NEURAL TRANSPLANTATION IN THE TREATMENT OF PATIENTS WITH PARKINSON’S DISEASE

Project Information

TRANSEURO

Grant agreement ID: 242003

Closed project

Start date 1 January 2010

End date 30 June 2016

Funded under

• Specific Programme "Cooperation": Health

Total cost € 16 142 794,19

EU contribution € 11 994 095,00

Coordinated by

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
United Kingdom

Final Report Summary - TRANSEURO (NEURAL TRANSPLANTATION IN THE TREATMENT OF PATIENTS WITH PARKINSON’S DISEASE)

Executive Summary:
Transeuro aims to demonstrate that replacement of dopaminergic cells in Parkinson’s disease
can be clinically efficacious in the absence of any troublesome off-state dyskinesias in patients with mild/moderate PD. The work performed in the Transeuro project has followed closely the aims of the original proposal.
We developed a fetal tissue dissection/preparation protocol that has been optimised throughout the project and has been applied in all centres. This protocol maximises cell survival within the transplant whilst minimising the risk of graft-induced dyskinesias and has been validated under full GMP conditions. We developed the hibernation media and established that 4 day hibernation does not significantly affect the survival of the cells. We also established that the serotonergic neuronal content within the graft does not seem to be detrimental for induction of graft induced dyskinesias when sufficient numbers of nigral dopaminergic cells are transplanted and survive.
As part of the first clinical trial, we developed the trial protocols and recruited 150 patients with the pre-defined desirable characteristics for neural grafting- that is younger onset, at an early stage of the disease and in the absence of significant levodopa induced dyskinesias, cognitive or affective deficits, or other significant medical illness. These patients have been entered into the clinical observational trial and have been regularly assessed with an extensive battery of tests for over 4 years. These follow ups include PET and MRI scans and the analysis of this data has led to several publications in key journals during this period, with more in preparation. A subset of these patients have been randomly selected into the transplant trial and offered a neural graft. Due to many unexpected problems the transplant trial has been significantly delayed, and to date 13 transplant procedures have been completed.
We also presented the first results from the ethical workpackage and based on this data, recommendations were made that should be taken into account when conducting clinical trials in PD.
We ran a predefined management structure to assure a smooth implementation of the research and training goals of the consortium and used several communication tools to support this. We paid particular attention to dissemination activities and successfully disseminated the major scientific advances to the scientific community, our trial participants, patients’ associations and charities, and the public. This has been done by oral and poster presentations during national and international conferences, patient newsletters, talks for patient support groups, organisation of open days, and participation in scientific outreach activities.

Project Context and Objectives:
The concept behind the Transeuro project is to develop an efficacious and safe treatment methodology for patients with Parkinson’s disease (PD) using fetal dopaminergic cell based treatments. One of the most effective reparative therapies in patients to date has been with allo-transplants of dopaminergic (DA) neuroblasts obtained from fetal ventral mesencephalic (VM) tissue, but this has failed to generate consistent benefits across all centres that have adopted this approach. Therefore the main objective of Transeuro is to develop a methodology that will translate into more consistently efficacious transplants with minimal side-effects.

The principal objectives of Transeuro include:

1) Showing that the consistency and efficacy of DA cell replacement in Parkinson’s disease can be improved by careful attention to tissue preparation and delivery, patient selection and immunosuppressive treatment. This will be done through a series of focused laboratory based experiments and pre-trial clinical studies, ahead of the new VM allograft trial in PD.

2) Showing that DA cell replacement can be clinically efficacious in the absence of any troublesome off-state dyskinesias in clinical trials of fetal ventral mesencephalic transplants in patients with mild/moderate PD.

3) Developing a protocol that can serve as a template for all future clinical trials in the cell therapy field including stem cell-based therapies and the ethical implications and ramifications of such work.

