The broad objective of this proposal is to test the hypothesis that L-dopa-induced dyskinesias (LID) in Parkinson's disease (PD) can be ameliorated by the reintroduction of aromatic L-amino acid decarboxylase (AADC) expression in the striatum, via gene transfer. L-dopa is the mainstay therapy for PD, despite the fact that most patients eventually develop LID, the most prominent motor complication of this treatment. LID reflects a loss of L-dopa conversion efficiency that underlies the progressive blunting of L-dopa responsiveness in PD patients. Infusion of a recombinant adeno-associated virus (AAV) encoding human AADC (AAV-hAADC) into the straitum of Parkinsonian monkeys leads to substantial restoration of neuronal ability to convert exogenously administered L-dopa into dopamine (DA). Preliminary clinical follow-up of patients receiving striatal infusions of AAV-hAADC, in a trial at our institution, has suggested that some patients may experience reduced LID following gene transfer. To explore this possibility, we plan to return to the preclinical nonhuman primate (NHP) model, with these two specific aims: to determine whether diffuse expression of AADC within the putamen of over-lesioned parkinsonian monkeys produces a reduction in LID, and to correlate these changes in L-dopa associated behavioral activity with regional changes in L-dopa induced metabolic activity within the basal ganglia thalamocortical circuitry. This information will significantly increase our understanding of the region-specific role of dopamine in LID, which will improve our ability to develop treatments that enhance the quality of life for PD patients receiving L-dopa therapy.
TO PUBLIC HEALTH: Most patients with Parkinson's disease eventually develop uncontrollable movements that are a debilitating side-effect of therapeutic medication. This research uses a neurosurgical gene therapy technique in an animal model of Parkinson's disease, to test whether increasing the level of dopamine in a specific part of the brain can relieve, these severe side-effects. ? ? ?
| Richardson, R Mark; Gimenez, Francisco; Salegio, Ernesto Aguilar et al. (2011) T2 imaging in monitoring of intraparenchymal real-time convection-enhanced delivery. Neurosurgery 69:154-63; discussion 163 |
| Richardson, R Mark; Kells, Adrian P; Rosenbluth, Kathryn H et al. (2011) Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson's disease. Mol Ther 19:1048-57 |
| Fiandaca, Massimo S; Salegio, Ernesto Aguilar; Yin, Dali et al. (2011) Human/nonhuman primate AC-PC ratio--considerations for translational brain measurements. J Neurosci Methods 196:124-30 |
| Richardson, R Mark; Kells, Adrian P; Martin, Alastair J et al. (2011) Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg 89:141-51 |
| Su, Xiaomin; Kells, Adrian P; Salegio, Ernesto A et al. (2010) Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther 18:1490-5 |
| Richardson, R M; Varenika, V; Forsayeth, J R et al. (2009) Future applications: gene therapy. Neurosurg Clin N Am 20:205-10 |
