We used an overlesioned hemiparkinsonian MPTP primate model to evaluate the safety and efficacy of AAV2-GDNF for PD. In this model, the nigrostriatal pathway is modestly lesioned in one hemisphere and severely lesioned in the other, resembling both early- and late-stage PD, respectively (Eberling et al.
). We chose this model to evaluate the effectiveness of GDNF at different stages of the degenerative process. FMT uptake was significantly increased by comparable magnitudes in the putamen in both hemispheres of AAV2-GDNF-treated monkeys, indicating increased dopaminergic activity in the nigrostriatal pathways. In addition, AAV2-GDNF-treated monkeys showed clinical improvement without the development of adverse effects, such as dyskinesia. The control monkeys did not show significant changes in FMT uptake with only slight recovery of clinical measures, as is often seen with the MPTP lesion model.
We reported the results of a parallel study in aged nonhuman primates treated with AAV2-GDNF and showed that this vector directed broadly distributed GDNF expression in the striatum, improved several clinically relevant measures of nigrostriatal function, and displayed no apparent adverse effects (Johnston et al.
). The use of aged and MPTP-treated NHP for the clinical development of novel therapeutics for PD addresses different critical issues for potential clinical application. The use of aged primates (>20 years) addresses issues related to the neuroregenerative potential of the aged brain. This is clearly significant because the mean age of onset for PD is about 60. Aged NHP undergo many of the changes seen in aged humans, including the loss of the dopaminergic phenotype in the substantia nigra, and improvements in dopaminergic function have been reported after treatment with growth factors (Kordower et al.
; Maswood et al.
; Grondin et al.
). The MPTP model is important because the clinical syndrome produced closely mimicks that seen in humans with PD, and therefore addresses questions regarding clinical efficacy (Fiandaca et al.
). In this respect, our studies resemble similar studies in aged and MPTP-treated, monkeys conducted before the phase 1 trial of CERE-120 (AAV2-NTN) (Kordower et al.
; Herzog et al.
; Marks et al.
; Palfi, 2008
The present study differs from previous reports by demonstrating the neuroregenerative potential of AAV2-GDNF in a stable primate model of PD. We previously showed temporal changes in nigrostriatal degeneration by evaluating monkeys at various time points after MPTP administration (Eberling et al.
). These findings guided subsequent work aimed at neuroprotection by administering growth factors and neurotoxins closely in time in order to prevent the degeneration that occurs several days after a neurotoxic insult to the dopaminergic system (Kordower et al.
; Eslamboli et al.
). This neuroprotective strategy is problematic because it assumes that the cause of idiopathic PD is a neurotoxic insult. The use of the overlesioned primate model, in which the dopaminergic deficit was well established (>5 months before the administration of AAV2-GDNF), enabled the simultaneous evaluation of the neuroregenerative capacity of severely and mildly injured nigrostriatal pathways. The increased FMT uptake in both hemispheres suggests that AAV2-GDNF may be effective in addressing early and later stages of the disease process when applied to clinical populations. It is important to note in this context that the placebo-controlled phase 2 efficacy study of CERE-120 was reported to have failed to meet its end points (see http://www.ceregene.com/press_112608.asp
), confirming early findings of modest clinical improvements that were not accompanied by changes in F-dopa uptake (Marks et al.
). The failure of this clinical trial to meet its primary objectives raises an important issue in addition to that raised previously. An often underappreciated factor is the key role of the vector infusion method used. In Kordower et al.
), distribution of neurturin immunoreactivity was restricted to a 3- to 4-mm radius, consistent with acute injection protocols. In contrast, the CED method produces complete coverage of the putamen by GDNF immunoreactivity (8- to 10-mm radius). This broad distribution of transgene within the putamen was also seen with AAV2-hAADC (Bankiewicz et al.
; Cunningham et al.
), and correlated with efficacy in NHPs (Forsayeth et al.
) and in humans (Eberling et al.
). In contrast, highly focal delivery of AAV2-hAADC was associated with the appearance of l
-dopa-induced dyskinesias in MPTP-lesioned NHPs (Bankiewicz et al.
In summary, interim in vivo
findings in stably lesioned NHPs presented here demonstrate that AAV2-GDNF delivered by CED into the putamen exhibits significant neuroregenerative capacity in both mildly and severely lesioned nigrostriatal pathways. This model more closely recapitulates the situation encountered in PD patients in whom more than 60% of the nigra is lost before symptoms appear. This initial report will be followed by detailed postmortem analyses that, together with our study in aged NHPs (Johnston et al.
), will form the basis of an Investigational New Drug application for AAV2-GDNF.