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

被引：75

作者：

Heiss, John D. ^{[1
]}

Lungu, Codrin ^{[2
,3
]}

Hammoud, Dima A. ^{[4
]}

Herscovitch, Peter ^{[5
]}

Ehrlich, Debra J. ^{[6
]}

Argersinger, Davis P. ^{[1
]}

Sinharay, Sanhita ^{[4
]}

Scott, Gretchen ^{[1
]}

Wu, Tianxia ^{[7
]}

Federoff, Howard J. ^{[8
]}

Zaghloul, Kareem A. ^{[1
]}

Hallett, Mark ^{[9
]}

Lonser, Russell R. ^{[10
]}

Bankiewicz, Krystof S. ^{[11
]}

机构：

[1] NINDS, Surg Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[2] NINDS, Div Clin Res, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[3] NINDS, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[4] NIH, Radiol & Imaging Sci, Clin Ctr, Bldg 10, Bethesda, MD 20892 USA

[5] NIH, Positron Emiss Tomog Dept, Clin Ctr, Bldg 10, Bethesda, MD 20892 USA

[6] NINDS, Parkinsons Dis Clin, Off Clin Director, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[7] NINDS, Clin Trials Unit, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[8] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA

[9] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA

[10] Ohio State Univ, Wexner Med Ctr, Dept Neurol Surg, Columbus, OH 43210 USA

[11] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

来源：

MOVEMENT DISORDERS | 2019年 / 34卷 / 07期

基金：

美国国家卫生研究院;

关键词：

convection-enhanced delivery; GDNF; gene therapy; Parkinson's; vector; CONVECTION-ENHANCED DELIVERY; NEUROTROPHIC FACTOR GDNF; SUBSTANTIA-NIGRA; DOPAMINERGIC-NEURONS; DOUBLE-BLIND; NEURTURIN; REGENERATION; AAV2-GDNF; STRIATUM; VECTORS;

D O I：

10.1002/mds.27724

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 mu L/hemisphere) at escalating doses: 9 x 10(10) vg (n = 6); 3 x 10(11) vg (n = 6); and 9 x 10(11) vg (n = 1). Intraoperative MRI monitored infusion distribution. Patients underwent UPDRS assessment and [F-18]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 [F-18]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 [F-18]FDOPA uptake suggests a neurotrophic effect on dopaminergic neurons. (c) 2019 International Parkinson and Movement Disorder Society

引用

页码：1073 / 1078

页数：6

共 26 条

[1] The GDNF family: Signalling, biological functions and therapeutic value
Airaksinen, MS
Saarma, M
[J]. NATURE REVIEWS NEUROSCIENCE, 2002, 3 (05) : 383 - 394
[2] Differential effects of glial cell line-derived neurotrophic factor and neurturin on developing and adult substantia nigra dopaminergic neurons
Åkerud, P
Alberch, J
Eketjäll, S
Wagner, J
Arenas, E
[J]. JOURNAL OF NEUROCHEMISTRY, 1999, 73 (01) : 70 - 78
[3] AAV viral vector delivery to the brain by shape-conforming MR-guided infusions
Bankiewicz, Krystof S.
Sudhakar, Vivek
Samaranch, Lluis
San Sebastian, Waldy
Bringas, John
Forsayeth, John
[J]. JOURNAL OF CONTROLLED RELEASE, 2016, 240 : 434 - 442
[4] Continuing trials of GDNF in Parkinson's disease
Barker, RA
[J]. LANCET NEUROLOGY, 2006, 5 (04) : 285 - 286
[5] Towards a neuroprotective gene therapy for Parkinson's disease:: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model
Björklund, A
Kirik, D
Rosenblad, C
Georgievska, B
Lundberg, C
Mandel, RJ
[J]. BRAIN RESEARCH, 2000, 886 (1-2) : 82 - 98
[6] Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas
Chittiboina, Prashant
Heiss, John D.
Warren, Katherine E.
Lonser, Russell R.
[J]. JOURNAL OF NEUROSURGERY-PEDIATRICS, 2014, 13 (03) : 276 - 282
[7] Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat
Connor, B
Kozlowski, DA
Schallert, T
Tillerson, JL
Davidson, BL
Bohn, MC
[J]. GENE THERAPY, 1999, 6 (12) : 1936 - 1951
[8] CONDITIONED MEDIA DERIVED FROM GLIAL-CELL LINES PROMOTE SURVIVAL AND DIFFERENTIATION OF DOPAMINERGIC-NEURONS INVITRO - ROLE OF MESENCEPHALIC GLIA
ENGELE, J
SCHUBERT, D
BOHN, MC
[J]. JOURNAL OF NEUROSCIENCE RESEARCH, 1991, 30 (02) : 359 - 371
[9] Pharmacokinetics and bioactivity of glial cell line-derived factor (GDNF) and neurturin (NTN) infused into the rat brain
Hadaczek, Piotr
Johnston, Louisa
Forsayeth, John
Bankiewicz, Krystof S.
[J]. NEUROPHARMACOLOGY, 2010, 58 (07) : 1114 - 1121
[10] Clinically Relevant Effects of Convection-Enhanced Delivery of AAV2-GDNF on the Dopaminergic Nigrostriatal Pathway in Aged Rhesus Monkeys
Johnston, Louisa C.
Eberling, Jamie
Pivirotto, Philip
Hadaczek, Piotr
Federoff, Howard J.
Forsayeth, John
Bankiewicz, Krystof S.
[J]. HUMAN GENE THERAPY, 2009, 20 (05) : 497 - 510

← 1 2 3 →