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The results of a multi-million-dollar clinical trial testing an experimental treatment for Parkinson’s disease that delivers a protein called GDNF into the brain have drawn a mixed response. Many commentators have stated that these highly anticipated and widely publicized results provide a glimmer of hope for patients, but the general consensus among Parkinson’s researchers seems to be that the overall outcome of the trial is disappointing, though they are still optimistic that this approach could work.
Parkinson’s disease is the second-most-common neurodegenerative disorder, affecting more than 6 million people worldwide. It is caused by the progressive loss of dopamine-producing neurons in the midbrain, which reduces dopamine levels there and in a connected ‘downstream’ region of the striatum called the putamen; this leads to the tremor, rigidity, and other motor symptoms characteristic of the disease, and also to cognitive impairments and problems with mood and motivation [See: Motivational Disorders in Brain Conditions]
There is no cure for Parkinson’s, but various treatments can help patients manage their symptoms. Most commonly, they take Levodopa, an amino acid that is converted into dopamine in the brain. This alleviates motor symptoms, but becomes less effective with time. More recently, deep brain stimulation (DBS) has been established as an effective therapy for advanced Parkinson’s, and more than 100,000 patients have benefited from it in the past two decades.
Researchers are also trying cell transplantation and stem-cell therapies to replace dopamine-producing neurons, and gene therapy to deliver glial cell-derived neurotrophic factor (GDNF), a growth protein known to be essential for the survival of midbrain dopamine neurons. The evidence for any of these being effective is thin on the ground, however; the few clinical trials testing GDNF-based treatments have produced mixed results and modest benefits, and one trial had to be halted due to safety concerns.
Aiming for the putamen
This latest trial was performed by a team of clinicians and researchers at the University of Bristol, and builds on promising earlier results showing a marked improvement in five Parkinson’s patients following infusion of GDNF directly into the putamen, using a method of delivering the protein that they created and have developed over the years. It involved 41 Parkinson’s patients, all of whom underwent surgery to have a small skull-mounted port implanted just behind the ear, through which a catheter can be fed. The device enabled the researchers to administer the therapy intermittently over an extended period: With the “brain port” in place, patients returned to the trial center once a month for 9 months, to have either GDNF or a placebo infused directly into the putamen.
PET imaging showed that those patients treated with GDNF exhibited significantly increased dopamine uptake throughout the putamen compared with those given the placebo. [See: The Revival of Brain PET] This did not translate into any clinical benefits for the patients, however. Many of them gave anecdotal reports of improvements, but in the final analysis, the treatment proved to be no more effective than the placebo, even when extended for a period of 80 weeks.
“This trial was the result of major campaigning by the Bristol team and UK charities to try and rescue GDNF from being abandoned,” says Thomas Foltynie, a professor of neurology at the UCL Institute of Neurology, “but unfortunately it was again negative in terms of its primary outcome.”
“[It showed] a 17 percent improvement in compared with 12 percent improvement in placebo treated patients [and] follow-up to 80 weeks showed a 25 percent improvement in the group as a whole, so there was no difference in the degree of improvement according to whether patients had received GDNF for 40 weeks or 80.”
It is possible the trial failed because the dosage was too small, because the treatment was administered too late, or because the clinical benefits associated with the observed improvements in dopamine function require longer periods of time to manifest. The imaging results come with an important caveat, though: While the imaging results are “consistent with there being an effect on dopamine cells in the putamen, the PET marker defines activity which is not necessarily specific for [these] cells,” Foltynie explains; the larger signal is not necessarily due to benefits to dopamine cells.
Method could transfer
“Current trial methodology does not provide definite answers,” says Andrew Lees, a professor of neurology at the National Hospital for Neurology and Surgery in London, “but if one looks at the neurologists’ opinions on individual patients there is hope,” adding that the Bristol group should pursue their work despite the disappointing trial results. “And, of course, all of the patients are champions.”
According to Foltynie, there are still too many unknowns to completely dismiss GDNF-based therapy as ineffective. “[We don’t know] whether long-term or earlier treatment might have more sustained benefits, or whether there are patient subtypes who might respond particularly well,” he says, but, “it is hard to escape the fact that the trials indicate that any beneficial effects of GDNF appear to be modest at best, [and] even if the [new] data are viewed optimistically, the outcome [is poor] in comparison to the standard surgical treatment option, DBS.”
The brain catheter device used in the trial also represents something of a technological advance. “This trial has shown that we can safely and repeatedly infuse drugs directly into patient’s brains over months or years through a small implanted port that emerges through the skin behind the ear,” says professor Stephen Gill, lead neurosurgeon involved in the study, and designer of the device.
“This is a significant breakthrough in our ability to treat neurological conditions, because most drugs that might work cannot cross from the blood stream into the brain due to a natural protective barrier.”