Research ArticleGene Therapy

Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity

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Science Translational Medicine  28 Nov 2018:
Vol. 10, Issue 469, eaau0713
DOI: 10.1126/scitranslmed.aau0713

The metabolic signature of gene therapy

Gene therapy delivering glutamic acid decarboxylase (GAD) is known to have therapeutic effects in patients with Parkinson’s disease (PD). However, the precise mechanisms mediating the improvements remain unclear. Now, Niethammer et al. used brain metabolic network analysis in patients with PD and showed that after gene therapy, patients developed a treatment-specific brain metabolic network involving motor-cortical regions. The network correlated with clinical outcome and was not affected by placebo effect. The results indicate that the therapeutic effects of GAD gene therapy are likely mediated by modulation of brain metabolism and suggest that metabolic network analysis might be useful for evaluating therapeutic efficacy in neurological disorders.


Gene therapy is emerging as a promising approach for treating neurological disorders, including Parkinson’s disease (PD). A phase 2 clinical trial showed that delivering glutamic acid decarboxylase (GAD) into the subthalamic nucleus (STN) of patients with PD had therapeutic effects. To determine the mechanism underlying this response, we analyzed metabolic imaging data from patients who received gene therapy and those randomized to sham surgery, all of whom had been scanned preoperatively and at 6 and 12 months after surgery. Those who received GAD gene therapy developed a unique treatment-dependent polysynaptic brain circuit that we termed as the GAD–related pattern (GADRP), which reflected the formation of new polysynaptic functional pathways linking the STN to motor cortical regions. Patients in both the treatment group and the sham group expressed the previously reported placebo network (the sham surgery–related pattern or SSRP) when blinded to the treatment received. However, only the appearance of the GADRP correlated with clinical improvement in the gene therapy–treated subjects. Treatment-induced brain circuits can thus be useful in clinical trials for isolating true treatment responses and providing insight into their underlying biological mechanisms.

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