Abstract
The use of viral vectors to express therapeutics genes in Parkinson’s disease (PD) trials has been hindered by a lack of understanding of the principles that guide effective distribution of vectors within the basal ganglia, even when we have a strong expectation of efficacy based on experimentation in animal models. The major problems we have faced include (1) scale-up from small rodent and nonhuman primates (NHP) brains to humans, (2) understanding how viral vectors distribute within the brain parenchyma, (3) prediction of how viral particles are disseminated by neuronal projections after direct delivery to the putamen and substantia nigra, (4) the mechanism of action of the therapeutic gene on dopaminergic system, and (5) the relevance of animal models to idiopathic PD. In this chapter, we will address these important issues and will try to put them into the context of data that has been obtained from current and recent clinical trials. In particular, we will address therapeutic strategies aimed at restoring dopaminergic function by either expressing genes that encode enzymes responsible for synthesis of dopamine (DA) or expressing growth factors capable of upregulating DA function in the degenerated neurons. We will not address inhibition of outflow innervation from the striatum in PD patients by expressing glutamic acid decarboxylase (GAD) as this strategy is described in the dedicated chapter in this book.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Aminoff MJ. Parkinson’s disease. Neurol Clin. 2001;19(1):119–28, vi.
Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol. 2000;247 Suppl 2:II3–10.
Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain. 2013;136(Pt 8):2419–31.
Palfi S. Towards gene therapy for Parkinson’s disease. Lancet Neurol. 2008;7(5):375–6.
Yin D, Valles FE, Fiandaca MS, Bringas J, Gimenez F, Berger MS, et al. Optimal region of the putamen for image-guided convection-enhanced delivery of therapeutics in human and non-human primates. Neuroimage. 2009;187(1):46–51.
Bartus RT, Herzog CD, Chu Y, Wilson A, Brown L, Siffert J, et al. Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson’s disease and nonhuman primate brains. Mov Disord. 2011;26(1):27–36.
Eberling JL, Jagust WJ, Christine CW, Starr P, Larson P, Bankiewicz KS, et al. Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology. 2008;70(21):1980–3.
Marks Jr WJ, Bartus RT, Siffert J, Davis CS, Lozano A, Boulis N, et al. Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2010;9(12):1164–72.
Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A. 1994;91(6):2076–80.
Hadaczek P, Yamashita Y, Mirek H, Tamas L, Bohn MC, Noble C, et al. The “perivascular pump” driven by arterial pulsation is a powerful mechanism for the distribution of therapeutic molecules within the brain. Mol Ther. 2006;14(1):69–78.
Fiandaca MS, Forsayeth JR, Dickinson PJ, Bankiewicz KS. Image-guided convection-enhanced delivery platform in the treatment of neurological diseases. Neurotherapeutics. 2008;5(1):123–7.
Richardson RM, Varenika V, Forsayeth JR, Bankiewicz KS. Future applications: gene therapy. Neurosurg Clin N Am. 2009;20(2):205–10.
Fiandaca MS, Varenika V, Eberling J, McKnight T, Bringas J, Pivirotto P, et al. Real-time MR imaging of adeno-associated viral vector delivery to the primate brain. Neuroimage. 2009;47 Suppl 2:T27–35.
Richardson RM, Kells AP, Martin AJ, Larson PS, Starr PA, Piferi PG, et al. Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg. 2011;89(3):141–51.
Richardson RM, Kells AP, Rosenbluth KH, Salegio EA, Fiandaca MS, Larson PS, et al. Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson’s disease. Mol Ther. 2011;19(6):1048–57.
Su X, Kells AP, Aguilar Salegio EA, Richardson RM, Hadaczek P, Beyer J, et al. Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther. 2010;18(8):1490–5.
Krauze MT, McKnight TR, Yamashita Y, Bringas J, Noble CO, Saito R, et al. Real-time visualization and characterization of liposomal delivery into the monkey brain by magnetic resonance imaging. Brain Res Brain Res Protoc. 2005;16(1–3):20–6.
Yin D, Zhai Y, Gruber HE, Ibanez CE, Robbins JM, Kells AP, et al. Convection-enhanced delivery improves distribution and efficacy of tumor-selective retroviral replicating vectors in a rodent brain tumor model. Cancer Gene Ther. 2013;20(6):336–41.
Chen PY, Ozawa T, Drummond DC, Kalra A, Fitzgerald JB, Kirpotin DB, et al. Comparing routes of delivery for nanoliposomal irinotecan shows superior anti-tumor activity of local administration in treating intracranial glioblastoma xenografts. Neuro Oncol. 2013;15(2):189–97.
Varenika V, Dickenson P, Bringas J, LeCouteur R, Higgins R, Park JW, et al. Real-time imaging of CED in the brain permits detection of infusate leakage. J Neurosurg. 2008;109:874–80.
Varenika V, Kells AP, Valles F, Hadaczek P, Forsayeth J, Bankiewicz KS. Controlled dissemination of AAV vectors in the primate brain. Prog Brain Res. 2009;175:163–72.
Sykova E. Extrasynaptic volume transmission and diffusion parameters of the extracellular space. Neuroscience. 2004;129(4):861–76.
Chen MY, Lonser RR, Morrison PF, Governale LS, Oldfield EH. Variables affecting convection-enhanced delivery to the striatum: a systematic examination of rate of infusion, cannula size, infusate concentration, and tissue-cannula sealing time. J Neurosurg. 1999;90(2):315–20.
