370. Reconstruction of the Nigrostriatal Pathway in Parkinsonian Macaques

The field of Gene Therapy in the CNS has recently witnessed a number of major conceptual changes. At present, ongoing strategies are focused on using vectors carrying genes to further modify brain circuits of interest. It is expected that these approaches will result in a great therapeutic potential being sustained by the induced changes in brain circuitry. Indeed, for the first time these advances will allow the implementation of “disease-modifying” therapies, e.g., trying to arrest or even revert the natural course of Parkinson's disease. Here we are using hRheb(S16H)-carrying Adeno-associated virus (AAV) vectors in parkinsonian macaques, in an attempt to reconstruct the damaged nigrostriatal pathway. Preliminary results reported here stand on the intracerebral delivery of h-Rheb-carrying AAV serotype 5 in the substantia nigra of two MPTP-treated macaques showing a severe parkinsonian syndrome. After a follow-up of six months, both macaques showed a lack of motor improvement, together with no changes on the conducted microPET neuroimage scans. However, the histopathological analysis revealed a moderate degree of axonal reinnervation in the putamen nucleus following a viral infection limited to 10-12 dopaminergic neurons per animal. These results, so far insufficient to elicit any motor/neuroimage improvements, are very appealing and indeed represent the first evidence that a damaged dopaminergic circuit can be reconstructed in adult parkinsonian macaques. A number of ongoing strategies are currently under development in an attempt to improve the amount of neurons being infected with the hRheb gene, therefore leading to a more complete reconstruction of the nigrostriatal pathway.