Basic science and preclinical development of cell transplantation for basal ganglia disorders

Lead Research Organisation: Cardiff University
Department Name: School of Biosciences

Abstract

This programme provides the infrastructure, models and expertise to deliver human neurons (primary fetal, expanded fetal and stem cells) for use in clinical trials of cell transplantation in neurodegenerative disease. Specifically, in the Cardiff Brain Repair Group, we have established an ethically sourced supply and quality-controlled production of human embryonic brain cells for transplantation in both Huntington?s and Parkinson?s disease. We have also established the cell culture and animal model test systems to determine the precise preparation and implantation protocols that are most likely to lead to functional benefit (i.e. recovery in both motor and cognitive symptoms) in trials set to commence/resume in both PD and HD in 2011-12. Moreover, the UK is a world leader in fundamental stem cell biology which are likely to yield the next generation of pluripotential cells for therapy in a wide range of diseases; however, if we are to reap the benefit from the signficant government support and public investment in this area, we need to have in place the infrastructure to test the functional efficacy of new stem cell-based preparations, to prepare cells to clinical-grade quality standards, and to undertake clinical trials with skilled surgery and fully validated assessment protocols in well characterised patients. Thus, alongside the present establishment of proof-of concept with primary fetal cells, this programme grant underpins the expertise and infrastructure within the Cardiff Brain Repair Group that is required to take new stem cell therapies rapidly into clinical trial as soon as they become available. Without such proactive preparation and support, the UKs intellectual lead in fundamental stem cell biology is likely to be squandered to implementation and commercialisation elsewhere.

Technical Summary

The UK is taking an international lead in developing stem cells for cell-based therapy applicable to a broad range of diseases. The purpose of this programme application is to address the translational gap to deliver clinical-grade human neuronal cells from primary, expanded and pluripotent origins for transplantation in clinical trials of human neurodegenerative disease. We complement other stem cell programmes in establishing and maintaining the infrastructure for ethically-sourced, safe, quality-assured processing of cells of clinical grade under regulatory licence, alongside establishing relevant patient cohorts, assessment programmes and clinical trial expertise, without which advances in basic cell biology cannot progress to human use or clinical trial. A major component of this programme is to develop and refine the animal models to evaluate alternative sources of cells with predictive validity of likely functional efficacy in man. Immediate applications are set to commence using primary fetal cells in 2011-2012 in Huntingtons disease and Parkinsons disease, with subsequent applications in stoke, and using expanded fetal progenitors, pending the availability of clinical grade stem cells.

Publications

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Bowles KR (2012) Gene expression and behaviour in mouse models of HD. in Brain research bulletin

 
Description GTAC
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Appointed expert memeber (cell therapy) to GTAC, national research ethics committee for gene therapy and stem cell trials
 
Description GTAC
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact member of GTAC committee reviewing applications and developing policy on stem cell and gene therapy trials in the UK
 
Description MRC
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Targetted direction, policy and funding of UK stem cell research .
 
Description MRC stem cell
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact I participate in the MRC Stem Cell Bank User's group and participate regularly in MRC stem cell policy and funding strategy meetings at Head Office.
 
Description MRC stem cells
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact I participate in the MRC Stem Cell Bank User's group and participate regularly in MRC stem cell policy and funding strategy meetings at Head Office.
 
Description UKSCB SC
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact Appointed as academic member of the UK Stem Cell Bank Steering Committee
 
Description regular citations in clinical reviews and publications
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact influence on development of NECTAR and ASNTR guidelines
 
Description Brain Repair and Intracranial Neurotherapeutics - the Wales BRAIN Unit
Amount £800,000 (GBP)
Organisation Welsh Assembly 
Sector Public
Country United Kingdom
Start 04/2018 
End 03/2020
 
Description research contract
Amount £906,000 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2012 
End 12/2013
 
Title Cognitive assessment 
Description Novel operant tests for rats of executive cognitive function associated with frontal striatal systems in the rat 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact publications of new methods 
 
Title Human embryonic cells 
Description human fetal cells collected via licenced and approved tissue bank. we use neural tissues, other tissues available for research use to others subject to appropriate ethical consents 
Type Of Material Technology assay or reagent 
Provided To Others? Yes  
Impact eyes, kidney, liver, brain all used sporadically by others 
 
Title Mouse cognitive phenotyping 
Description Development of novel operant and maze test analyses for mice 
Type Of Material Data analysis technique 
Year Produced 2011 
Provided To Others? Yes  
Impact new collaborations 
 
