New Parkinson's Gene Therapy Shows Promise

January 14, 2014

A new approach to gene therapy for Parkinson's disease (PD) has shown promising results in a phase 1/2 study, with no major safety issues and some improvement in motor symptoms in all 15 patients treated.

The therapy, known as ProSavin, is in development by Oxford BioMedica (Oxford, United Kingdom) and consists of 3 enzymes necessary for the biosynthesis of dopamine in a lentivirus vector delivered directly by injection into to the striatum, the area of the brain where dopaminergic neurons have degenerated in PD.

The study, published online in The Lancet on January 10, was conducted by a group led by Stéphane Palfi, MD, Groupe Henri-Mondor Albert-Chenevier, Créteil, France.

Professor Palfi explained to Medscape Medical News that traditional treatment for PD with L-dopa is not ideal because over time the therapeutic response lessens, probably as a result of a reduction in the enzyme that converts L-dopa to dopamine. And the fluctuations in dopamine concentrations caused by intermittent oral dosage can lead to dopaminergic adverse effects, such as dyskinesia, vomiting, and hallucinations.

A Continuous Supply of Dopamine?

"In theory, by providing the continuous release of dopamine, our gene therapy should overcome these issues, and by directly targeting the striatum, then this should minimize side effects caused by excess dopamine in other areas of the brain and body," he said.

Professor Palfi noted that the neurons that normally make dopamine have been destroyed in PD, but by injecting the new gene therapy directly into the striatum, the genes coding for the 3 enzymes needed to synthesize dopamine — tyrosine hydroxylase, cyclohydrolase 1, and amino acid decarboxylase (AADC) — are taken up by other neurons, which then become able to make dopamine.

"This new biosynthesis could in theory last forever as the genes are inserted in to the genome of the neurones. In our study, we followed patients for between 1 and 4 years and there were signs that dopamine was being released for all this time," he added.

In an accompanying Comment, A. Jon Stoessl, MD, University of British Columbia, Vancouver, Canada, says the study could be seen as a proof of principle for future studies focused on more rigorous assessment of efficacy. But he points out that the real challenge of PD is the management of nonmotor problems, many of which have a nondopamine basis, which will not be addressed by this therapy.

For the study, 15 patients received the ProSavin gene therapy (3 low dose, 6 mid-dose, and 6 high dose) while under general anesthesia.

During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild and 3 moderate). Most common were increased on-medication dyskinesias (20 events in 11 patients) and on–off phenomena (12 events in 9 patients). No serious adverse events related to the study drug or the surgical procedure were reported.

In terms of efficacy, motor function significantly improved up to 12 months in all patients. Long-term follow-up data showed long-term tolerability and evidence of clinical benefit for up to 4 years after treatment.

The authors note, "Although the efficacy findings show promise, the magnitude of effects are within the placebo range reported in other clinical trials for Parkinson's disease using surgical techniques, and must be interpreted with caution."

Dose-Related Response

They add that although dose effects are difficult to assess in small sample populations, there are indications that the highest dose evaluated in this study provided the greatest level of dopaminergic activity. Specifically, patients in the highest-dose cohort had a consistent requirement for a reduction in dopaminergic medication, the highest mean improvement in the United Parkinson's Disease Rating Scale Part III (off medication) motor scores relative to baseline, and a significant change in raclopride binding potential, which was interpreted by the investigators as an increase in availability of endogenous dopamine.

Dr. Stoessl, however, points out that the imaging data are difficult to interpret, and the efficacy results must be taken as preliminary, particularly because this was an open study.

To Medscape Medical News, Professor Palfi commented: "We saw some signs of clinical efficacy. This was characterized by better motor effects — including rigidity, movement and speed of movement, and locomotion. In addition, tremor improved. These symptoms all generally improved more as the dose of the genes given increased."

He noted that dyskinesia, an adverse effect of dopamine therapy, also increased with increasing doses of the gene therapy. He explained that patients still received their usual dopamine agonist therapy during the study, and so it would make sense to see an increase in dyskinesia with the gene therapy, which could signal an overdose of dopamine. In these cases, the dopamine agonist therapy was reduced. "In theory, if the gene therapy works, patients will not need L-dopa treatment as well."

Professor Palfi agreed with Dr. Stoessl that the effects seen could be caused by a placebo effect, and for this reason a double-blind, placebo-controlled study is needed, which they are now planning.

"But the fact that there was some evidence of a dose-related effect on symptoms and dyskinesia is a very promising sign that the therapy is working," he added. "In addition, the raclopride PET [positron emission tomography] scans suggested increased dopamine production, and the fact that we could only see this in the high-dose group also suggests a positive effect of the therapy."

Professor Palfi pointed out that the study started with low doses for safety reasons and then graduated to higher doses. "We don't know the best dose to use, but after these results, we are planning the next study with higher doses again." The researchers have also modified the vector for future studies to enable more dopamine to be secreted with a lower injection volume and reduced surgical time.

Three patients have now been followed for 4 years, all of whom received the lowest dose, as this was administered first. The patients given the highest dose have been followed for only 1 year so far, he said. "Although there was some improvement in symptoms to begin with in the low-dose group, by 4 years they are about at the same level of symptoms as they were at baseline. This could be explained by some loss of effect over time and disease progression. It is too early to tell what will happen long term with the higher doses."

He noted that several different gene therapy approaches in PD have been tried before, but to his knowledge none have yet progressed beyond phase 2. "We haven't got there yet, but we are hopeful that ours will be effective because of the dose response seen in this study."

Other approaches have used adenovirus vectors, but the lentivirus used in this study represents an improvement because it can carry a higher gene load, enabling delivery of 3 genes at the same time, Professor Palfi said. This is the first report of a clinical trial using in vivo administration of lentiviral vectors in humans in any disease indication, the researchers report.

The study was funded by Oxford BioMedica. Professor Palfi is a consultant for Oxford BioMedica. Disclosures for coauthors appear in the paper. Dr. Stoessel reports he has consulted for Biogen-Idec, Bioscape Imaging, Kyowa, Medgenesis, and Ono Pharma; has participated in advisory boards for AbbVie and UCB; and received speaking honoraria or travel expenses from Abbott, Fujimoto, Medscape, and Teva.

Lancet. Published online January 10, 2014. Abstract Comment

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