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Vol. 89, No. 3, 2011
Issue release date: June 2011
Free Access
Stereotact Funct Neurosurg 2011;89:141–151
(DOI:10.1159/000323544)

Novel Platform for MRI-Guided Convection-Enhanced Delivery of Therapeutics: Preclinical Validation in Nonhuman Primate Brain

Richardson R.M.a · Kells A.P.a · Martin A.J.b · Larson P.S.a · Starr P.A.a · Piferi P.G.c · Bates G.c · Tansey L.c · Rosenbluth K.H.a · Bringas J.R.a · Berger M.S.a · Bankiewicz K.S.a
Departments of aNeurological Surgery and bRadiology, University of California San Francisco, San Francisco, Calif., and cSurgiVision Inc., Irvine, Calif., USA
email Corresponding Author

Abstract

Background/Aims: A skull-mounted aiming device and integrated software platform has been developed for MRI-guided neurological interventions. In anticipation of upcoming gene therapy clinical trials, we adapted this device for real-time convection-enhanced delivery of therapeutics via a custom-designed infusion cannula. The targeting accuracy of this delivery system and the performance of the infusion cannula were validated in nonhuman primates. Methods: Infusions of gadoteridol were delivered to multiple brain targets and the targeting error was determined for each cannula placement. Cannula performance was assessed by analyzing gadoteridol distributions and by histological analysis of tissue damage. Results: The average targeting error for all targets (n = 11) was 0.8 mm (95% CI = 0.14). For clinically relevant volumes, the distribution volume of gadoteridol increased as a linear function (R2 = 0.97) of the infusion volume (average slope = 3.30, 95% CI = 0.2). No infusions in any target produced occlusion, cannula reflux or leakage from adjacent tracts, and no signs of unexpected tissue damage were observed. Conclusions: This integrated delivery platform allows real-time convection-enhanced delivery to be performed with a high level of precision, predictability and safety. This approach may improve the success rate for clinical trials involving intracerebral drug delivery by direct infusion.


 goto top of outline Key Words

  • Convection-enhanced delivery
  • Interventional MRI
  • Gene therapy
  • Drug delivery

