By the time people are diagnosed with Parkinson’s disease, they have lost a sizable fraction of their dopamine making cells in the substantia nigra pars compacta region of the brain, together with the vital axonal projections that deliver dopamine to the striatum. While orally administered L-dopa replaces some of this missing dopamine, the uneven delivery (3 or 4 times a day) leads eventually to disabling “motor complications,” including involuntary writhing movements (dyskinesias), and on-off fluctuations – in which the medicine’s power to combat Parkinson's disease suddenly vanishes without warning.
Now Stéphane Palfi and colleagues at the Henri Mondor Hospital in Paris (in collaboration with a British firm, Oxford BioMedica) have announced results of a phase1/2 open label trial of a new and potentially smoother way of delivering dopamine – a gene therapy called ProSavin. As the team’s Lancet article describes, Palfi et al took a gutted virus, inserted three genes that collectively can manufacture dopamine, and surgically delivered multiple copies of the viral vector to the putamens of 15 patients with advanced PD. All patients had had the disease for more than 5 years. The hope, says Palfi, is that these three critical genes –for tyrosine hydroxylase (the enzyme that converts tyrosine into L-dopa), AADC (the enzyme that turns L-dopa into dopamine) and GTP-cyclohydylase – would convert the surviving striatal neurons “into dopamine-producing factories to replace the constant source of dopamine that is lost in Parkinson's disease."
After a 12-month follow up period, Palfi reports that the technique appears pretty safe. The ProSavin cohort – aged 48 to 65 – experienced only mild to moderate side effects. The team also reports encouraging signs of efficacy. Patients evaluated in the off medication state showed a reduction (i.e. improvement) in UPDRS part III motor scores of about 30%. This is about the benefit seen from taking Sinemet.
But the authors end with a placebo alert, saying 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."
Indeed. On numerous occasions over the last 15 years, promising open label PD trials – of, for example, fetal grafts or neurotrophic factor gene therapy – have failed to hold up in double-blind placebo controlled trials. Surgical studies have proved to be especially susceptible to powerful and long lasting placebo effects. In his classic study examining patients in the placebo arms of 11 major PD trials, Rush neuroscientist Christopher Goetz found that some patients in surgical studies (which typically use “sham surgery” as a placebo control) experienced gigantic benefits (50% drops in UPDRS III scores), which persisted for more than 18 months. Since these effects are larger than what’s been observed so far with ProSavin, the team is right to be cautious. Before putting ProSavin to the critical test they wisely want to optimize the process. They want to refine the patient selection (i.e. age, type, stage), decide the appropriate follow up period, determine the right dose etc. As Palfi et al say, “only when we have an optimum mode and dose of delivery will we proceed to a more definitive double-blind placebo controlled trial.”