Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease

John D Heiss; Codrin Lungu; Dima A Hammoud; Peter Herscovitch; Debra J Ehrlich; Davis P Argersinger; Sanhita Sinharay; Gretchen Scott; Tianxia Wu; Howard J Federoff; Kareem A Zaghloul; Mark Hallett; Russell R Lonser; Krystof S Bankiewicz

doi:10.1002/mds.27724

Trial of magnetic resonance-guided putaminal gene therapy for advanced Parkinson's disease

Mov Disord. 2019 Jul;34(7):1073-1078. doi: 10.1002/mds.27724. Epub 2019 May 30.

Authors

Affiliations

¹ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
² Division of Clinical Research, and Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
³ Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Positron Emission Tomography Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Parkinson's Disease Clinic, Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
⁶ Clinical Trials Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
⁷ Department of Neurology, University of California-Irvine, Irvine, California, USA.
⁸ Human Motor Control Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
⁹ Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
¹⁰ Department of Neurological Surgery, University of California-San Francisco, San Francisco, California, USA.

Abstract

Objective: To investigate the safety and tolerability of convection-enhanced delivery of an adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor into the bilateral putamina of PD patients.

Methods: Thirteen adult patients with advanced PD underwent adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor and gadoteridol (surrogate MRI tracer) coinfusion (450 μL/hemisphere) at escalating doses: 9 × 10¹⁰ vg (n = 6); 3 × 10¹¹ vg (n = 6); and 9 × 10¹¹ vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [¹⁸ F]FDOPA-PET scanning preoperatively and 6 and 18 months postoperatively.

Results: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor was tolerated without clinical or radiographic toxicity. Average putaminal coverage was 26%. UPDRS scores remained stable. Ten of thirteen and 12 of 13 patients had increased [¹⁸ F]FDOPA Kis at 6 and 18 months postinfusion (increase range: 5-274% and 8-130%; median, 36% and 54%), respectively. Ki differences between baseline and 6- and 18-month follow-up were statistically significant (P < 0.0002).

Conclusion: Adeno-associated virus, serotype-2 vector carrying glial cell line-derived neurotrophic factor infusion was safe and well tolerated. Increased [¹⁸ F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. © 2019 International Parkinson and Movement Disorder Society.

Keywords: GDNF; Parkinson's; convection-enhanced delivery; gene therapy; vector.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Dependovirus / genetics*
Female
Genetic Therapy*
Humans
Magnetic Resonance Imaging / methods
Male
Parkinson Disease / drug therapy*
Parkinson Disease / genetics
Parkinsonian Disorders / drug therapy*
Parkinsonian Disorders / genetics
Parkinsonian Disorders / therapy
Putamen / drug effects

Grants and funding

Z99 NS999999/Intramural NIH HHS/United States