Human pluripotent stem cell differentiation, safety, and preparation for therapeutic transplantation in HD
By: Christiane Dascher-Nadel, Anne Rosser, Stephen Dunnett
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:
- 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.
- 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.
- 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.
- 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.
- 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
Professor Stephen Dunnett (Deputy Coordinator) is the co-director with Professor Rosser of the Brain Repair Group in the Cardiff University School of Biosciences. He has internationally recognized expertise in animal models of PD and HD, development of novel tests for analysis of cognitive and motor function in these models, systematic functional assessment of cell transplantation, and analysis of the mechanisms of functional recovery, as the basis for translational and preclinical development of methods for cell therapy in human neurodegeneration.
Professor Anne Rosser (Coordinator) heads the South Wales clinical neurology service for HD as consultant neurologist. She chairs the UK HD research network and the UK arm of the European HD Network, and serves on the Scientific Advisory Committee of the global project Enroll-HD. As a scientist, Professor Rosser co-directs the Brain Repair Group in the Cardiff University School of Biosciences with particular responsibility for neural stem cell studies, and is the clinical director of the Cardiff Foetal Tissue Bank.
Profs. Anne Rosser and Stephen Dunnett, leaders of the Repair-HD research network, comment: “Repair-HD brings to fruition 35 years of development, from the very first studies of cell transplantation in animal models of HD to the implementation of all the tools… needed to bring a practical, effective and efficient stem cell therapy into the clinic to benefit patients and their families with this devastating disease. It is a privilege to be working with such a great team of colleagues, each of whom is an international leader in their respective area of expertise. We are also indebted to HD families who have patiently and generously contributed their time to this work, and to the funders and lay associations who have supported it over many years.”
More information on the project, as well as a list of participating sites and investigators, can be found at repair-hd.edu.
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.
Acknowledgements: Repair-HD has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n°602245.