 goto top of outline Abstract

Background/Aims: A skull-mounted aiming device and integrated software platform has been developed for MRI-guided neurological interventions. In anticipation of upcoming gene therapy clinical trials, we adapted this device for real-time convection-enhanced delivery of therapeutics via a custom-designed infusion cannula. The targeting accuracy of this delivery system and the performance of the infusion cannula were validated in nonhuman primates. Methods: Infusions of gadoteridol were delivered to multiple brain targets and the targeting error was determined for each cannula placement. Cannula performance was assessed by analyzing gadoteridol distributions and by histological analysis of tissue damage. Results: The average targeting error for all targets (n = 11) was 0.8 mm (95% CI = 0.14). For clinically relevant volumes, the distribution volume of gadoteridol increased as a linear function (R2 = 0.97) of the infusion volume (average slope = 3.30, 95% CI = 0.2). No infusions in any target produced occlusion, cannula reflux or leakage from adjacent tracts, and no signs of unexpected tissue damage were observed. Conclusions: This integrated delivery platform allows real-time convection-enhanced delivery to be performed with a high level of precision, predictability and safety. This approach may improve the success rate for clinical trials involving intracerebral drug delivery by direct infusion.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 1994;91:2076–2080.
  2. Bankiewicz KS, Eberling JL, Kohutnicka M, Jagust W, Pivirotto P, Bringas J, Cunningham J, Budinger TF, Harvey-White J: Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 2000;164:2–14.
  3. Bankiewicz KS, Forsayeth J, Eberling JL, Sanchez-Pernaute R, Pivirotto P, Bringas J, Herscovitch P, Carson RE, Eckelman W, Reutter B, Cunningham J: Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-HAADC. Mol Ther 2006;14:564–570.
  4. Daadi MM, Pivirotto P, Bringas J, Cunningham J, Forsayeth J, Eberling J, Bankiewicz KS: Distribution of AAV2-HAADC-transduced cells after 3 years in parkinsonian monkeys. Neuroreport 2006;17:201–204.
  5. Forsayeth JR, Eberling JL, Sanftner LM, Zhen Z, Pivirotto P, Bringas J, Cunningham J, Bankiewicz KS: A dose-ranging study of AAV-HAADC therapy in parkinsonian monkeys. Mol Ther 2006;14:571–577.
  6. Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins RA, VanBrocklin HF, Wright JF, Bankiewicz KS, Aminoff MJ: Safety and tolerability of putaminal AADC gene therapy for parkinson disease. Neurology 2009;73:1662–1669.
  7. Eberling JL, Jagust WJ, Christine CW, Starr P, Larson P, Bankiewicz KS, Aminoff MJ: Results from a phase I safety trial of HAADC gene therapy for parkinson disease. Neurology 2008;70:1980–1983.
  8. Nguyen TT, Pannu YS, Sung C, Dedrick RL, Walbridge S, Brechbiel MW, Garmestani K, Beitzel M, Yordanov AT, Oldfield EH: Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging. J Neurosurg 2003;98:584–590.
  9. Richardson RM, Varenika V, Forsayeth JR, Bankiewicz KS: Future applications: gene therapy. Neurosurg Clin N Am 2009;20:205–210.
  10. Fiandaca MS, Forsayeth JR, Dickinson PJ, Bankiewicz KS: Image-guided convection-enhanced delivery platform in the treatment of neurological diseases. Neurotherapeutics 2008;5:123–127.
  11. Fiandaca MS, Varenika V, Eberling J, McKnight T, Bringas J, Pivirotto P, Beyer J, Hadaczek P, Bowers W, Park J, Federoff H, Forsayeth J, Bankiewicz KS: Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage 2009;47(suppl 2):T27–T35.
  12. Gimenez F, Krauze MT, Valles F, Hadaczek P, Bringas J, Sharama N, Forsayeth J, Bankiewicz KS: Image-guided convection-enhanced delivery of GDNF protein into monkey putamen. Neuroimage 2011;54(suppl 1):S189–195.
  13. Su X, Kells AP, Aguilar Salegio EA, Richardson RM, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Forsayeth J, Bankiewicz KS: Real-time MR imaging with gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther 2010;18:1490–1495.
  14. Lonser RR, Warren KE, Butman JA, Quezado Z, Robison RA, Walbridge S, Schiffman R, Merrill M, Walker ML, Park DM, Croteau D, Brady RO, Oldfield EH: Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 2007;107:190–197.
  15. Krauze MT, Saito R, Noble C, Tamas M, Bringas J, Park JW, Berger MS, Bankiewicz K: Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 2005;103:923–929.
  16. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S: Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 1998;57:1–9.
  17. Su X, Kells AP, Huang EJ, Lee HS, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Penticuff J, Eberling J, Federoff HJ, Forsayeth J, Bankiewicz KS: Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum Gene Ther 2009;20:1627–1640.
