Parkinson: a promising triple gene therapy

This may be a new therapeutic alternative for patients with Parkinson's disease. Tested in primates, a triple gene enabled animals to recover 80% of their motor skills.

Above all, the benefit was maintained for months without evidence of side effects. These impressive results achieved by Bashir Jarraya and Stéphane Palfi, both neurosurgeons at the Henri Mondor Hospital (Creteil) and CEA-Inserm researchers. The results were published in a scientific journal Science Translational Medicine. Clinical trials are underway in six patients.

Parkinson's disease is caused by degeneration of Locus Niger, the area of the brain where neurons that produce dopamine. The deficiency of this neurotransmitter leads to symptoms such as resting tremor, rigidity, difficulty in movements initiating etc. As a  treatment L-DOPA (the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline)) has been used for fifty years. This precursor of dopamine can stimulate the production of the neurotransmitter.

But after a period of "honeymoon", L Dopa has the drawback of causing abnormal movements (dyskinesias), bothersome symptoms of the disease. Other molecules such as rasagiline that could halt the progression of Parkinson's are being tested.

For fifteen years, some patients have a deep brain electrical stimulation. The brain electrodes, implanted in the subthalamic nucleus, are activated by a sort of pacemaker, placed at chest level.

"In patients who take L Dopa, abnormal movements are related to irregular stimulation of dopamine during the day," says Dr. Bashir Jarraya. The solution is to avoid obtaining a local and continuous secretion of neurotransmitter.

The idea of the researchers is to establish a mini-factory of dopamine in the brain. "The principle here is not to replace a defective gene (hereditary forms of Parkinson's disease represent less than 15% of cases), but to bring the three genes required for synthesis of dopamine," says Bashir Jarraya.

To introduce these three genes in the bundle (a real challenge!) the researchers used a lentivirus equine, a harmless virus of the HIV family. This cocktail is made by a British company, Oxford BioMedica.

The study was conducted on 18 monkeys with Parkinson. They were separated into three groups. Six of them received bilateral injections of genes in intracerebral, in an area called the striatum. Six others received the viral vector without the gene therapy. The last six were used as a control group.

"After a period of four to six weeks, treated animals had a 80% improvement in their motor function, measured objectively," says Dr. Jarraya. This result remained stable during 12 months of experience. Moreover, unlike the L Dopa, gene therapy has not resulted in movement disorders, nor has it other side effects.

The researchers were able to verify that the improvement of clinical signs is consistent with an increased level of dopamine in the injection of therapeutic genes. They also established that this strategy could be effective in animals already treated with L dopa, which means lower doses of medication.

Now to the question whether these exciting results are reproducible in humans. Clinical trials began in Henri-Mondor hospital in six patients with advanced Parkinson. "With more than a year back, there was no problem of tolerance. All patients in varying degrees, have had a beneficial effect, but we are still looking for the optimal dose, " says Professor Stéphane Palfi.

According to the neurosurgeon, the injection of therapeutic genes in the striatum, which is done under general anesthesia, is technically easier than the implantation of stimulation electrodes in the subthalamic nucleus.

It would also have the advantage of being more specific, which might prevent some behavioral problems described after deep brain stimulation.

Clinical phase 2 trials (on twelve patients) and on a larger scale are planned in the coming years. In the United States, other gene therapy approaches are under study. One evaluates one of the three genes studied by the French, the other two test genes neuroprotection.

Ultimately, we might even consider a gene therapy with a cocktail of genes, promoting both the synthesis of dopamine and neuroprotection.

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