Gene Therapy for Parkinson's Disease
Gene Therapy for Parkinson's Disease
Striatal dopamine depletion in PD leads to hyperactivity of the STN, disrupting basal ganglia circuits, resulting in impaired motor function. The importance of these pathways is seen with DBS therapy, which is thought to inhibit STN overactivity via high frequency electrical stimulation, producing clinical improvements. Alternative approaches to inhibiting the STN include increasing the local availability of the inhibitory neurtransmitter GABA through increased local production. The biosynthesis of GABA is well understood, with GAD the rate-limiting biosynthetic enzyme, existing as two genetically distinct isoforms (GAD65 and GAD67), with differing anatomical distributions and properties. As a consequence, studies have included viral constructs coding for either isoform, finding that STN injection of AAV constructs resulted in long-term GAD isoform expression in predictable cellular distributions. Electrophysiological recordings found that AAV-GAD65 treated rats showed increased GABA release following STN stimulation and improved motor function in 6-OHDA lesioned rats. One study suggested a neuroprotective action, with improved TH-positive dopaminergic neuron survival. Subsequent studies found that AAV-GAD treated MPTP-lesioned macaques showed significant improvements in clinical measures of parkinsonism more than 56 weeks, with an associated significant increase in FDG-PET activity on the injected side.
An open-label Phase I human study followed, using unilateral stereotactic STN injection of an AAV2-GAD65 or GAD67 vector (ClinicalTrials.gov identifier: NCT00195143). Twelve patients each received a single injection of 50 µl of viral vector in the most symptomatic hemisphere, using a range of concentrations, with a follow-up period of at least 12 months. No adverse events related to the trial intervention were recorded, no patient withdrew from the study and no patient was lost to follow-up. Significant improvements in UPDRS motor scores were observed in both the 'on' and 'off' states, with improvement in ipsilateral FDG-PET appearances. A subsequent Phase II double-blind randomized, sham-surgery controlled trial of bilateral STN injection of AAV2–GAD (ClinicalTrials.gov identifier: NCT00643890) found a greater improvement in UPDRS scores in the active treatment group. Side effects were felt to be relatively minor, including headache and nausea. Overall, these clinical trials of AAV2-GAD suggest the approach is generally safe and efficacious. The overall UPDRS score improvements were relatively modest (8.1 in actively treated subjects vs 4.7 in controls), so future studies will have to compare these results with benefits obtained from conventional DBS.
Glutamic Acid Decarboxylase
Striatal dopamine depletion in PD leads to hyperactivity of the STN, disrupting basal ganglia circuits, resulting in impaired motor function. The importance of these pathways is seen with DBS therapy, which is thought to inhibit STN overactivity via high frequency electrical stimulation, producing clinical improvements. Alternative approaches to inhibiting the STN include increasing the local availability of the inhibitory neurtransmitter GABA through increased local production. The biosynthesis of GABA is well understood, with GAD the rate-limiting biosynthetic enzyme, existing as two genetically distinct isoforms (GAD65 and GAD67), with differing anatomical distributions and properties. As a consequence, studies have included viral constructs coding for either isoform, finding that STN injection of AAV constructs resulted in long-term GAD isoform expression in predictable cellular distributions. Electrophysiological recordings found that AAV-GAD65 treated rats showed increased GABA release following STN stimulation and improved motor function in 6-OHDA lesioned rats. One study suggested a neuroprotective action, with improved TH-positive dopaminergic neuron survival. Subsequent studies found that AAV-GAD treated MPTP-lesioned macaques showed significant improvements in clinical measures of parkinsonism more than 56 weeks, with an associated significant increase in FDG-PET activity on the injected side.
An open-label Phase I human study followed, using unilateral stereotactic STN injection of an AAV2-GAD65 or GAD67 vector (ClinicalTrials.gov identifier: NCT00195143). Twelve patients each received a single injection of 50 µl of viral vector in the most symptomatic hemisphere, using a range of concentrations, with a follow-up period of at least 12 months. No adverse events related to the trial intervention were recorded, no patient withdrew from the study and no patient was lost to follow-up. Significant improvements in UPDRS motor scores were observed in both the 'on' and 'off' states, with improvement in ipsilateral FDG-PET appearances. A subsequent Phase II double-blind randomized, sham-surgery controlled trial of bilateral STN injection of AAV2–GAD (ClinicalTrials.gov identifier: NCT00643890) found a greater improvement in UPDRS scores in the active treatment group. Side effects were felt to be relatively minor, including headache and nausea. Overall, these clinical trials of AAV2-GAD suggest the approach is generally safe and efficacious. The overall UPDRS score improvements were relatively modest (8.1 in actively treated subjects vs 4.7 in controls), so future studies will have to compare these results with benefits obtained from conventional DBS.
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