Neural transplantation in Parkinson's disease: moving forward

A new multicentre, international research programme – TRANSEURO – aims to refine cell transplantation techniques for replacing the lost cells that lie at the heart of Parkinson’s disease (PD). This progressive and ultimately fatal neurodegenerative disorder affects approximately 1% of people over 65 years of age.

Repairing the neural circuits has long been an aim of clinical neuroscientists like Dr Roger Barker, who leads the new programme and is based at Cambridge’s Centre for Brain Repair. But neural transplantation in PD has had something of a roller coaster history, as he explains: ‘Close to 100 patients have received cell transplants as part of well-conducted clinical trials worldwide in the past two decades. In some, the transplanted cells survive, grow and significant clinical improvements can be seen for as many as 15 years post-transplant. Yet, in others, the therapy not only fails, but the patient develops side effects.’

This variability has hampered progress in the field. TRANSEURO‘s goal is to coordinate research efforts to develop a best practice for any type of cell transplantation in PD and to move forward to a new phase of cell therapy trials.

A complex disease

A key feature of PD is the progressive loss of cells that produce a chemical called dopamine. Located deep in the substantia nigra of the brain, the dopaminergic cells send their connections to the striatum in the forebrain. Here, the dopamine they release mediates a vast range of activities, including voluntary movement, cognition, motivation and reward – behaviours that are disturbed when the cells, for reasons not yet understood, begin to die in PD. The first symptoms of tremors, stiffness and slowness of movement appear when half of the total number (about a million) of cells has already died.

In the 1960s, it was discovered that L-DOPA, a precursor to dopamine, reduces the intensity of Parkinsonian symptoms.

Fifty years on, it is still the most effective drug to alleviate symptoms, although it has the inevitable side effect over time of generating involuntary movements (L-DOPA-induced dyskinesia). In the 1990s, the development of deep brain stimulation with high-frequency electrical impulses delivered to the damaged circuits was used successfully to manage this aspect of PD.

In fact it’s now known that the loss of dopamine cells is part of a much wider pathological process throughout the brain. This additional complexity has meant that it has become increasingly important to characterise subtypes of PD in terms of symptoms, signs and underlying pathology – an area that scientists at the Centre for Brain Repair have made a major contribution to in the past decade.

Such complexity raises an important point about treating PD, as Barker explains: ‘The starting point for therapeutic strategies has been to replace or restore the loss of the dopamine-producing cells. This clearly won’t cure the disease, not just because the additional pathology is so diffuse and widespread, but also because whatever causes PD has not been removed simply by placing in a graft. Nevertheless, reparative strategies used early in the disease course have the potential to give patients many drug-free years, which would be a major therapeutic step forward.’

Rebuilding the dopamine circuit

Brain repair for PD has taken several forms in recent years, including approaches that transfer genes coding for dopamine-producing enzymes into the patient’s own brain cells, and approaches that deliver growth factors into the brain to enhance the effects of the remaining dopamine-producing cells.

However, ever since pioneering experiments by Professor Anders Björklund in Lund University Hospital, Sweden, in the 1970s and 1980s, the most effective and well-advanced treatment has been the transplantation of new, undamaged cells to replenish those that are lost or dying. In this procedure, cells from the developing midbrain from aborted fetuses are transplanted into the striatum of the patient, to a site where dopamine normally functions. The original Swedish trials showed that these fetal dopaminergic cells survived and grew, and patients improved.

But, when two larger, placebo-controlled, clinical trials in the USA in the 1990s showed no major benefits, combined with some side effects, further trials were halted. Most alarming of the side effects was the development in some patients of graft-induced dyskinesia (GID). Unlike L-DOPA-induced dyskinesia, where the abnormal movements can be reduced by stopping the drug, this is not possible in GID. In some cases, further surgery (albeit that used normally in PD deep brain stimulation) was needed to ‘undo’ the side effect the graft had induced.

As a consequence, the field was faced with a paradox: fetal cell therapy appeared to have no future in PD because the US trials had failed, yet some patients had done phenomenally well. In the meantime, the stem cell field was advancing and it was clear that dopamine neurons derived from stem cells might one day be an alternative approach to repair the brain in PD.

Barker and colleagues believed that hidden in the data from the clinical trials would be clear evidence for the factors that determine the success rate. ‘With the benefit of hindsight, early trials might now be regarded as only ever being powered to fail,’ he says. ‘There has been huge variability in patients’ stage of disease and medication history; the clinical techniques used for cell delivery; the viability and durability of the cells being transplanted; and even in how outcomes were measured. It’s easy to see how differences in average improvement could be obscured within the data.’

TRANSEURO

In 2006, Barker and Björklund set up an international working group to look at these issues. Over the course of the next three years, they contacted and worked with groups worldwide who had used cell therapy in PD. Out of these discussions has come TRANSEURO, a five-year, €12 million programme funded by the European Union. It brings together 14 institutions spread across five European countries, as well as close collaboration with research groups in the USA.

As well as a reassessment of the early trials data, the programme will investigate GIDs, optimal patient subgroups for grafting, the complex logistics of tissue procurement, and other critical factors. The goal is to arrive at a ‘best guess’ for the protocol most likely to provide safe, more consistent and clinically effective benefits for patients. It’s anticipated that the programme will recruit at least 80 patients across the TRANSEURO network, of which the first 20 will be entered into an open-label Phase I transplantation trial in 2011/12.

Alongside the scientific and clinical arms of the programme, a project will consider the types of ethical issues that work of this nature throws up; this will touch upon the use of fetal tissue and the choice of patients (who are likely to be at an early stage of their disease), and issues such as what society will accept as ethical in emerging cell-based therapies.

From fetal to stem

‘We regard TRANSEURO as a stepping stone that will refine the clinical methods needed for any kind of cell-based therapy, whatever the source of cells,’ says Barker. The expectation is that the study will pave the way for larger trials using dopaminergic neurons derived from stem cells, a purer and more plentiful source, and already a research strength in Cambridge. ‘Our goal is to provide the impetus to push the field ahead to a new phase of cell therapy trials in PD.’

For more information, please contact Dr Roger Barker (rab46@cam.ac.uk) or Danielle Jackson (dmj34@cam.ac.uk) at the Centre for Brain Repair in the Department of Clinical Neurosciences or visit www.transeuro.org.uk/ TRANSEURO is not currently recruiting patients for the trial as ethical approval is not yet in place.