Title comparative skilled reaching 
Description Comparative analysis of skilled motor tests relevant for translation between rodents and man 
Type Of Material Data analysis technique 
Year Produced 2011 
Provided To Others? Yes  
Impact Publication and New international collaborations 
 
Description EU FP& Repalces 
Organisation Sapienza University of Rome
Country Italy 
Sector Academic/University 
PI Contribution collaborative experiments
Collaborator Contribution collaborative experiments
Impact publications
Start Year 2008
 
Description EU FP7 NeuroStemCell 
Organisation University of Milan
Country Italy 
Sector Academic/University 
PI Contribution functional analysis of stem cell transplantation in PD and HD models
Collaborator Contribution supply of cells in collaborative experiments
Impact publications and research progress
Start Year 2009
 
Description EU FP7 Transeuro 
Organisation University of Cambridge
Department John van Geest Centre for Brain Repair
Country United Kingdom 
Sector Academic/University 
PI Contribution supply of cells and protocols
Collaborator Contribution collabortive experiments
Impact collaborative clinical trial
Start Year 2010
 
Description O&G/UHW 
Organisation University Hospital of Wales
Country United Kingdom 
Sector Hospitals 
PI Contribution Ongoing collaboration with O&G fundamental to our consented ethical collection of human fetal tissues. Processing, preparation, and validation in vitro and in vivo of cell and tissue viability and potential for functional repair
Collaborator Contribution Ongoing collaboration with O&G fundamental to our consented ethical collection of human fetal tissues.
Impact Recent major development in identification of mTOPs as new source of fetal tissues for research and therapy.
 
Title GMP grade human cells 
Description GMP processing of human cells Trials ready to commence. Funding expired and all initial applications rejected 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2012
Development Status Actively seeking support
Impact no impact as stalled due to funding hiatus 
 
Description 10-15 presentations to HDA and PDS patient groups. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact I present regular medical and lay seminars around the country and internationally. I am afraid I am unable to list all the individual presentations.

various
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description EHDN plenary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion with scientists, clinicians and also with patients. Has led to further invitations to speak at meetings.
Year(s) Of Engagement Activity 2016
 
Description Genetics road show 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Schools
Results and Impact Approximately 50 school pupils attended a talk about science, which included work related to stem cell biology and cell replacement therapy in Parkinson's and Huntington's. There was a linked discussion session in which pupils asked questions about the science and careers in science.

There has been feedback that some pupils were inspired to think further about a career in science and there has been a request to take the presentation to other schools in the region.
Year(s) Of Engagement Activity 2013
 
Description HD regional public engagement event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Discussion with patients and carers about pace and challenges of cell replacement therapy.
Year(s) Of Engagement Activity 2016
 
Description NECTAR 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion and development of research plans.
Year(s) Of Engagement Activity 2016
 
Description Plenary to Early Career Scientist day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Plenary talk to Early Career scientists, Bristol Sept 21st.
Year(s) Of Engagement Activity 2015
 
Description Presentation at stem cell meeting in Oxford 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Oxford stem cell meeting. Stimulated discussion which led to a change in ongoing experimental program.
Year(s) Of Engagement Activity 2016
 
Description Presentation to final year medical students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact approx 40 undergraduate and graduate medical students. Precipitated discussion which continued after the formal presentation. Have had follow-up enquiries from medical students asking to work in Brain Repair Group.
Year(s) Of Engagement Activity 2016
 
Description Public engagement seminar event for patients and carers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Event for patients with Huntington's disease and carers on the topic of activity as a therapy. Format: plenary talk by national patient advocate, international speaker on activity in HD, and then stands and posters to represent other areas of work going on in Cardiff.
Year(s) Of Engagement Activity 2013,2014
URL http://medicine.cf.ac.uk/news/charles-sabine-talk-recording/
 
Description Science of Me 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Presentations on brain repair during Brain Awareness Week in Cardiff

third mission
Year(s) Of Engagement Activity 2011
 
Description Swiss society neuroscience 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Discussion with postgraduate students/
Year(s) Of Engagement Activity 2017
 
Description Workshop trial design for cell therapy 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 2 day workshop on ethics and trial design for cell replacement therapies. Workshop led to report and publication being prepared.
Year(s) Of Engagement Activity 2016
 
Description results included in multiple public and academic lectures and seminars 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact results included in multiple public and academic lectures and seminars

various
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010