Project Results:
• The use of tissue from medical in addition to surgical terminations of pregnancy (mTOPs and sTOPs) was established and validated. We showed that the quality of the cell suspension obtained from mTOPs does not significantly differ from the ones obtained from sTOPs.
• A neuroprotective additive to the medium was defined, and the 2 batches were manufactured to GMP grade and supplied to the relevant centres involved in tissue preparation.
• A central database to collect, analyse and validate the fetal tissue preparation information from all groups was established. Data from all centres involved in the tissue preparation process was collected for the purposes of validation and optimization of the tissue processing.
• The Transeuro protocol for the pre-clinical handling of fetal tissue was established, validated, and approved. It was further refined and re-validated under full GMP conditions. Sets of SOPs were prepared, adapted to local GMP conditions and approved by partners.
• Dry runs were carried out in the GMP lab, following the SOP´s for the clinical trial.
• We showed that 4 day hibernation does not significantly affect the overall viability of cells in suspension, and TH/VM graft yields remain unchanged after 4 days of hibernation in comparison to fresh tissue.
• Longer hibernation periods (up to 8 days) were investigated, showing all viabilities remained above the threshold needed for clinical use, and confirming the previous findings that showed that hibernation of 1-4 days yield the best results.
• HTA approval was obtained.
• Dry runs were carried out from tissue collection to operating theatre.
• The microbial contamination protocol was validated.
• Further adjustments to the protocol resulted in a dramatic rise in TH yields, representing a near 6-fold increase in the yield of TH cell per embryo, representing a leap forward in terms of TH yields.
• The transportation of tissue between Cardiff and Cambridge was validated. Dry runs of SOP’s for collection, reception, processing, and storage of tissue in GMP facilities were carried out (incl. microbiology tests).
• The long-term (6 month) survival and functional recovery experiments initiated during the reporting periods 1 and 2 were completed and were published as part of an article in Cell Stem Cell
• Additional data on behaviour of embryonic neuronal cell suspensions, in metal and glass injection cannulae using a 0.25mm ID cannula was generated and a full analysis of the data was carried out.
• The tissue processing protocol was further refined following the start of the transplant procedures, with changes made to the packaging of the final cell preparation.
• Agreements for tissue transfer for clinical use between Cambridge, Cardiff and Lund were approved and implemented
• A battery of validated clinical assessment tools including novel measures of motor and cognitive function for PD patients’ clinical assessment and study structure was established, discussed and approved.
• The protocol for the functional imaging study of PD patients was discussed and accepted by all partners
• The PET and MRI scanning protocols were initiated and continued until the end of the project. This included baseline scans and follow up scans. Up till June 2016, a total of 188 PET were completed: 106 were conducted at first baseline, 78 at second baseline, and 4 at V3. To date a total 122 MRI scans were completed: 49 at baseline, 44 at the second visit and 29 at visit 3.
• Analysis of the PET and MRI data was initiated and is ongoing, leading to several publications in key journals.
• Preliminary analysis of resting state fMRI data has been completed with further analysis methods underway
• Region of interest analysis of the diffusion weighted imaging showed that mean diffusivity (extend of water diffusion) increased and fractional anisotropy (directionality of water diffusion) increased significantly over time on the substantia nigra.
• Analysis of the susceptibility weighted imaging showed significantly higher iron deposition in the patients compared to controls in several brain structures (caudate, putamen, pallidum and substantia nigra). In addition, patients with severe PD had significantly higher iron deposition in the substantia nigra compared to patients with moderate and mild PD.
• Our results indicate that in patients with ‘early’ PD, the ¹¹C-PE2I PET scan is more sensitive to nigro-striatal loss than the current ‘gold’ standard’ ¹⁸F-DOPA scan.
• Analysis of the serotonin transporter (SERT) to dopamine transporter (DAT) ratio is ongoing, but the preliminary results indicate that at baseline, patients without levodopa-induced dyskinesias (LID’s) display a significantly higher SERT to DAT ratio in the putamen compared to patients without LID’s.
• Serotonergic neuronal content within the graft seems not to be detrimental for GID induction when sufficient numbers of nigral dopaminergic cells are transplanted and survive.
• Storage of fetal tissue used for grafting limits its survival and changes its innervation pattern but has no apparent consequences on GID genesis.
• The extrastriatal dopamine system is also involved in the expression of L-DOPA-induced dyskinesia.
• GID seems to be primarily linked to the graft itself and not to the conditions in the host brain
(with the exception of the presence or not of pre-operative L-DOPA-induced dyskinesia).
• The Transeuro Trial Monitoring Committee (TMC) was established to provide advice to the investigators on all aspects of the trial based on their wide clinical expertise and experience.
• Trial Steering Committee (TSC) was established to provide overall supervision of the trial
• The first fetal ventral mesencephalic transplant trial in patients with early PD was defined and divided into two studies: Study 1 (observational trial) and study 2 (transplant trial).
• The study 1 protocol was submitted and approved by the Ethics Committees in all the clinical centres.
• The protocols and study documentation for the transplant trial was submitted and approved by ethics committees in Cambridge, ICL, UCL, Cardiff, Freiburg and Lund).
• The recruitment to the observational study closed when the target of 150 patients was reached across theTranseuro centres in Europe: Cambridge, Imperial College London, University College London, Cardiff, Lund, Paris and Freiburg.)
• The new Transeuro electronic case report form (eCRF) was designed and implemented
• Data monitoring visits were conducted
• Dry runs were completed in Lund and Cambridge in preparation for the first transplant (from tissue collection to surgical procedure)
• The transplantation instrument was manufactured in Addenbrooke’s hospital and was further improved.
• The transplantation procedures started in the UK in May 2015 and 12 procedures have been completed to date.
• The transplantation procedures started in Sweden in April 2016 and 1 procedure has been completed to date.
• One hundred and six patients continue to be enrolled in the observational trial, and a total of 1157 visits have been completed to date. Analysis of the observational data is ongoing.
• The European Observatory on Brain Repair (EOBR) was launched
• The work of Transeuro was reviewed by the Ethical Committee and scrutinized for its ethical aspects, so as to minimize and eliminate any ethical issues which could arise later on.
• First results from the Transeuro focus groups research were collected, analysed and presented to the consortium as well as to a lay audience.
• Based on the above data, several recommendations were made that should be taken into account when thinking about PD and clinical trials in society.
• Focus-groups for the EOBR studies were completed, with 1 publication in submission and further publications to follow.

