Elsevier

The Lancet

Volume 383, Issue 9923, 29 March–4 April 2014, Pages 1138-1146
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(13)61939-XGet rights and content

Summary

Background

Parkinson's disease is typically treated with oral dopamine replacement therapies; however, long-term treatment leads to motor complications and, occasionally, impulse control disorders caused by intermittent stimulation of dopamine receptors and off-target effects, respectively. We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin, a lentiviral vector-based gene therapy aimed at restoring local and continuous dopamine production in patients with advanced Parkinson's disease.

Methods

We undertook a phase 1/2 open-label trial with 12-month follow-up at two study sites (France and UK) to assess the safety and efficacy of ProSavin after bilateral injection into the putamen of patients with Parkinson's disease. All patients were then enrolled in a separate open-label follow-up study of long-term safety. Three doses were assessed in separate cohorts: low dose (1·9×107 transducing units [TU]); mid dose (4·0×107 TU); and high dose (1×108 TU). Inclusion criteria were age 48–65 years, disease duration 5 years or longer, motor fluctuations, and 50% or higher motor response to oral dopaminergic therapy. The primary endpoints of the phase 1/2 study were the number and severity of adverse events associated with ProSavin and motor responses as assessed with Unified Parkinson's Disease Rating Scale (UPDRS) part III (off medication) scores, at 6 months after vector administration. Both trials are registered at ClinicalTrials.gov, NCT00627588 and NCT01856439.

Findings

15 patients received ProSavin and were followed up (three at low dose, six mid dose, six high dose). During the first 12 months of follow-up, 54 drug-related adverse events were reported (51 mild, three moderate). Most common were increased on-medication dyskinesias (20 events, 11 patients) and on–off phenomena (12 events, nine patients). No serious adverse events related to the study drug or surgical procedure were reported. A significant improvement in mean UPDRS part III motor scores off medication was recorded in all patients at 6 months (mean score 38 [SD 9] vs 26 [8], n=15, p=0·0001) and 12 months (38 vs 27 [8]; n=15, p=0·0001) compared with baseline.

Interpretation

ProSavin was safe and well tolerated in patients with advanced Parkinson's disease. Improvement in motor behaviour was observed in all patients.

Funding

Oxford BioMedica.

Introduction

Parkinson's disease is a common neurodegenerative disorder mainly characterised by motor dysfunction resulting in bradykinesia, rigidity, tremor, gait impairment, and postural instability. The disease has a prevalence of around 1% in people aged 60 years, affecting around 5 million people worldwide.1 Several risk factors are associated with Parkinson's disease including inheritance (5–10% of patients)2 and exposure to chemicals such as pesticides.3 A crucial pathological component is the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta that project axons to the striatum, where dopamine is released. The rate of dopamine biosynthesis is limited by three enzymes that are expressed in nigral neurons: tyrosine hydroxylase and cyclohydrolase 1, which facilitate the conversion of tyrosine to levodopa, and aminoacid decarboxylase (AADC), which converts levodopa to dopamine.4, 5, 6

Current therapies for Parkinson's disease, which are mainly based on the oral dopamine precursor levodopa, provide excellent control of motor symptoms in the initial stages of the disease.7 However, as the disease progresses, levodopa therapy becomes less effective as side-effects emerge such as on–off phenomena (when the patient has improved mobility [on] due to levodopa and which is then followed by sudden unpredictable impaired mobility [off]) and dyskinesias.8 Previous studies have shown that the intermittent nature of oral levodopa administration and subsequent irregular stimulation of postsynaptic dopamine receptors is at least partly responsible for these motor complications.9 Inappropriate dopaminergic stimulation of the mesolimbic area by systemic intake of dopaminergic drugs can also induce dopamine dysregulation syndrome and impulse control disorders.10 Thus, a therapeutic approach that provides continuous and stable dopamine replacement, restricted to the dopamine-depleted striatum, might provide an effective long-term treatment without the onset of behavioural complications.

