Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, chief, Division of Anatomic Pathology, and professor, Department of Pathology, University of California, San Diego; James Solomon, MD, PhD, resident, Department of Pathology, UCSD; Richard Wong, MD, PhD, molecular pathology fellow, Department of Pathology, UCSD; and Sounak Gupta, MBBS, PhD, molecular pathology fellow, Memorial Sloan Kettering Cancer Center, New York.

Development of brain circuits after gene therapy for Parkinson’s disease

Parkinson’s disease is caused by a loss of dopamine-producing nerves in the specialized substantia nigra pars compacta area of the brain. As these nerves degenerate, brain metabolism and nerve connections change, which ultimately leads to overactivity in the subthalamic nucleus (STN), resulting in movement dysfunction. A mainstay of therapy for Parkinson’s disease is medication such as levodopa, which provides replacement dopamine to the brain, but it loses its effect over time. More recent therapies include deep brain stimulator implants that target the STN, although numerous side effects may occur due to surgery and implantation of the device. To provide better long-term benefit to patients with the disease, a group of scientists is using adeno-associated virus (AAV) to deliver the glutamic acid decarboxylase (GAD) gene to reduce substantia nigra overactivity. The resultant GAD protein is an enzyme that catalyzes the production of gamma-aminobutyric acid, an inhibitory neurotransmitter that reduces nerve signaling, from L-glutamic acid. This research builds on work initially published in a phase one study in 2007, which showed that catheter infusion of AAV-GAD to the STN was safe and had potential benefits in reducing symptoms. The rationale behind this approach was that GAD gene therapy could convert some of these neurons into an inhibitory subtype, thereby reducing STN activity and mitigating symptoms. However, the mechanism underlying the way in which AAV-GAD worked remained unclear. To address this issue, the authors of the current study used ¹⁸F-fluorodeoxyglucose positron emission tomography (PET) scans to compare brain metabolism between 15 patients with Parkinson’s disease who underwent successful delivery of AAV2-GAD and completed longitudinal brain imaging and 20 patients who received a sham control during a 12-month period. The authors assessed the Parkinson’s disease-related covariance pattern (PDRP), a disease-specific network PET signal that indicates symptom progression. But despite the improvement in symptoms, the authors did not see a difference in PDRP scores between control and treatment groups. Therefore, they returned to the scans and found a new metabolic signature, which they termed GAD-related pattern (GADRP). It correlated with reduced metabolism in areas normally overactivated in Parkinson’s disease and also increased metabolism in the premotor cortex and supramarginal gyrus. The GADRP signature increased over time in AAV-GAD–treated patients and was seen in 14 of 15 AAV-GAD patients compared with only one of 20 control patients. This signature corresponded to new connections developed in the brain between the STN and the motor regions of the brain. These new connections were also associated with improved clinical outcomes. The results of this study suggest that viral gene therapy for Parkinson’s disease is effective and, while it may not alter the background disease process, can help the brain overcome abnormal activity by making new nerve connections and restructuring how the brain works in the areas affected by Parkinson’s disease.

Niethammer M, Tang CC, Vo A, et al. Gene therapy reduces Parkinson’s disease symptoms by reorganizing functional brain connectivity. Sci Transl Med. 2018;10. http://stm.sciencemag.org. Accessed December 12, 2018.

Correspondence: Dr. David Eidelberg at deidelbe@northwell.edu

Kaplitt MG, Feigin A, Tang C, et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase 1 trial. Lancet. 2007;369:2097–2105.