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Gene therapy tested for Parkinson's

Thursday 17 March 2011

Gene therapy has been proven to work for Parkinson’s disease, The Independent has reported. A number of other newspapers also express the hope offered by the new procedure, which is intended to boost levels of a brain chemical called GABA, which is lacking in people with Parkinson’s.

In a small trial of the technique, 45 participants with severe disease had their brains implanted with tubes that led to areas of the brain that deal with movement. Half were injected with a virus carrying a gene that would increase GABA production. The other half were given a harmless saline solution. After six months, those treated with gene therapy showed a 23% improvement in movement, twice that seen among those given sham surgery.

This early human research was carefully designed to test both the safety and effectiveness of the new therapy. Apart from headaches in a few patients, there were few adverse effects. In comparison to other gene therapies that have been tried for Parkinson’s, this one appears to be more successful and may now lead to larger and longer trials.

Where did the story come from?

The study was carried out by researchers from across the US. It was funded by Neurologix, the US biotechnology company that developed the technique. The study was published in the peer-reviewed medical journal, The Lancet Neurology.

Most newspapers have reported this study fairly and they feature quotes from independent experts who were very encouraged by the results. Some have highlighted the safety concerns that arose in previous trials of gene therapy, including deaths and cancer.

What kind of research was this?

This was a randomised controlled trial designed to investigate whether some symptoms of advanced Parkinson’s disease could be improved with gene therapy, a relatively new experimental technique which can theoretically be used to introduce new genes into the body. In this case, gene therapy was used to transfer a gene for producing a chemical called glutamic acid decarboxylase (GAD) into the basal ganglia, a collection of brain areas that control movement. The GAD gene being introduced is involved in increasing levels of a signalling chemical called GABA. Levels of GABA are lower in some parts of the basal ganglia in people with Parkinson’s disease.

The trial was conducted as a ‘proof of concept’, which tested gene therapy against sham surgery. The patients allocated sham treatment received the same surgical implant as the gene therapy patients but no gene therapy. The trial was double-blind, meaning that neither the patients nor the researchers knew if the gene therapy or a sham treatment had been given.

Further to this, the researchers took steps that would eliminate bias in assessments of movement. They did this by blinding those assessing this measure so that they did not know whether patients had received the gene therapy treatment or the sham treatment. The short follow-up and small size of the study suggests that more trials will be required to check long-term safety before the treatment can be made more generally available.

What did the research involve?

The researchers explain that loss of certain neurons underlies the movement problems seen in people with Parkinson's disease. When mild, Parkinson's disease is generally well-controlled by drugs. But as the disease progresses, these drugs may fail to produce the same response, thereby creating fluctuations in the disability caused by the movement problems, e.g. stiffness. They said that new gene therapy had been tried in animal models of Parkinsonism and in several open-label, or non-randomised/un-blinded trials. But the gene therapy had not been tested in a randomised double-blind clinical trial.

The researchers place their trial into context by highlighting that two other gene therapy approaches for Parkinson's disease had shown promise in phase 1 open-label clinical trials, but were not confirmed in subsequent randomised double-blind controlled trials. This therefore emphasised the need for the study design chosen here.

In this trial, 66 patients aged 30 to 75 years were enrolled at seven centres in the US between 2008 and 2010 if they had symptoms of advanced Parkinson's disease for at least 5 years and had received no previous brain surgery. Scans and other tests were done to ensure they had an accurate diagnosis. Researchers excluded unusual cases of Parkinson’s and patients with dementia.

Patients were surgically implanted with a tube system that would allow the basal ganglia to receive either a gene therapy solution or a harmless saline solution if they were assigned to the sham group. The gene therapy solution contained a virus, AAV2, attached to the GAD gene, which increases the GABA chemical that is lacking in Parkinson’s. The virus helps the gene get into the nerve cell.

Some patients were excluded after they had received surgery but before they entered randomisation (before they had received the gene therapy or control injection into the brain). They did this if the small tube inserted into the brain during this surgery could not be located correctly or the injection had problems. This left 23 patients who were randomly assigned to receive sham infusion, and 22 patients randomly assigned to receive gene therapy infusions. Of these, 21 patients in the sham group and 16 patients in the treatment group were included in the final analysis.