  18. Truwit CL, Liu H: Prospective stereotaxy: a novel method of trajectory alignment using real-time image guidance. J Magn Reson Imaging 2001;13:452–457.
  19. Hall WA, Liu H, Martin AJ, Maxwell RE, Truwit CL: Brain biopsy sampling by using prospective stereotaxis and a trajectory guide. J Neurosurg 2001;94:67–71.
  20. Martin AJ, Hall WA, Roark C, Starr PA, Larson PS, Truwit CL: Minimally invasive precision brain access using prospective stereotaxy and a trajectory guide. J Magn Reson Imaging 2008;27:737–743.
  21. Martin AJ, Larson PS, Ostrem JL, Keith Sootsman W, Talke P, Weber OM, Levesque N, Myers J, Starr PA: Placement of deep brain stimulator electrodes using real-time high-field interventional magnetic resonance imaging. Magn Reson Med 2005;54:1107–1114.
  22. Starr PA, Martin AJ, Ostrem JL, Talke P, Levesque N, Larson PS: Subthalamic nucleus deep brain stimulator placement using high-field interventional magnetic resonance imaging and a skull-mounted aiming device: technique and application accuracy. J Neurosurg 2010;112:479–490.
  23. Marks WJ Jr, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, Vitek J, Stacy M, Turner D, Verhagen L, Bakay R, Watts R, Guthrie B, Jankovic J, Simpson R, Tagliati M, Alterman R, Stern M, Baltuch G, Starr PA, Larson PS, Ostrem JL, Nutt J, Kieburtz K, Kordower JH, Olanow CW: Gene delivery of AAV2-neurturin for parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 2010;9:1164–1172.
  24. Bartus RT, Herzog CD, Chu Y, Wilson A, Brown L, Siffert J, Johnson EM Jr, Olanow CW, Mufson EJ, Kordower JH: Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson’s disease and nonhuman primate brains. Mov Disord 2010, Epub ahead of print.
  25. Eberling JL, Kells AP, Pivirotto P, Beyer J, Bringas J, Federoff HJ, Forsayeth J, Bankiewicz KS: Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys. Hum Gene Ther 2009;20:511–518.
  26. Johnston LC, Eberling J, Pivirotto P, Hadaczek P, Federoff HJ, Forsayeth J, Bankiewicz KS: Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys. Hum Gene Ther 2009;20:497–510.
  27. Morrison PF, Lonser RR, Oldfield EH: Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J Neurosurg 2007;107:74–83.
  28. Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VG, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M: Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006;59:459–466.
  29. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS: Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 2005;57:298–302.
  30. Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B: Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg 2005;102:216–222.
  31. Sampson JH, Archer G, Pedain C, Wembacher-Schroder E, Westphal M, Kunwar S, Vogelbaum MA, Coan A, Herndon JE, Raghavan R, Brady ML, Reardon DA, Friedman AH, Friedman HS, Rodriguez-Ponce MI, Chang SM, Mittermeyer S, Croteau D, Puri RK: Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg 2010;13:301–309.
  32. Lidar Z, Mardor Y, Jonas T, Pfeffer R, Faibel M, Nass D, Hadani M, Ram Z: Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg 2004;100:472–479.
  33. Sampson JH, Raghavan R, Provenzale JM, Croteau D, Reardon DA, Coleman RE, Rodriguez Ponce I, Pastan I, Puri RK, Pedain C: Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin. AJR Am J Roentgenol 2007;188:703–709.
  34. Holloway KL, Gaede SE, Starr PA, Rosenow JM, Ramakrishnan V, Henderson JM: Frameless stereotaxy using bone fiducial markers for deep brain stimulation. J Neurosurg 2005;103:404–413.
  35. Yin D, Valles FE, Fiandaca MS, Bringas J, Gimenez F, Berger MS, Forsayeth J, Bankiewicz KS: Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates. Neuroimage 2009, Epub ahead of print.
  36. Yin D, Richardson RM, Fiandaca MS, Bringas J, Forsayeth J, Berger MS, Bankiewicz KS: Cannula placement for effective convection-enhanced delivery in the nonhuman primate thalamus and brainstem: implications for clinical delivery of therapeutics. J Neurosurg 2010;113:240–248.
  37. Heiss JD, Walbridge S, Asthagiri AR, Lonser RR: Image-guided convection-enhanced delivery of muscimol to the primate brain. J Neurosurg 2010;112:790–795.
  38. Szerlip NJ, Walbridge S, Yang L, Morrison PF, Degen JW, Jarrell ST, Kouri J, Kerr PB, Kotin R, Oldfield EH, Lonser RR: Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles. J Neurosurg 2007;107:560–567.
  39. Richardson RM, Larson PS, Bankiewicz KS: Gene and cell delivery to the degenerated striatum: status of preclinical efforts in primate models. Neurosurgery 2008;63:629–642; discussion 642–644.

