Aims Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial... Show moreAims Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. Toxic accumulation of misfolded mutant huntingtin protein induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. We evaluated the safety, pharmacokinetics and pharmacodynamics of SBT-020, a novel compound to improve mitochondrial function, in a 2-part study in early stage HD patients.Methods Part 1 consisted of 7-day multiple ascending dose study to select the highest tolerable dose for Part 2, a 28-day multiple dose study. Mitochondrial function was measured in the visual cortex and calf muscle, using phosphorous magnetic resonance spectroscopy, and in circulating peripheral blood mononuclear cells.Results Treatment-emergent adverse events were mild and more present in the SBT-020 group. Injection site reactions occurred in 91% in Part 1 and 97% in Part 2. Mitochondrial function in calf muscle, peripheral blood mononuclear cells or visual cortex was not changed overall due to treatment with SBT-020. In a posthoc analysis, patients with a higher degree of mitochondrial dysfunction (below the median [ increment psi(m) < 3412 and tau PCr > 42.5 s]) showed more improvement than patients with a relatively lower level of mitochondrial dysfunction.Conclusion SBT-020 was safe at all doses, but no significant differences in any of the pharmacodynamic measurements between the treatment groups and placebo group could be demonstrated. The data suggest that the better than expected mitochondrial function in our patient population at baseline might explain the lack of effect of SBT-020. Show less
Background: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces... Show moreBackground: Huntington's disease (HD) is a neurodegenerative disease with cognitive, motor and psychiatric symptoms. A toxic accumulation of misfolded mutant huntingtin protein (Htt) induces mitochondrial dysfunction, leading to a bioenergetic insufficiency in neuronal and muscle cells. Improving mitochondrial function has been proposed as an opportunity to treat HD, but it is not known how mitochondrial function in different tissues relates.Objective: We explored associations between central and peripheral mitochondrial function in a group of mild to moderate staged HD patients.Methods: We used phosphorous magnetic resonance spectroscopy (31P-MRS) to measure mitochondrial function in vivo in the calf muscle (peripheral) and the bio-energetic state in the visual cortex (central). Mitochondrial function was also assessed ex vivo in circulating peripheral blood mononuclear cells (PBMCs). Clinical function was determined by the Unified Huntington's Disease Rating Scale (UHDRS) total motor score. Pearson correlation coefficients were computed to assess the correlation between the different variables.Results: We included 23 manifest HD patients for analysis. There was no significant correlation between central bio-energetics and peripheral mitochondrial function. Central mitochondrial function at rest correlated significantly to the UHDRS total motor score (R = -0.45 and -0.48), which increased in a subgroup with the largest number of CAG repeats.Discussion: We did not observe a correlation between peripheral and central mitochondrial function. Central, but not peripheral, mitochondrial function correlated to clinical function. Muscle mitochondrial function is a promising biomarker to evaluate disease-modifying compounds that improve mitochondrial function, but Huntington researchers should use central mitochondrial function to demonstrate proof-of-pharmacology of disease-modifying compounds. Show less
Huntington’s disease (HD) is a progressive neurodegenerative disorder, which is clinically characterized by motor impairment, cognitive decline, and behavioral symptoms. In this thesis we have... Show moreHuntington’s disease (HD) is a progressive neurodegenerative disorder, which is clinically characterized by motor impairment, cognitive decline, and behavioral symptoms. In this thesis we have investigated measurement properties of the Unified Huntington’s Disease Rating Scale (UHDRS) and the Unified Huntington’s Disease Rating Scale-For Advanced Patients (UHDRS-FAP). These assessment scales have been developed to monitor the presence, severity, and progression of symptoms systematically over time. To measure change of symptoms accurately, reliable and valid scales are essential. Poor interrater reliability was found for all dystonia items of the UHDRS. We concluded that the rating of these items is difficult to interpret, probably as a consequence of the subjective nature of the response options. Future studies are required to explore how the dystonia items can be improved. We have also demonstrated that the motor and cognitive scores of the UHDRS-FAP deteriorated in patients with advanced HD during six months follow-up, while the motor and cognitive scores of the UHDRS did not show any change. This finding suggests that the UHDRS-FAP can detect disease progression in late stage HD, contrary to the UHDRS. Therefore, we recommended the use of the UHDRS-FAP motor and cognitive scores in long-term care facilities to optimize HD care. Show less
