The most direct rationale for treating PD is to confer a dopaminergic phenotype to cells within the striatum. This method should result in local production of levodopa or dopamine, thereby avoiding side effects of systemic drug delivery. To this end, several groups have designed therapies that deliver, via a viral carrier, genes in the dopamine biosynthetic pathway. The first reports in the early 1990s relied on the implantation of exogenously modified fibroblasts. These cells were harvested, amplified, and then genetically modified to produce enzymes such as tyrosine hydroxylase. Reimplantation resulted in an increase in striatal dopamine levels in rodent models (83-85).
Later studies accomplished the delivery of such genes directly to striatal cells with viral agents. A study by During et al. demonstrated that direct striatal transmission of tyrosine hydroxylase to rats by defective herpes simplex virus (HSV) produced substantial increases in levodopa and dopamine (as measured by striatal microdialysis), and produced a 60% reduction in amphetamine-induced spinning behavior which was maintained for a full year after treatment (86). Another study demonstrated the adeno-associated virus (AAV) delivery of aromatic amino acid decarboxylase (AADC) in a rat model of PD. Transfer of the AADC gene restored dopamine production from 5% to 50% of normal in 6-OHDA-lesioned rats. In these rats, behavioral effects were also noted, but this required the administration of systemic levodopa, although in smaller doses (87).
The generation and release of dopamine is a complex process. Dopamine synthesis requires tyrosine hydroxylase, guanosine triphosphate cyclohydrolase I (GTP-CHI), and AADC (87-89). Further, production alone does not confer the machinery for transmitter packaging and organized release. For this reason, several researchers have adopted strategies designed to deliver the multiple genes involved in dopamine production. Results suggest that the combined delivery of these genes is more effective than transduction with individual genes (90). One study additionally provided a vesicular monoamine transporter (VAT-2), enabling coordinated dopamine release and preventing elevated dopamine in the cytosol from inhibiting the action of tyrosine hydroxylase. This construct had a greater effect on rotational behavior than constructs without the VAT-2 gene and produced local levels of dopamine that were similar to those measured in normal rats (91). The conference of multiple enzymes has been shown to decrease drug-induced dyskinesia by 85%. It is thought that the continuous release of dopamine conferred by gene transfer corrects the otherwise pulsatile delivery, even when medical therapies are ongoing (92).
Studies have been extended to primate models as well. An early study demonstrated the feasibility of transfecting tyrosine hydroxylase and AADC to produce dopamine in the primate striatum but showed no significant behavioral changes (93). Later, Matsumura et al. demonstrated that AAV transmission of tyrosine hydroxylase, AADC, and GTP-CHI in primates produced substantial improvements in manual dexterity tasks and resulted in increased striatal dopamine levels relative to the untreated side (94).
These techniques certainly hold great promise for the clinical treatment of PD by methods that are more physiologic with potentially fewer side effects. Clinical trials employing viral delivery of dopamine synthetic enzymes are ongoing.
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