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Neurosurgery
Review
Data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s disease
  1. R Mark Richardson1,2,
  2. Krystof S Bankiewicz3,4,
  3. Chadwick W Christine5,
  4. Amber D Van Laar6,7,
  5. Robert E Gross8,9,
  6. Russell Lonser4,
  7. Stewart A Factor9,
  8. Sandra K Kostyk10,
  9. Adrian P Kells7,
  10. Bernard Ravina11,
  11. Paul S Larson3
  1. 1 Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2 Harvard Medical School, Boston, Massachusetts, USA
  3. 3 Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA
  4. 4 Department of Neurological Surgery, Ohio State University College of Medicine, Columbus, Ohio, USA
  5. 5 Department of Neurology, University of California San Francisco, San Francisco, California, USA
  6. 6 Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  7. 7 Brain Neurotherapy Bio, Inc, Columbus, Ohio, USA
  8. 8 Department of Neurosurgery, Emory University, Atlanta, Georgia, USA
  9. 9 Department of Neurology, Emory University, Atlanta, Georgia, USA
  10. 10 Departments of Neuroscience and Neurology, Ohio State University College of Medicine, Columbus, Ohio, USA
  11. 11 Praxis Precision Medicines, Inc, Cambridge, Massachusetts, USA
  1. Correspondence to Dr R Mark Richardson, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, USA; mark.richardson{at}mgh.harvard.edu

Abstract

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson’s disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

  • neurosurgery
  • Parkinson's disease
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jnnp-2020-322904

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    Footnotes

    • Correction notice This article has been corrected since it appeared Online First. Figure 2 has been replaced.

    • Contributors RMR, APK and PSL contributed to the conception of the review and prepared the initial draft with the assistance of a medical writer. RMR, KSB, CWC, ADVL, REG, RL, SAF, SKK, APK, BR and PSL reviewed the manuscript critically and revised it for intellectual content, approved the final manuscript before submission, and are accountable for the accuracy and integrity of the work.

    • Funding The Michael J. Fox Foundation and Voyager Therapeutics, Inc, provided funding for the PD-1101 and PD-1102 trials, including for data collection and analyses.

    • Competing interests RMR, CWC, ADVL, REG and SAF received grants from Voyager Therapeutics, Inc. KSB received grants and personal fees from Voyager Therapeutics. Voyager Therapeutics is funding this research and is developing products related to the research described in this paper. REG serves as a consultant to Voyager Therapeutics and personally receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict-of-interest policies. RL received consulting fees from Voyager Therapeutics. SKK has nothing to disclose. APK is a former employee of Voyager Therapeutics and owns stock in that company. BR is a former employee of Voyager Therapeutics. PSL has received grants from Voyager Therapeutics and non-financial support from ClearPoint Neuro (formerly MRI Interventions, Inc).

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.