Lentiviral Vector-Based Gene Therapy in Parkinson Disease

Despite the recent failure of the second Phase 2 trial of adeno-associated virus serotype 2 (AAV2) vector-mediated delivery of neurturin, expectations for the eventual success of gene therapy approaches to treat Parkinson disease (PD) remain quite high. Currently, there are 2 clinical trials underway to study the delivery of other AAV2 vector-based therapeutics: aromatic-L-amino acid decarboxylase (AADC), the final rate limiting enzyme in dopamine synthesis (NCT01973543), and glial cell-derived neurotrophic factor (GDNF), a potent neurotropic factor in the same family as neurturin (NCT01621581). These trials are employing convection-enhanced delivery via interventional-magnetic resonance imaging for real-time imaging of vector distribution, in an attempt to overcome obstacles that may have prevented previous PD drug delivery trials from reaching efficacy goals. Whether replacing dopamine synthesis directly (AADC) or rescuing dopaminergic activity in the nigrostriatal pathway by trophic support (GDNF) is a better approach is an open question. It is possible that a combination of these strategies ultimately may be most effective.

Expanding the strategy for replacement of dopamine synthesis, Palfi and colleagues¹ reported the results of a 2-center (Créteil, France and Cambridge, United Kingdom), Phase 1/2 open label trial of ProSavin, a lentiviral vector that encodes not only AADC, but the other rate-limiting dopamine biosynthetic enzymes tyrosine hydroxylase and cyclohydrolase 1. Although lentiviral vectors have the advantage of being able to carry a larger genetic payload than AAV vectors, no clinical trial using in vivo administration of lentiviral vectors in any human disease had previously been reported. In this open-label, dose-escalation study with 12-month follow-up, 3 doses of ProSavin were assessed in 4 patient cohorts with bilateral delivery to the putamen. The primary endpoints were the number and severity of adverse events and change in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores assessed at 6 months after vector administration. The most common therapy-related adverse events were increased on-medication dyskinesias, which resolved in each case with reduction of dopaminergic medication. Importantly, no patients developed off-medication dyskinesias or any signs of an inflammatory response to the viral vector. Off-medication UPDRS motor scores were significantly reduced at both 6 and 12 months in all patients, relative to their baselines (33% and 31%, respectively); however, no significant difference was seen between the different dose cohorts.

The therapeutic goal of this gene therapy strategy was to produce a continuous and stable production of dopamine in the motor region of the putamen. Evaluation of this effect by Positron emission tomography scanning, however, produced conflicting results. There was no effect in ¹⁸F-levodopa uptake, an analog of levodopa used to evaluate striatal dopaminergic presynaptic function, after ProSavin administration. In contrast, ¹¹C-raclopride binding, which assesses the degree of dopamine binding to the D₂ dopamine receptor, increased in a dose-dependent manner. The authors hypothesize that the former finding was a result of an inability of cellular machinery in transduced neurons to store and accumulate radiolabeled dopamine. Patients in the highest dose cohort did have consistent requirement for a reduction in dopaminergic medication, the highest mean relative improvement in UPDRS motor scores, and a significant change in ¹¹C-raclopride binding potentials. These findings suggest that the highest dose evaluated in this study resulted in the greatest level of dopaminergic activity, but this was not shown conclusively.

Similarly, there was no dose-dependent effect on UPDRS motor scores, despite the fact that the authors introduced a “modified delivery method” in between the second and third cohorts “to increase the rate of delivery and enhance the distribution of the vector.” The supplementary methods indicate that this decision was based on non-human primate studies demonstrating similar vector distribution when switching to a continuous infusion method, increasing the delivery rate to 3 μL/min, and decreasing the cannula diameter. The authors conclude the manuscript by stating, “Only when we have an optimum mode and dose of delivery will we proceed to a more definitive double-blind placebo controlled trial.” It should be noted that with regard to delivery, an optimized, interventional-magnetic resonance imaging-guided platform for convection-enhanced delivery of viral vectors has been described.² Without real-time magnetic resonance imaging during infusion of the viral vector, it is not possible to determine if the infusate has been delivered to the target in the intended manner.

Nonetheless, the work reported by Palfi and colleagues represents a significant advance in the field of neurosurgical gene therapy by demonstrating the safety of this first-in-man use of a lentiviral-based vector for a central nervous system disorder. As their report points out, the magnitude of clinical effects were within the placebo range reported in other clinical trials, and should be interpreted with caution. Fortunately, these investigators have described their intention to optimize the delivery of ProSavin before engaging in a blinded, randomized phase 2 trial to assess efficacy.

Figure 1.

Trial design.¹ Reprinted from The Lancet, Vol 383/edition number 9923, Palfi S, Gurruchaga JM, Ralph GS, et al., Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial, Pages No. 1138-1146, Copyright (2014), with permission from Elsevier.