By: Meredith A. Achey, BM
The June 2014 MDS Congress held in Stockholm, Sweden, focused on emerging and experimental therapies for movement disorders. Novel imaging techniques, biomarkers, and models for HD progression and promising cell-based therapies emerged as particular highlights of the Congress’s sessions on HD.
Presentations on new markers and models gave a glimpse into the future of HD clinical trial design. Two posters described the use of phosphodiesterase 10A (PDE-10A) PET ligands for imaging the pre-manifest HD brain (see HD Insights, Vol. 5). Dr. Flavia Niccolini and colleagues used a [11C]-labelled ligand to demonstrate differences in PDE-10A binding between premanifest HD gene carriers and controls. This dysregulation was posited as a potential measure of disease progression in premanifest HD.1 Dr. David Russell of the Institute for Neurodegenerative Diseases presented the results of their studies using [18F]MNI-659, another PDE-10A PET imaging ligand. This ligand appears to be an “excellent striatal imaging biomarker for early manifest HD.”2 A third imaging study, presented by Dr. Laurent Cleret de Langavant, described the use of an algorithm called SPHARM3 to identify HD-related changes in striatal nuclei. SPHARM identified changes in the striatum more effectively than Freesurfer or voxel-based morphometry analysis.4 Dr. Charles Venuto presented a mathematical model of HD progression developed using data from the Care-HD study. Decline in total functional capacity (TFC) could be fitted to a bounded linear model, providing a valuable predictive tool for future trials.5
Ongoing clinical trials were also highlighted at the Congress. A session entitled “An update on Huntington’s disease,” chaired by Drs. Joachim Ferreira and Sarah Tabrizi, featured presentations on the importance of understanding the neurophysiology of HD when designing HD trials; biomarkers and other objective measures; and a look at ongoing studies. Dr. Bernhard Landwehrmeyer presented a poster on the PRIDE-HD study, a recently begun randomized, controlled trial testing a larger dose of pridopidine than prior studies to attempt to demonstrate a more significant signal of TFC improvement than seen in the MermaiHD and HART studies (see HD Insights, Vol. 4).6 Dr. Anne-Catherine Bachoud-Lévi reviewed the possibilities and pitfalls of stem cell therapy for HD during a session on improving clinical translation of stem cell therapy for neurodegenerative disease. She described the disappointing and highly variable results of pilot studies conducted since 2000, and her work to improve translation of stem cell therapy for HD.
Another session explored HD as a model condition for novel gene silencing approaches. Dr. Blair Levitt described attempts to create an allele-specific silencing approach that will allow selective silencing of mutant huntingtin (mHTT) while enabling continued expression of wild-type huntingtin (HTT), using antisense oligonucleotides. This approach down-regulates mHTT and up-regulates HTT, resulting in lasting neurological benefit and symptomatic improvement in mouse models (see HD Insights, Vol. 3). Dr. Nicole Déglon highlighted another approach using small interfering RNA (siRNA) to target messenger RNA (mRNA) prior to translation. Her lab currently focuses on several issues raised by this approach, including whether gene silencing needs to be allele-specific; identifying the best viral vectors; exploring the long-term effects of expressing this RNA within cells; and how to optimize delivery to the human brain. All of the presenters discussed the need for better animal and cell-based models (see “Animal Models of HD,” p. 2, and “Meet the Investigator,” p. 4).
The Congress sessions on HD provided an excellent meeting place for clinicians, industry leaders, researchers, and students to exchange ideas and share knowledge. The future of HD research seems bright, with many exciting therapies on the horizon.
1 Niccolini F, Reis Marques T, Haider S, Muhlert N, et al. Brain phosphodiesterase 10A (PDE-10A) density in early premanifest HD gene carriers [abstract]. Mov Disord. 2014;29 Suppl 1:575. Available at: mdsabstracts.com/abstract.asp?MeetingID=801&id=111563&meeting=MDS062014.
2 Russell DS, Barret O, Jennings DL, Friedman JH, et al.[18F]MNI-659 and PET as an imaging biomarker of PDE10A for longitudinal studies of Huntington’s disease (HD) [abstract]. Mov Disord. 2014;29 Suppl 1:583. Available at: mdsabstracts.com/abstract.asp?=MeetingID=801&id=111571&meeting=MDS062014
4 Cleret de Langavant L, Nazir M, Gaura V, Lavisse S, et al. Longitudinal changes in volume and shape of striatal nuclei in manifest Huntington’s disease [abstract]. Mov Disord. 2014;29 Suppl 1:554. Available at: mdsabstracts.com/abstract.asp?MeetingID=801&id=111542&meeting=MDS062014
5 Venuto CS, Dorsey ER, Kieburtz KD. Huntington’s disease progression model of total functional capacity scores [abstract]. Mov Disord. 2014;29 Suppl 1:592. Available at: mdsabstracts.com/abstract.asp?MeetingID=801&id=111580&meeting=MDS062014?
6 Landwehrmeyer GB, Reilmann R, Kieburtz K, Eyal E, et al. Design of the dose-range finding (DRF), randomized, double-blind, placebo-controlled study, evaluating the safety and efficacy of pridopidine for symptomatic treatment in patients with Huntington’s disease [abstract]. Mov Disord. 2014;29 Suppl 1:571. Available at: mdsabstracts.com/abstract.aspMeetingID=801&id=111559&meeting=MDS062014