 goto top of outline Author Contacts

R. Mark Richardson, MD, PhD
Department of Neurological Surgery
505 Parnassus Avenue, Room M779
San Francisco, CA 94143-0112 (USA)
E-Mail richardsonma@neurosurg.ucsf.edu


 goto top of outline Article Information

Received: September 18, 2010
Accepted after revision: December 10, 2010
Published online: April 14, 2011
Number of Print Pages : 11
Number of Figures : 7, Number of Tables : 1, Number of References : 39


 goto top of outline Publication Details

Stereotactic and Functional Neurosurgery

Vol. 89, No. 3, Year 2011 (Cover Date: June 2011)

Journal Editor: Roberts D.W. (Lebanon, N.H.)
ISSN: 1011-6125 (Print), eISSN: 1423-0372 (Online)

For additional information: http://www.karger.com/SFN


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background/Aims: A skull-mounted aiming device and integrated software platform has been developed for MRI-guided neurological interventions. In anticipation of upcoming gene therapy clinical trials, we adapted this device for real-time convection-enhanced delivery of therapeutics via a custom-designed infusion cannula. The targeting accuracy of this delivery system and the performance of the infusion cannula were validated in nonhuman primates. Methods: Infusions of gadoteridol were delivered to multiple brain targets and the targeting error was determined for each cannula placement. Cannula performance was assessed by analyzing gadoteridol distributions and by histological analysis of tissue damage. Results: The average targeting error for all targets (n = 11) was 0.8 mm (95% CI = 0.14). For clinically relevant volumes, the distribution volume of gadoteridol increased as a linear function (R2 = 0.97) of the infusion volume (average slope = 3.30, 95% CI = 0.2). No infusions in any target produced occlusion, cannula reflux or leakage from adjacent tracts, and no signs of unexpected tissue damage were observed. Conclusions: This integrated delivery platform allows real-time convection-enhanced delivery to be performed with a high level of precision, predictability and safety. This approach may improve the success rate for clinical trials involving intracerebral drug delivery by direct infusion.



 goto top of outline Author Contacts

R. Mark Richardson, MD, PhD
Department of Neurological Surgery
505 Parnassus Avenue, Room M779
San Francisco, CA 94143-0112 (USA)
E-Mail richardsonma@neurosurg.ucsf.edu


 goto top of outline Article Information

Received: September 18, 2010
Accepted after revision: December 10, 2010
Published online: April 14, 2011
Number of Print Pages : 11
Number of Figures : 7, Number of Tables : 1, Number of References : 39


 goto top of outline Publication Details

Stereotactic and Functional Neurosurgery

Vol. 89, No. 3, Year 2011 (Cover Date: June 2011)

Journal Editor: Roberts D.W. (Lebanon, N.H.)
ISSN: 1011-6125 (Print), eISSN: 1423-0372 (Online)

