Share this article on:

Three-Pronged Gene Therapy Used For Early Clinical PD Trial


doi: 10.1097/01.NT.0000368613.52327.c4
Back to Top | Article Outline


A gene therapy designed to replace three enzymes that lead to dopamine production is in open label testing in France, with early signs of efficacy in mid-to late-stage Parkinson disease.

MIAMI BEACH—A combined gene therapy approach may help patients with late stage Parkinson disease (PD), according to the results of a proof-of-concept animal study and a small trial, investigators reported here at the World Federation of Neurology World Congress on Parkinson's Disease and Related Disorders in December.

In a PD animal model involving macaque models treated with the complex 1 mitochondrial inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), gene therapy restored extracellular concentrations of dopamine and corrected motor deficits for 12 months. The findings were reported in the Oct. 14, 2009, issue of the journal, Science Translational Medicine.

And in a small trial, PD patients who received the first two of three planned dose levels of the therapy showed improved motor function — as measured by the Unified Parkinson Disease Rating Scale (UPDRS) Part III — by three months over baseline scores; the first, lowest dose cohort sustained improvement for up to 12 months.

The gene therapy (branded ProSavin) uses a lentiviral vector to stimulate production of three enzymes in the pathway to produce dopamine — tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), and GTP cyclohydrolase-1 (CH1).

The combination therapy “converts the striatum into a dopamine factory,” said one of the investigators G. Scott Ralph, PhD, director of neurobiology at Oxford BioMedica plc, in Oxford, UK, which sponsored the study led by Stéphane Palfi, MD, PhD, professor of neurosurgery at the Henri Mondor Hospital in Paris.

Intermittent increases in dopamine provided by current medical therapies are likely to produce the eventual side effects of dyskinesias, said Dr. Ralph. “Hopefully, the [gene] therapy will reduce these dopamine side effects in patients, as we have already observed in preclinical studies.”

Back to Top | Article Outline


Three Parisian PD patients were assigned to each of the two dose levels tested so far; the data from the lower dose at three months were reviewed before proceeding to the higher level. The vector with therapeutic genes was delivered by stereotaxic surgery in the putamen bilaterally. The study design includes a cohort that will receive a sham surgery. This will only take place once an optimal dose has been determined from the current dose escalation phase of the trial, Dr. Ralph reported by e-mail.

No adverse events have occurred. Patients were ambulatory 24 hours after surgery. No antibodies have been detected to any of the vector components.

“We have encouraging early signs of efficacy,” Dr. Ralph said. A 33 percent improvement was seen at six months at the higher dose level as reflected by the UPDRS motor scores. No changes in dyskinesias occurred, and questionnaires and patient diaries reflected improved quality of life.

The levodopa equivalent dose was used to standardize the mix of drugs being used for each participant's symptoms. Patients were assessed after the night of being off medications. Therapy with levodopa remained the same or was reduced in those patients who showed the best improvement, Dr. Ralph said. “We are encouraged by these early signs of efficacy in the clinical trial.”

Back to Top | Article Outline


Krystof Bankiewicz, MD, PhD, professor of neurosurgery and neurology, and Kinetics Foundation Chair in Translational Research in Neurological Surgery at the University of California-San Francisco, called the findings encouraging.

“However, little if any increase of dopamine has been shown in MPTP non-human primates, so it is hard to understand what the mechanism is,” Dr. Bankiewicz said. He noted that the mechanism may be similar to the one he and co-investigators found in their own gene therapy trial for PD involving adeno-associated viral type 2 vector containing the human AADC gene, but “levels with this vector are very low.”

Dr. Bankiewicz added that in the current report there was no confirmation yet with PET of expression in patients — which he and co-investigators did obtain in their gene therapy trial. [An article about that trial, reported Oct. 14, 2009, online in advance of the print edition of Neurology, was published in the Dec. 3, 2009, Neurology Today; see “Gene Therapy Delivers Benefit in Parkinson Disease.”]

Mark A. Stacy, MD, associate professor of neurology and director of the Movement Disorders Program at Duke University in Durham, NC, who co-chaired the session at the meeting, said that the study investigators presented “compelling animal data. They had the start of a safety trial that looked similar to phase I safety studies of similar concepts.” But, he cautioned, “double-blind studies have not borne fruit” for gene therapies in PD. “It is still a good idea,” he said, “they have a different strategy and I hope they are able to see some positive results on double-blind testing.”

Back to Top | Article Outline


• Jarraya B, Boulet S, Palfi S, et al. Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia. Science Transl Med 2009; 1(2):2ra4.
    • Christine CW, Starr PA, Aminoff MJ, e t al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology 2009; 73:1662–1669;E-pub 2009 Oct. 14.
      ©2010 American Academy of Neurology