw) and the UK (London, Manchester). Patients were randomised to receive either 10 or 100 mg of selisistat or placebo for 2 weeks. Safety data collected included vital signs, ECGs, clinical laboratory parameters and type and frequency of adverse events. Clinical assessments included UHDRS and a cognitive battery. Serial blood sampling for pharmacokinetics and pharmacodynamics was performed on days 1 and 14 and at follow-up after a washout phase of 14 days.Results and ConclusionsA total of 55 patients completed the treatment as per protocol; there were four screening failures and four patients withdrew consent. No Serious Adverse Events were reported and no patient withdrew from the study as a result of an adverse event. We will present full data on safety, tolerability, pharmacokinetics and clinical assessments, while pharmacodynamic data will be reported elsewhere.

BackgroundResearch into Huntington's disease (HD) has revealed white-matter loss in individuals more than 10 years prior to predicted disease onset, focused around the striatum, corpus callosum (CC) and posterior white-matter tracts. Degeneration of the CC is of interest since it provides interhemispheric connections to cortical areas known to be affected in HD.AimsThis study aims to investigate the utility of volumetric measurements of the CC in HD using a novel segmentation technique, multiple time-points and a large well-characterised cohort. Structure-function relationship in the CC will also be explored.MethodsVolumetric 3T MRI from controls, premanifest gene carriers and early HD subjects enrolled in the TRACK-HD study will be analysed at baseline and 24 months. The CC will be delineated using a semi-automated segmentation protocol. Differences in baseline volumes and atrophy rates between groups will be examined, as well as correlations between volume loss and clinical impairment.ResultsPreliminary analysis of a subset of subjects indicates that early HD subjects have reduced CC volume compared with controls and premanifest subjects (p<0.001). Increased longitudinal CC volume change was found in early HD subjects, compared with controls (p<0.001). Interestingly there was significant difference in longitudinal change between controls and premanifest subjects close to disease onset (p<0.05). This work will be extended to include multi-site data and correlations between atrophy and clinical and cognitive decline.ConclusionsMeasurement of CC atrophy may have potential as an imaging biomarker for HD and may prove useful for exploring interhemispheric structure-function relationships.FundingHelen Crawford is supported by the CHDI Foundation, a not for profit organisation dedicated to finding treatments for HD.