For additional information: http://www.karger.com/SFN


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH: Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 1994;91:2076–2080.
  2. Bankiewicz KS, Eberling JL, Kohutnicka M, Jagust W, Pivirotto P, Bringas J, Cunningham J, Budinger TF, Harvey-White J: Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 2000;164:2–14.
  3. Bankiewicz KS, Forsayeth J, Eberling JL, Sanchez-Pernaute R, Pivirotto P, Bringas J, Herscovitch P, Carson RE, Eckelman W, Reutter B, Cunningham J: Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-HAADC. Mol Ther 2006;14:564–570.
  4. Daadi MM, Pivirotto P, Bringas J, Cunningham J, Forsayeth J, Eberling J, Bankiewicz KS: Distribution of AAV2-HAADC-transduced cells after 3 years in parkinsonian monkeys. Neuroreport 2006;17:201–204.
  5. Forsayeth JR, Eberling JL, Sanftner LM, Zhen Z, Pivirotto P, Bringas J, Cunningham J, Bankiewicz KS: A dose-ranging study of AAV-HAADC therapy in parkinsonian monkeys. Mol Ther 2006;14:571–577.
  6. Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins RA, VanBrocklin HF, Wright JF, Bankiewicz KS, Aminoff MJ: Safety and tolerability of putaminal AADC gene therapy for parkinson disease. Neurology 2009;73:1662–1669.
  7. Eberling JL, Jagust WJ, Christine CW, Starr P, Larson P, Bankiewicz KS, Aminoff MJ: Results from a phase I safety trial of HAADC gene therapy for parkinson disease. Neurology 2008;70:1980–1983.
  8. Nguyen TT, Pannu YS, Sung C, Dedrick RL, Walbridge S, Brechbiel MW, Garmestani K, Beitzel M, Yordanov AT, Oldfield EH: Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging. J Neurosurg 2003;98:584–590.
  9. Richardson RM, Varenika V, Forsayeth JR, Bankiewicz KS: Future applications: gene therapy. Neurosurg Clin N Am 2009;20:205–210.
  10. Fiandaca MS, Forsayeth JR, Dickinson PJ, Bankiewicz KS: Image-guided convection-enhanced delivery platform in the treatment of neurological diseases. Neurotherapeutics 2008;5:123–127.
  11. Fiandaca MS, Varenika V, Eberling J, McKnight T, Bringas J, Pivirotto P, Beyer J, Hadaczek P, Bowers W, Park J, Federoff H, Forsayeth J, Bankiewicz KS: Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage 2009;47(suppl 2):T27–T35.
  12. Gimenez F, Krauze MT, Valles F, Hadaczek P, Bringas J, Sharama N, Forsayeth J, Bankiewicz KS: Image-guided convection-enhanced delivery of GDNF protein into monkey putamen. Neuroimage 2011;54(suppl 1):S189–195.
  13. Su X, Kells AP, Aguilar Salegio EA, Richardson RM, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Forsayeth J, Bankiewicz KS: Real-time MR imaging with gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther 2010;18:1490–1495.
  14. Lonser RR, Warren KE, Butman JA, Quezado Z, Robison RA, Walbridge S, Schiffman R, Merrill M, Walker ML, Park DM, Croteau D, Brady RO, Oldfield EH: Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 2007;107:190–197.
  15. Krauze MT, Saito R, Noble C, Tamas M, Bringas J, Park JW, Berger MS, Bankiewicz K: Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 2005;103:923–929.
  16. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S: Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 1998;57:1–9.
  17. Su X, Kells AP, Huang EJ, Lee HS, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Penticuff J, Eberling J, Federoff HJ, Forsayeth J, Bankiewicz KS: Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum Gene Ther 2009;20:1627–1640.
  18. Truwit CL, Liu H: Prospective stereotaxy: a novel method of trajectory alignment using real-time image guidance. J Magn Reson Imaging 2001;13:452–457.
  19. Hall WA, Liu H, Martin AJ, Maxwell RE, Truwit CL: Brain biopsy sampling by using prospective stereotaxis and a trajectory guide. J Neurosurg 2001;94:67–71.
  20. Martin AJ, Hall WA, Roark C, Starr PA, Larson PS, Truwit CL: Minimally invasive precision brain access using prospective stereotaxy and a trajectory guide. J Magn Reson Imaging 2008;27:737–743.
