Although L-dopa remains the mainstay of Parkinson's disease therapy, two-thirds of all patients develop motor complications within six years of initiation of therapy, the most prominent of which are so-called dopa dyskinesias. In an effort to restore the benefits of L-dopa therapy to these patients and to minimize or eliminate the side effects of chronic dopa therapy, we performed several experiments in monkey and rodent models of PD. We demonstrated that, by using an approach which combines the aromatic L-amino acid decarboxylase (AADC) gene and the pro-drug (L-dopa), the neurotransmitter involved in PD (dopamine) can be synthesized and regulated. Striatal neurons, transduced with the AADC gene by an adeno-associated viral vector (AAV), can convert peripheral L-dopa to dopamine and stimulate DA receptors. Positron emission tomography (PET) and the AADC tracer, 6-[""""""""F]fluoro-L-m-tyrosine (FMT) demonstrated complete and long-term restoration of AADC enzyme in PD monkeys. This approach to treating Parkinson's disease may reduce the need for L-Dopa/Carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. In an effort to demonstrate clinical application of this approach, we propose the following translational experiments in the MPTP-treated Parkinsonian primate model: (i) evaluate clinical efficacy of AADC gene transfer combined with levodopa administration; (ii) evaluate the efficacy of AAV/AADC gene transfer aimed at alleviating levodopa-induced dyskinesias. More specifically, we will assess the effects of intracerebral transfer of AADC gene using AAV vector on dopa-dyskinesias using squirrel monkeys rendered Parkinsonian by systemic injection of the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These animals develop dopa-dyskinesias, which are indistinguishable from those observed in patients with Parkinson's disease. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration and may restore benefits of L-dopa treatment in patients with Parkinson's disease.
| Bankiewicz, Krystof S; Daadi, Marcel; Pivirotto, Philip et al. (2006) Focal striatal dopamine may potentiate dyskinesias in parkinsonian monkeys. Exp Neurol 197:363-72 |
