Conference details: The Cure Parkinson’s Trust Research Meeting 4th April 2016 held at Jones Day London
Posted in Online First on 30th Jun 2016
Report by: Leah Mursaleen
Published online: 30/6/16
People with Parkinson’s (PwP) have to make huge decisions about their health and often have to assess the prospective risks and benefits of trying new treatments and/or participating in clinical trials. This research meeting asked searching questions of representatives from the scientific, clinical, ethical and patient communities and addressed key facts that need to be understood by PwP in order to make informed and good decisions.
The first presentation was by Dr Mariah Lelos, Cardiff University entitled ‘An introduction to stem cell therapy, the good, the bad and the ugly’. This informative and easy to understand talk highlighted the advantages and disadvantages of using foetal and embryonic stem cells. Foetal stems cells can differentiate into neuronal cells of regional specification, are relatively safe and do not develop tumours. But there is a limited availability of foetal stem cells and large variability between differentiated cells. In addition there are viability concerns as well as ethical sensitivity with their use. Embryonic stem cells, on the other hand, are more widely available and more viable cells can be produced with less variability. That said, it is a precise art to initiate neuronal differentiation and regional specification and there are more safety concerns due to their capacity to continually differentiate.
Dr Lelos presented data that shows that human embryonic stem cell grafts can improve motor dysfunctions in Parkinson’s disease. And that stem cell derived dopamine grafts form functional connections within host brains in multiple animal models.
Dr Lelos’ talk provided a neat introduction to the topic which was elaborated by Professor Roger Barker from The Brain Repair Centre, Cambridge University – ‘Distinguishing Cell Therapy from Sell Therapy’. This excellent talk discussed the rationale of using stem cells for Parkinson’s, the pitfalls of past studies using stem cells, the TRANSEURO trial (http://transeuro.org.uk/) and what is needed for the future.
Although Parkinson’s is a heterogeneous disease (a disease with multiple causes), one thing that all PwPs have in common is that they have all lost at least 250,000 nigral dopamine neurons. It is evident that dopamine replacement works – as anyone who takes levodopa demonstrates. However, these medications have side-effects including involuntary movements (dyskinesia) as they are absorbed in a variable way and stimulate the brain with dopamine in a non-physiological manner. This stimulation is everywhere, not only in the areas that are dopamine depleted, which can result in complications in the long term such as behavioural changes. Cell based therapies on the other hand would have the benefits of the drugs, whilst specifically targeting the depleted areas and releasing dopamine physiologically, from neurons. These therapies could dramatically change the treatment of Parkinson’s.
Professor Barker explained that in the past there have been mixed results from foetal cell-based therapies in trials. In the early 1980s in Europe there was an open-label study that showed some very positive results – long term survival and connectivity of cells which release dopamine. But in the US there were two double-blind placebo trials that were inconclusive. Just because a trial fails does not mean that the therapy fails. The main reason for such mixed findings was that because these trials were so different it was almost impossible to compare them. For example, they all used different groups of patients, different amounts of tissue, different delivery approaches, different endpoints and different doses of immunosuppressant drugs to prevent rejection.
Professor Barker’s present study, TRANSEURO, collected all the data together and found that in a third of patients who received transplants, there was a significant, sustained positive effect. The TRANSEURO team has optimised the delivery procedure and are undergoing an open-label study of 150 patients around Europe with patients randomly selected for transplant. In the last year there have been 10 bilateral transplants with eight more in the UK and seven more in Sweden by the end of the year. The problem is that 3-4 foetuses are needed to obtain enough tissue for transplant in each side – not only does this incur ethical issues but it would not be a sustainable treatment for all PwP. This is why research has turned to different sources of stem cells.
The two main sources of stem cells that have the potential as Parkinson’s therapies are induced pluripotent stem cells (iPSCs) and human embryonic stem cells (hESC). iPSCs are reprogrammed from adult skin cells, into embryonic-like stem cells using different factors. These can then be differentiated into any cell type, including nigral dopamine cells. They have the potential to be used for personalised medicine and transplantation would be of the patient’s own cells so there is no risk of rejection. That said, if these cells have been taken from PwP and dopamine cells have been generated from them, what is to say that these will not become faulty like the original dopamine cells from these patients? What’s more, with each cell line costing an estimate of £2-3 million, it is unlikely that this would ever be funded for every PwP. hESCs on the other hand, have been shown to be capable of generating working nigral dopamine cells in animals. Studies have shown that these dopamine cells behave like foetal dopamine cells. To date over 800 cells have been transplanted and no tumours have been seen, which suggests that they are very safe. Professor Barker has recently applied for funding of the final preclinical testing of their hESC with the hope of positive results and a clinical trial beginning in 2018.
Professor Barker highlighted that we need to learn from past mistakes and that there is a great need for pre-clinical data before open-label trials are carried out. And open-label trials are required before designing double-blind trials. With this in mind, G-Force PD was developed to get everyone in the stem cell arena working together and sharing information. But with the surgical price of immunosuppressant drugs currently at £23,000 (excluding the cost of the cells), no one in the charitable sector will be able to afford the phase 3 trials. Professor Baker commented that this is when we have to turn to the pharmaceutical industry and government to fund such work. And we need PwP and patient communities to advocate for this work to ensure not only that the therapy gets into clinic but that once in clinic it is affordable for all.
Moving on from stem cells specifically, Dr Richard Wyse (Director of Research and Development at The Cure Parkinson’s Trust) gave a brief update on The Cure Parkinson’s Trust’s Link Clinical Trial (LCT) Research programme, where developed drugs from different disease areas are repurposed for Parkinson’s because they show potential to slow, stop or reverse Parkinson’s. Dr Wyse briefly talked about Bydureon, Liraglutide, EPI-589, Deferiprone, Ambroxol and Simvastatin – these are all drugs which have been prioritised by the LCT Committee and clinical trials are already underway – to read about these drugs in more detail see the section on repurposed drugs on the website (https://www.cureparkinsons.org.uk/trials-repurposed-drugs) Dr Wyse also presented about Lixisenatide, N-Acetyl Cysteine, UDCA, MSDC-0160, cAbl /Nilotinib/Bosutinib. These are drugs which have been prioritised and trials are in preparation (https://www.cureparkinsons.org.uk/trials-pending)
Dr Jon Stamford (Scientific & Advocate Communications Coordinator) and Mr Tom Isaacs, (President of The Cure Parkinson’s Trust) closed with ‘From Snake Oil to Shake Oil, witch doctors and which doctors?’ – giving some wise but nonetheless light hearted advice for PwP making decisions. Dr Stamford highlighted that outrageous claims are nothing new and the Internet has provided wider opportunities for fraudsters. He advises healthy scepticism when reading about new breakthroughs, highlighting that the best research is usually reported by scientists not journalists. Mr Isaacs added that everyone within the Parkinson’s community (patients, scientists, clinicians, industry and regulators) need to be better communicators so that the right decisions are made about our individual health, but also the wider picture. He emphasised that PwP need to be able to distinguish between medical hype and medical hope and this understanding is the responsibility of all, not just scientists and clinician, ending the meeting with the idea that teamwork is the key to accelerating evidence-based breakthroughs in the treatment of Parkinson’s.
Each presentation can be viewed in full on The Cure Parkinson’s Trust’s You Tube channel.
For further information about The Cure Parkinson’s Trust go to www.cureparkinsons.org.uk
Photographs by Hannah Zeffert