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. 2020 Oct 30;17(4):1539–1562. doi: 10.1007/s13311-020-00940-4

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© The Author(s) 2020

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — Rationale for the different gene therapy strategies currently used in PD, compared with deep brain stimulation. (A) Normal motor circuit anatomy and activity. (B) In PD, there is degeneration of the nigrostriatal (NS) projection from the substantia nigra pars compacta (SNc) to the putamen. This results in abnormalities of motor circuit activity, including hyperactivity of the STN nucleus. (C) DBS stimulation of the STN inhibits STN hyperactivation and so restores normal circuit activity. (D) Normal motor circuit function can be restored through GT: (a) Circuit modifying GT uses gene transfer of the enzyme GAD to the STN, so directly inhibiting STN activity. (b) DA synthetic gene GT replenishes DA supply within the putamen, so normalizing circuit activity and function. (c) Growth factor GT exposes axonal terminals of NS projection neurons within the putamen to GFs, so facilitating transport of such GFs to the SNc. This may prevent further degeneration of the NS projection and boost function of residual axonal arbors.