The researchers were mainly interested in the six-month change of a score called the off-medication UPDRS motor score, which is a rating scale that assesses movement. For this, patients received score of their movement judged by a movement disorder specialist at each centre, who was also unaware of the treatment they had been allocated.

The patients were assessed after overnight medication withdrawal while they were experiencing a good response to medication with few symptoms (in an “on” state) and when they had no response to medication with movement symptoms (in an “off” state). This and other scoring was conducted at one, three and six months after treatment. Only those with a baseline UPDRS motor score of 25 or more prior to surgery (indicating advanced disease) were enrolled into this trial.

The main measure was the difference in off-medication state UPDRS motor ratings between the sham and AAV2-GAD-treated groups. In the analysis, the researchers adjusted for individual differences in UPDRS motor scores at the start of the study and calculated the ratios of scores at each of the three post-operative time points to this baseline score.

What were the basic results?

After six months, the UPDRS score for the gene therapy group decreased by 8.1 points, a 23.1% improvement from baseline score (Standard deviation [SD] 1.7, p<0.0001). Scores in the sham group decreased by 4.7 points, a 12.7% improvement over baseline scores (SD 1.5, 12.7%; p=0.003). The difference between these groups was statistically significant.

There was one serious adverse event, a case of bowel obstruction, in the AAV2-GAD treated group. But this was not thought to be due to treatment or the surgical procedure. The patient fully recovered. The researchers say that other adverse events were mild or moderate. Of those likely to be related to surgery, the most common was headache, experienced by seven patients in the treated group compared with two in the sham group.

How did the researchers interpret the results?

The researchers say that the efficacy and safety of an infusion of AAV2-GAD in the subthalamic nucleus (part of the basal ganglia) supports its further development as a treatment for Parkinson's disease. They also say that their research “shows the promise for gene therapy for neurological disorders”.

The researchers go on to say that in this proof-of-concept study they sought to avoid a number of potential confounding factors, taking steps such as carefully screening patients to assure enrolment of only patients with confirmed Parkinson's disease, and excluding those with atypical Parkinsonism. They also pre-specified that the main analysis would be limited to patients who received the full assigned treatment, deciding ahead of time that their analysis would exclude any individuals with pump failures or inaccurate targeting of the subthalamic nucleus. The researchers add that this approach has found evidence of a benefit of subthalamic nucleus AAV2-GAD surgery versus sham surgery in this small phase 2 study.


This randomised double-blind clinical trial of gene therapy for Parkinson’s disease has met its primary outcome of improved UPDRS motor score at six months, and raised no major concerns regarding safety over this time. The researchers make a few other points worth noting:

  • By limiting the analysis to patients where placement of the small tube had been successful, this trial is not testing what actually might happen in real clinical practice where skill in placement of the tube and the surgery will be important.
  • They say that the problems and side effects they were looking for, including those of the immune response or the inability to reverse gene expression, were mild and did not suggest unforeseen risks associated the treatment. However these will need to be appraised through longer follow-up.
  • The treatment may not be appropriate for all patients with Parkinson’s, such as those with mild or atypical disease. This is because only people with typical, advanced Parkinson’s were included. Patients with the milder disease, in particular, have alternative treatment options, and the additional benefit of this new therapy was not tested against these groups.

The researchers call for further trials, saying that theirs has been valuable for informing how these larger trials might be conducted. These will be needed to confirm the present results, assess safety in the longer term, and to assess whether this treatment is practical for more widespread clinical use.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Gene therapy 'treats' Parkinson's

BBC News, 17 March 2011

Parkinson's sufferers given hope by gene therapy trial

The Daily Telegraph, 17 March 2011

Gene therapy proven to work in treatment of Parkinson's disease

The Independent, 17 March 2011

Parkinson's jab hope

Daily Express, 17 March 2011

Links to the science

LeWitt PA, Rezai Ali R, Leehey MA et al.

AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial

The Lancet Neurology, Early Online Publication, 17 March 2011