Viability, specificity and yields of clinical grade primary and expanded human fetal cells for neural transplantation

Lead Research Organisation: Cardiff University
Department Name: Research and Commercial Division

Abstract

The MRC has sponsored a multicentre clinical trial on the safety and fesibility of fetal neural tissue transplantation in a severe progressive degenerative disease of the brain, Huntington s disease. However, this trial has been suspended after completion of the first 5 transplants because of the implementation of new EU regulations that require pharmaceutical grade handling of any cells or tissues used in patients. Although the UK trial had fully assessed the safety of the cells, we could not comply with the very stringent environmental control conditions required for accreditation. We have therefore undertaken a full rebuild of the laboratories to comply with the new regulations. In the present grant, we will undertake the detailed studies required to validate new laboratory procedures for cell preparation and expansion in cell culture and confirm the efficacy of the cells in animal models. This will allow us to complete the suspended HD trial, and to extend the multicentre UK cell transplant programme to trials in Parkinson s as well as Huntington s disease.

Technical Summary

The MRC-sponsored multicentre UK pilot trial on the safety and fesibility of fetal neural tissue transplantation in Huntington s disease is currently suspended following introduction of the EU Cells and Tissue directive. We are just completing conversion of a small GMP laboratory in Cardiff University for handling of clinical-grade primary and short-term expanded fetal neural progenitor cells for application in neurodegenerative disease. This application is to undertake the translational studies required to validate cell preparation and expansion protocols under GMP, both to allow us to complete the suspended HD trial, and to define improved cell preparations for subsequent multicentre UK trials in both Parkinson s and Huntington s diseases.

Publications

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Dunnett SB (2011) Cell-based treatments for huntington's disease. in International review of neurobiology

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Dunnett SB (2011) Clinical translation of cell transplantation in the brain. in Current opinion in organ transplantation

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Döbrössy M (2010) Neurorehabilitation with neural transplantation. in Neurorehabilitation and neural repair

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Kelly CM (2009) Medium spiny neurons for transplantation in Huntington's disease. in Biochemical Society transactions

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Orth M (2011) Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY. in Journal of neurology, neurosurgery, and psychiatry

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Quarrell OW (2012) Discrepancies in reporting the CAG repeat lengths for Huntington's disease. in European journal of human genetics : EJHG

 
Description Citations in clinical guidelines and reviews
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical reviews
Impact we contribute to ongoing debate and updating of guidelines on ethical sourcing of human fetal tissues for research and clinical cell transplantation.
 
Description GTAC
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact development of national ethical and regulatory guidelines
 
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 Cells
Geographic Reach National 
Policy Influence Type Participation in advisory committee
Impact I participate in the MRC UK Stem Cell Bank users group and contribute regularly to the policy discussions at head office on stem cell strategy and funding.
 
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
 
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 mTOPs 
Description Validation of alternative protocols for consented collection of human fetal tissue 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Resolves the outstanding block on limited tissue availability to allow multiple international research and clinical trials to resume. 
 
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 A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 10-15 presentations to HDA and PDS patient groups. I present regular medical and lay seminars around the country and internationally. I am afraid I am unable to list all the individual presentations.

academic, medical and patient contacts
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description 10-15 presentations to HDA and PDS patient groups. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact 10-15 presentations to HDA and PDS patient groups. 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 10-15 presentations to HDA and PDS patient groups. 
Form Of Engagement Activity A talk or presentation
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 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 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
 
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
Geographic Reach International
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