  21. Martin AJ, Larson PS, Ostrem JL, Keith Sootsman W, Talke P, Weber OM, Levesque N, Myers J, Starr PA: Placement of deep brain stimulator electrodes using real-time high-field interventional magnetic resonance imaging. Magn Reson Med 2005;54:1107–1114.
  22. Starr PA, Martin AJ, Ostrem JL, Talke P, Levesque N, Larson PS: Subthalamic nucleus deep brain stimulator placement using high-field interventional magnetic resonance imaging and a skull-mounted aiming device: technique and application accuracy. J Neurosurg 2010;112:479–490.
  23. Marks WJ Jr, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, Vitek J, Stacy M, Turner D, Verhagen L, Bakay R, Watts R, Guthrie B, Jankovic J, Simpson R, Tagliati M, Alterman R, Stern M, Baltuch G, Starr PA, Larson PS, Ostrem JL, Nutt J, Kieburtz K, Kordower JH, Olanow CW: Gene delivery of AAV2-neurturin for parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 2010;9:1164–1172.
  24. Bartus RT, Herzog CD, Chu Y, Wilson A, Brown L, Siffert J, Johnson EM Jr, Olanow CW, Mufson EJ, Kordower JH: Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson’s disease and nonhuman primate brains. Mov Disord 2010, Epub ahead of print.
  25. Eberling JL, Kells AP, Pivirotto P, Beyer J, Bringas J, Federoff HJ, Forsayeth J, Bankiewicz KS: Functional effects of AAV2-GDNF on the dopaminergic nigrostriatal pathway in parkinsonian rhesus monkeys. Hum Gene Ther 2009;20:511–518.
  26. Johnston LC, Eberling J, Pivirotto P, Hadaczek P, Federoff HJ, Forsayeth J, Bankiewicz KS: Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys. Hum Gene Ther 2009;20:497–510.
  27. Morrison PF, Lonser RR, Oldfield EH: Convective delivery of glial cell line-derived neurotrophic factor in the human putamen. J Neurosurg 2007;107:74–83.
  28. Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, Penn R, Brooks DJ, Hotton G, Moro E, Heywood P, Brodsky MA, Burchiel K, Kelly P, Dalvi A, Scott B, Stacy M, Turner D, Wooten VG, Elias WJ, Laws ER, Dhawan V, Stoessl AJ, Matcham J, Coffey RJ, Traub M: Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006;59:459–466.
  29. Patel NK, Bunnage M, Plaha P, Svendsen CN, Heywood P, Gill SS: Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 2005;57:298–302.
  30. Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B: Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg 2005;102:216–222.
  31. Sampson JH, Archer G, Pedain C, Wembacher-Schroder E, Westphal M, Kunwar S, Vogelbaum MA, Coan A, Herndon JE, Raghavan R, Brady ML, Reardon DA, Friedman AH, Friedman HS, Rodriguez-Ponce MI, Chang SM, Mittermeyer S, Croteau D, Puri RK: Poor drug distribution as a possible explanation for the results of the PRECISE trial. J Neurosurg 2010;13:301–309.
  32. Lidar Z, Mardor Y, Jonas T, Pfeffer R, Faibel M, Nass D, Hadani M, Ram Z: Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. J Neurosurg 2004;100:472–479.
  33. Sampson JH, Raghavan R, Provenzale JM, Croteau D, Reardon DA, Coleman RE, Rodriguez Ponce I, Pastan I, Puri RK, Pedain C: Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin. AJR Am J Roentgenol 2007;188:703–709.
  34. Holloway KL, Gaede SE, Starr PA, Rosenow JM, Ramakrishnan V, Henderson JM: Frameless stereotaxy using bone fiducial markers for deep brain stimulation. J Neurosurg 2005;103:404–413.
  35. Yin D, Valles FE, Fiandaca MS, Bringas J, Gimenez F, Berger MS, Forsayeth J, Bankiewicz KS: Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates. Neuroimage 2009, Epub ahead of print.
  36. Yin D, Richardson RM, Fiandaca MS, Bringas J, Forsayeth J, Berger MS, Bankiewicz KS: Cannula placement for effective convection-enhanced delivery in the nonhuman primate thalamus and brainstem: implications for clinical delivery of therapeutics. J Neurosurg 2010;113:240–248.
  37. Heiss JD, Walbridge S, Asthagiri AR, Lonser RR: Image-guided convection-enhanced delivery of muscimol to the primate brain. J Neurosurg 2010;112:790–795.
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