Gene transfer technology can provide long-term expression of therapeutic proteins in vivo. Three therapeutic approaches using adeno-associated virus (AAV) vectors have been evaluated in clinical trials of Parkinson's disease. These strategies were aimed at neuroprotection using the neurotrophic factor neurturin; enhanced conversion of levodopa to dopamine by gene transfer of AADC; and modulation of basal ganglia activity with glutamic acid decarboxylase.11, 12, 13, 14, 15 All these AAV-based gene therapies were shown to be safe and well tolerated, and showed some benefit in clinical motor assessments.12, 16, 17 Gene therapy approaches using lentiviral vectors have not previously been evaluated in clinical trials of CNS disorders. However, these vectors have been repeatedly shown to have low immunogenicity and an ability to transduce neuronal cells with high efficiency and carry a larger therapeutic cargo than AAV vectors.18, 19, 20, 21

We have generated a tricistronic lentiviral vector (ProSavin, Oxford BioMedica, Oxford, UK) that is based on the equine infectious anaemia virus encoding the rate-limiting dopamine biosynthetic enzymes tyrosine hydroxylase, AADC, and cyclohydrolase 1. Previous studies have shown that expression of these three enzymes in nondopaminergic cells, such as striatal neurons, is sufficient to enable these cells to manufacture dopamine.22 Thus, the therapeutic rationale for ProSavin is to deliver the vector to the motor region of the striatum (putamen) and convert striatal cells into so-called “dopamine factories”, thereby replacing the constant source of dopamine that is lost in Parkinson's disease.

Integrating vectors have the potential for insertional mutagenesis, as observed in clinical trials using gammaretroviral vectors to modify haematopoietic stem cells.23 Several risk factors for insertional mutagenesis were identified in these clinical studies. These factors included the use of gammaretroviral vectors with active promoter regions (and their preference for insertion at transcription start sites), the nature of the transgenes expressed, the proliferative nature of the target cell type, and the immunocompetence of the patients treated.23 The risk of insertional mutagenesis has been mitigated in the design of the lentiviral vector by removal of the viral control signals from the duplicated long terminal repeat by using the self-inactivating vector configuration, thereby reducing the potential for gene activation. ProSavin has also been shown to target postmitotic neurons and this factor is also likely to minimise the risk of oncogenesis. Additionally the preference of lentiviral vectors to integrate into active genes suggests that insertion near a proliferation or oncogene is unlikely. The genes delivered by ProSavin do not impart a proliferative advantage and the patients in this study are immunocompetent. We believe, therefore, that the weight of evidence suggests that the risk of oncogenesis is very low. No evidence for insertional mutagenesis was observed in supporting non-clinical studies.

In preclinical studies, surgical administration of ProSavin to the striatum was well tolerated and led to local dopamine production and significant behavioural improvement in rat and non-human primate models of Parkinson's disease.24 We aimed to assess the safety, tolerability, and efficacy of bilateral, intrastriatal delivery of ProSavin in patients with advanced Parkinson's disease.

Section snippets

Study design and setting

We undertook an open-label, dose-escalation phase 1/2 study with 12-month follow-up at two study sites (France and UK). All patients were subsequently enrolled into a separate open-label follow-up study to provide long-term (up to 9 years) safety data. After that point annual survival is assessed by follow-up phone calls for life. The study protocols (NCT00627588 and NCT01856439) were approved by the institutional review board of each participating institution and complied with the Declaration

Results

Between Jan 14, 2008, and Aug 8, 2011, 17 patients were enrolled in the study; two patients (both men) withdrew before receiving treatment (both screening failures; the first due to an intercurrent illness and the second due to a failure to meet the inclusion criteria of 50% improvement in UPDRS part III). The remaining 15 patients received ProSavin and were followed up according to the protocol (figure 1). Three patients were included at dose level one, six patients at dose level two, and six

Discussion

We report the results of a clinical trial describing the first-in-man use of a lentiviral-based gene therapy vector for a chronic neurodegenerative disorder of the CNS (panel). In view of the novelty of this approach the safety findings were of paramount importance and the favourable safety profile observed is highly encouraging. In terms of efficacy, a significant improvement in motor function was shown up to 12 months in all patients. Long-term follow-up data showed long-term tolerability and

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