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

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

Cancer Systems Imaging

Research output: Contribution to journal › Article › peer-review

65 Scopus citations

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 [¹⁸F]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 [¹⁸F]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 [¹⁸F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons.

Original language	English (US)
Pages (from-to)	1073-1078
Number of pages	6
Journal	Movement Disorders
Volume	34
Issue number	7
DOIs	https://doi.org/10.1002/mds.27724
State	Published - Jul 2019

Keywords

GDNF
Parkinson's
convection-enhanced delivery
gene therapy
vector

ASJC Scopus subject areas

Neurology
Clinical Neurology

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Heiss, J. D., Lungu, C., Hammoud, D. A., Herscovitch, P., Ehrlich, D. J., Argersinger, D. P., Sinharay, S., Scott, G., Wu, T., Federoff, H. J., Zaghloul, K. A., Hallett, M., Lonser, R. R., & Bankiewicz, K. S. (2019). Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson's disease. Movement Disorders, 34(7), 1073-1078. https://doi.org/10.1002/mds.27724

@article{c162b937a71e45b1b8b1797d25bf4956,

title = "Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson's disease",

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 [18F]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 [18F]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 [18F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons.",

keywords = "GDNF, Parkinson's, convection-enhanced delivery, gene therapy, vector",

author = "Heiss, {John D.} and Codrin Lungu and Hammoud, {Dima A.} and Peter Herscovitch and Ehrlich, {Debra J.} and Argersinger, {Davis P.} and Sanhita Sinharay and Gretchen Scott and Tianxia Wu and Federoff, {Howard J.} and Zaghloul, {Kareem A.} and Mark Hallett and Lonser, {Russell R.} and Bankiewicz, {Krystof S.}",

note = "Publisher Copyright: {\textcopyright} 2019 International Parkinson and Movement Disorder Society",

year = "2019",

month = jul,

doi = "10.1002/mds.27724",

language = "English (US)",

volume = "34",

pages = "1073--1078",

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T1 - Trial of magnetic resonance–guided putaminal gene therapy for advanced Parkinson's disease

AU - Heiss, John D.

AU - Lungu, Codrin

AU - Hammoud, Dima A.

AU - Herscovitch, Peter

AU - Ehrlich, Debra J.

AU - Argersinger, Davis P.

AU - Sinharay, Sanhita

AU - Scott, Gretchen

AU - Wu, Tianxia

AU - Federoff, Howard J.

AU - Zaghloul, Kareem A.

AU - Hallett, Mark

AU - Lonser, Russell R.

AU - Bankiewicz, Krystof S.

PY - 2019/7

Y1 - 2019/7

N2 - 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 [18F]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 [18F]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 [18F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons.

AB - 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 [18F]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 [18F]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 [18F]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons.

KW - GDNF

KW - Parkinson's

KW - convection-enhanced delivery

KW - gene therapy

KW - vector

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U2 - 10.1002/mds.27724

DO - 10.1002/mds.27724

M3 - Article

C2 - 31145831

AN - SCOPUS:85066470261

SN - 0885-3185

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SP - 1073

EP - 1078

JO - Movement Disorders

JF - Movement Disorders

IS - 7

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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