Potential Impact:
Transeuro has capitalized on a partnership of Europe’s leading experts in the field of PD cell therapies, which collectively have unique expertise and resources to achieve the goals described above. This can be achieved through collaborative interactions that allow for the merging of unique and complementary expertise in the field. Additionally, the final transplantation protocol/trial design developed during the project duration can serve as a template for all future reparative clinical trials in PD.

Impact on science
Transeuro has been designed to address how this disease can be approached using novel therapeutics from a range of different perspectives- scientific, clinical and ethical. This requires not only input from the scientists and clinicians involved with this type of innovative therapy, but also ethicists, social scientists, patients and the general public. All this is integrated into a coherent package of work that seeks to embrace how experimental medicine can be used in the clinic in a scientifically robust way which is also ethically acceptable.

Economic benefits
Neurodegenerative diseases, including Parkinson’s disease (PD), are one of the major causes of chronic disability in European communities. Parkinson’s disease (PD) affects approximately 1% of people over 65 years of age, and as such is likely to become more common as the population ages and lives longer. With the increasing number of elderly people, coupled with the successful treatment of non-neurological causes of chronic illness, the incidence of neurodegenerative diseases will increase and based on the available prevalence studies, there are likely to be more than 6 million people with PD worldwide. This has stimulated a growth in the need for effective and widely applicable therapies which can have a significant impact on disease burden.
Regenerative medicine represents an exciting and increasingly realistic and feasible approach for treating such disorders, and in light of the increase in ageing populations and associated economic issues associated with linked diseases, there is now a real necessity for this field to be considered as a possible first line therapeutic option- especially given the work on stem cells that has been undertaken over the last 10 years.
While significant and valid efforts have focused on direct interventions with high costs using standard pharmacological agents, the use of innovative approaches such as cell therapies and the use of transplants represent an exciting new therapeutic area. In addition better developing such therapies may also help shed light on the underlying problems in the disease itself, whilst also opening up for the future, whole new therapeutic approaches. Transeuro is thus contributing to the alleviation of these chronic diseases by developing cell based treatments that can be optimally delivered to the clinic. Thus over the next 10 years it is probable that cell therapies will significantly reduce patient morbidity and mortality and be highly cost-effective.

Impact on society
Degenerative diseases create a life-altering experience for the affected person, their partner, parents, siblings, and children. The impact on, and subsequent loss of, body functions associated with the diseases can cause depression and loss of self-esteem. In many cases, PD patients require continuous physical and medical care depending on the disease state and disease severity. The burden of care needed most frequently falls on the partner. Care giving partners are often severely affected, particularly due to health issues that arise after the disease begins. Caregivers have a higher incidence of physical and emotional stress, burnout, fatigue, anger, and resentment. Hope is considered an important coping strategy for both the person and family with PD. Goal-directed hope based on realistic perceptions of life, focusing on progress, positive interpretation of events, are important in helping people and families cope with the disease. Hope is also focused towards society at large, and the development and use of novel therapeutics. In addition to imposing direct medical costs on society, degenerative diseases also result in indirect costs, primarily related to reduced productivity due to disability with a further loss of self-esteem of the sufferer and diminished integration into society. Thus, Transeuro aims to provide more than hope: we aim to provide a validated treatment for Parkinson’s disease.

List of Websites:
Professor Roger Barker
John van Geest Centre for Brain Repair
ED Adrian Building
University of Cambridge
CB2 0PY
Tel: [phone]
Fax: [phone]
http://www.transeuro.org.uk/