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Enzyme Replacement Strategies: Gene Delivery of AADC, GCH1 & TH
The dopaminergic biosynthetic pathway is well described, including the various rate-limiting steps and important cofactors. Synthesis of dopamine begins with the conversion of l-tyrosine to levodopa (L-dopa) by TH, followed by conversion to dopamine by AADC. GCH1 acts as a rate-limiting enzyme in the synthesis of tetrahydrobiopterin, a cofactor for TH. The rationale for targeting this pathway is, in part, justified by the observation that PD patients frequently develop dyskinesias, potentially the result of pulsatile stimulation of striatal dopamine receptors from intermittent delivery of oral medication. As oral dosage requirements increase, elevated levels of dopamine outside the basal ganglia lead to further side effects. Thus, continuous L-dopa delivery using ectopic biosynthetic enzymes within the striatum could lead to improved clinical outcomes, in part through a reduced requirement for oral medication.
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