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European researchers are taking on the complex task of exploring cell replacement therapy in HD over the next four years, in a project called Repair-HD. Repair-HD brings together an innovative and unique combination of expertise from five academic research teams based in the United Kingdom, France and Italy, and two small-to-medium-size enterprises in the United Kingdom and Germany. Funded under the Seventh Framework Programme (FP7), the project aims to enable efficient translation of experimental stem cell therapies to preclinical work in small and large animal models, and readiness for clinical application. The project aims to establish all the components necessary to generate functional striatal medium spiny neurons from human pluripotent stem cells (Figure 1), and to bring them to 'first-in-man' clinical trials in HD. Figure 2 represents the interrelated work packages (WP) which will be undertaken as part of Repair-HD. The program has five principal objectives over the next four years: 1. Improve understanding of mechanisms of neuronal differentiation Repair-HD will investigate fundamental principles of fate determination and lineage selection for effective differentiation of human pluripotent stem cells from different sources through to authentic medium spiny neurons, with a high degree of reliability, stability and reproducibility, as required for clinical application. 2. Develop new objective clinical assessment tools The Core Assessment Program for Intracerebral Transplantation in Huntington's Disease is a well- established protocol for assessment of neural transplant patients, 1 but it fails to incorporate recent developments in test design, and lacks key clinical dimensions. Since the original test battery was developed, more focus has been placed on developing quantitative motor assessments; HD-specific quality of life measures; and improved neuropsychiatric measures. Repair-HD will evaluate and validate new assessment tools in language and social cognition, quality of life, and behavioral deficits using performance-based measures for longitudinal assessment of disease progression. 3. Improve health for HD patients HD has devastating effects on patients' health and quality of life. Cognitive deterioration, behavioral abnormalities and motor dysfunction all play a role. Even a modest improvement in function arising from Repair-HD could be significant to patients. Moreover, a disease-modifying treatment for HD would represent an example of a dementia being treated by regenerative medicine. 4. Create innovative tools for quality control Repair-HD will develop a specific set of tools for quality assessment of differentiated cells, and fully validate them in HD animal models to prepare them for clinical use. This will act as a template for the development of the full translational pathway, including all essential quality control measures for cell replacement therapy in other neurodegenerative conditions. 5. Reduce long-term healthcare costs HD and neurodegenerative diseases are associated with high economic burden. If transplantation of stem cell-derived medium spiny neurons is feasible and effective in HD, the technology should be readily transferable to other neurodegenerative conditions that have widespread economic and health impact. 2 Copyright © Huntington Study Group 2014. All rights reserved. By: Christiane Dascher-Nadel, Anne Rosser, Stephen Dunnett Repair-HD 1 Quinn N, Brown R, Craufurd D, et al. Core Assessment Program for Intracerebral Transplantation in Huntington's Disease (CAPIT-HD). Mov Disord. Mar 1996;11(2):143-150. 2 Kefalopoulou Z, Politis M, Piccini P, et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. Jan 2014;71(1):83-87. Human pluripotent stem cell differentiation, safety, and preparation for therapeutic transplantation in HD Figure 1. Medium spiny neurons derived from RC9 hES cells: Immunocytochemistry DARPP32 (red) CTIP2 (green). Image courtesy A. Perrier, Inserm U861 (I-Stem) Figure 2. Schematic representing the design of the Repair-HD study, including work packages (WP) which will combine to bring stem cell transplantation to Phase I trials H D I N S I G H T S HD Insights, Vol. 8 9