Lentiviral vector-based gene therapy is well tolerated and may improve motor function in patients with Parkinson’s disease (PD), shows an open-label study published in The Lancet.
Most adverse events were related to PD itself or to stereotactic surgery, which was the means of delivering the lentiviral vector containing genes for the three rate-limiting dopamine biosynthetic enzymes – tyrosine hydroxylase, aminoacid decarboxylase, and cyclohydrolase 1 – directly into the striatum.
The most common events related to the gene therapy were on-medication dyskinesias, which occurred in 11 of the 15 patients during up to 48 months of follow-up. All of these resolved with a reduction in patients’ oral dopaminergic medication and, moreover, the side effect is consistent with successful delivery “of an efficacious dopaminergic therapy,” say researcher Stéphane Palfi (Groupe Hospitalier Henri-Mondor, Créteil, France) and co-workers.
In support of this, there was also evidence that the on-medication dyskinesias were dose-dependent; they occurred in all six patients given the highest dose of gene therapy within 6 weeks of surgery, compared with three of the six patients in the mid-dose group and one of the three given the low dose.
Also dose-related were reductions in 11C-raclopride binding potential on positron emission tomography, an indirect measurement of dopamine release, with a 10.07% and 9.57% reduction in the high- and mid-dose groups, respectively, compared with a 5.33% increase in the low-dose group.
Off-medication motor status also improved over time, with Unified PD Rating Scale (UPDRS) III scores falling to an average of 27 at 12 months, compared with 38 at baseline, with significant reductions seen in all 15 patients.
“These data are encouraging in view of the expected disease progression of a 3–4 point increase in UPDRS part III (off medication) motor score per year,” say Palfi et al. But they add: “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.”
Also, two patients underwent deep-brain stimulation during the course of the trial, implying that gene therapy and medication had not provided adequate symptom control. Both these patients received the mid dose.
In an accompanying commentary, A Jon Stoessl (University of British Columbia and Vancouver Coastal Health, Canada) points out that, however effective gene therapy proves to be, good options for managing motor symptoms already exist, whereas there are few strategies for tackling nonmotor complaints.
“The therapy described here will not address these issues, but the safety of the approach could be seen as a proof of principle for future studies focused on rigorous assessment of efficacy as well as targeting these devastating problems.”
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