Life Sciences Division

France counts around 100,000 patients with Parkinson’s disease, making it the most common neurological degenerative disorder after Alzheimer’s disease – and a major public health issue.

What is Parkinson’s disease?
Parkinson’s disease is a neurological disorder that is essentially characterized by a progressive and increasingly severe loss of motor skills, manifested as tremor, muscle rigidity, and a slowing of physical movement. The disease reflects a degeneration of the neurons producing dopamine, a neurotransmitter that plays a role in controlling body movements.

How is it treated?
Parkinson’s patients today are being given what is called a dopaminergic therapy, which is the oral administration of drugs that mimic the action of the dopermine missing from their brains. Although this treatment does improve motor activity in early-stage Parkinson’s, it has severe adverse effects over longer timeframes, including on-off fluctuations in treatment effectiveness and involuntary movements called dyskinesias.

How is it possible to engineer physiological restoral of the missing dopamine?
One hypothesis carried forward by Parkinson’s disease experts from researchers to doctors has gathered momentum over the last few years. The assertion is that the daytime intermittent drug administration at different times of the day alters brain functioning due to the excessively-irregular patterns of neuronal stimulation triggered, which is thought to cause the complications associated with dopaminergic treatment.
The challenge facing antiparkinsonian therapy today is to develop technologies able to induce:

1 MIRCen (for ‘molecular imaging research center’) is a pre-clinical imaging platform developed through a CEA–Inserm partnership. It is purposed towards innovating novel therapies, primarily for neurodegenerative disease but also for cardiac and hepatic disease and infectious disease. MIRCen is hosted at CEA Fontenay-aux-Roses.

2. local dopaminergic stimulation in order to achieve beneficial motor-activity effects while avoiding the neuropsychological complications triggered when stimulating other brain regions that have escaped the disease.
Despite the fact that dopaminergic drugs are a flourishing research field, it remains extremely difficult to restore a physiological pattern of brain stimulation.
1. continuous dopaminergic stimulation

This is why expectations are turning towards gene therapy, which entails triggering brain cells to directly express a therapeutic gene. Under current state-of-the-art, the systems most effective in triggering the expression of genes-of-interest in vivo are dependent on the use of viral vectors – viral envelopes with their proliferative properties knock-out and rendered non-pathogenic.

How is the dopamine synthesis capacity transferred along with the genes?

The background cause of most Parkinson’s disease cases is not genetic. However, the biochemical alterations that cause the symptoms could be corrected by “replace or restore” functional gene therapy to boost dopamine synthesis (via the expression of the genes involved in dopamine biosynthesis) and at least partially restore dopaminergic cell function.

This was the approach that was employed in the study published today. The team first studied the safety and efficacy of a viral vector (engineered from equine infectious anaemia virus, EIAV) encoding the three critical genes for dopamine biosynthesis: AADC, TH, and CH1. They established proof-of-principle for the transfer of these genes into the striatum [2], which is the dopamine-deficient region of the brain, and observed local and continuous in vivo dopamine synthesis.

The trial went on to demonstrate the long-term (44-month follow-up) therapeutic efficacy of this viral vector in the same primate model of Parkinson’s disease, and without the complications (on-off fluctuations and dyskinesias) associated with oral dopaminergic drugs.

How can this technology be transferred from bench to bedside?

Spurred by this success, the clinical research team from Henri-Mondor hospital working on this programme syndicated the MIRCen and SHFJ3 (CEA) and, with authorization from the French Health Products Safety Agency (Afssaps), clearance from the regional ethics board (CPP Ile-de-France IX) and sponsorship backing from Oxford BioMedica, has launched a phase I/II clinical trial. This trial is designed to demonstrate the safety and efficacy of the approach in patients presenting advanced forms of Parkinson’s disease. Results in from the first patients to benefit from this treatment showed promising improvements in motor skills and quality of life at 12 months post-injection of the gene drug. The treatment offers the added benefits of being well-tolerated, with no severe adverse events reported.

 

Interim results from the trial will be unveiled by one of the pioneers of this gene therapy protocol, Pr. Stéphane Palfi [4], at the European Society of Gene and Cell Therapy 2009 annual congress in Hannover, Germany, in November 2009.
These sophisticated therapeutic developments offer an outstanding illustration of public-private partnership and demonstrate the harnessing of synergies between academic and industrial biomedical research. This approach, known as translational medical research, is cornerstone strategy at both the MIRCen and Henri Mondor Hospital’s Neuromotor research department, as it enables fast, controlled technology transfer from ‘bench-to-bedside’.