Krauze MT, Saito R, Noble C, Bringas J, Forsayeth J, McKnight TR, et al. Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen. Exp Neurol. 2005;196(1):104–11.
Szerlip NJ, Walbridge S, Yang L, Morrison PF, Degen JW, Jarrell ST, et al. Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles. J Neurosurg. 2007;107(3):560–7.
Krauze MT, Saito R, Noble C, Tamas M, Bringas J, Park JW, et al. Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg. 2005;103(5):923–9.
Sanftner LM, Sommer JM, Suzuki BM, Smith PH, Vijay S, Vargas JA, et al. AAV2-mediated gene delivery to monkey putamen: evaluation of an infusion device and delivery parameters. Exp Neurol. 2005;194(2):476–83.
Yin D, Forsayeth J, Bankiewicz KS. Optimized cannula design and placement for convection-enhanced delivery in rat striatum. J Neurosci Methods. 2010;187(1):46–51.
Valles F, Fiandaca MS, Bringas J, Dickinson P, LeCouteur R, Higgins R, et al. Anatomic compression caused by high-volume convection-enhanced delivery to the brain. Neurosurgery. 2009;65(3):579–85. discussion 85–6.
Valles F, Fiandaca MS, Eberling JL, Starr PA, Larson PS, Christine CW, et al. Qualitative imaging of adeno-associated virus serotype 2-human aromatic L-amino acid decarboxylase gene therapy in a phase I study for the treatment of Parkinson disease. Neurosurgery. 2010;67(5):1377–85.
Christine CW, Starr PA, Larson PS, Eberling JL, Jagust WJ, Hawkins RA, et al. Safety and tolerability of putaminal AADC gene therapy for Parkinson disease. Neurology. 2009;73(20):1662–9.
Yin D, Richardson RM, Fiandaca MS, Bringas J, Forsayeth J, Berger MS, et al. Cannula placement for effective convection-enhanced delivery in the non-human primate thalamus and brainstem: implications for clinical delivery of therapeutics. J Neurosurg. 2010;113(2):240–8.
Truwit CL, Liu H. Prospective stereotaxy: a novel method of trajectory alignment using real-time image guidance. J Magn Reson Imaging. 2001;13(3):452–7.
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(1):67–71.
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(4):737–43.
Martin AJ, Larson PS, Ostrem JL, Keith Sootsman W, Talke P, Weber OM, et al. Placement of deep brain stimulator electrodes using real-time high-field interventional magnetic resonance imaging. Magn Reson Med. 2005;54(5):1107–14.
Martin AJ, Larson PS, Ostrem JL, Starr PA. Interventional magnetic resonance guidance of deep brain stimulator implantation for Parkinson disease. Top Magn Reson Imaging. 2009;19(4):213–21.
Starr PA, Martin AJ, Larson PS. Implantation of deep brain stimulator electrodes using interventional MRI. Neurosurg Clin N Am. 2009;20(2):193–203.
Gao G, Vandenberghe LH, Alvira MR, Lu Y, Calcedo R, Zhou X, et al. Clades of adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004;78(12):6381–8.
Rabinowitz JE, Samulski RJ. Building a better vector: the manipulation of AAV virions. Virology. 2000;278(2):301–8.
Koerber JT, Klimczak R, Jang JH, Dalkara D, Flannery JG, Schaffer DV. Molecular evolution of adeno-associated virus for enhanced glial gene delivery. Mol Ther. 2009;17(12):2088–95.
Maheshri N, Koerber JT, Kaspar BK, Schaffer DV. Directed evolution of adeno-associated virus yields enhanced gene delivery vectors. Nat Biotechnol. 2006;24(2):198–204.
Li W, Zhang L, Johnson JS, Zhijian W, Grieger JC, Ping-Jie X, et al. Generation of novel AAV variants by directed evolution for improved CFTR delivery to human ciliated airway epithelium. Mol Ther. 2009;17(12):2067–77.
Gray SJ, Blake BL, Criswell HE, Nicolson SC, Samulski RJ, McCown TJ. Directed evolution of a novel adeno-associated virus (AAV) vector that crosses the seizure-compromised blood-brain barrier (BBB). Mol Ther. 2010;18(3):570–8.
Asokan A, Conway JC, Phillips JL, Li C, Hegge J, Sinnott R, et al. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat Biotechnol. 2010;28(1):79–82.
Ciesielska A, Mittermeyer G, Hadaczek P, Kells AP, Forsayeth J, Bankiewicz KS. Anterograde axonal transport of AAV2-GDNF in rat basal ganglia. Mol Ther. 2011;19(5):922–7.
Kells AP, Hadaczek P, Yin D, Bringas J, Varenika V, Forsayeth J, et al. Efficient gene therapy-based method for the delivery of therapeutics to primate cortex. Proc Natl Acad Sci U S A. 2009;106(7):2407–11.
Hadaczek P, Mirek H, Bringas J, Cunningham J, Bankiewicz K. Basic fibroblast growth factor enhances transduction, distribution, and axonal transport of adeno-associated virus type 2 vector in rat brain. Hum Gene Ther. 2004;15(5):469–79.
Salegio EA, Samaranch L, Kells AP, Mittermeyer G, San Sebastian W, Zhou S, et al. Axonal transport of adeno-associated viral vectors is serotype-dependent. Gene Ther. 2013;20(3):348–52.
San Sebastian W, Samaranch L, Heller G, Kells AP, Bringas J, Pivirotto P, et al. Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain. Gene Ther. 2013;20(12):1178–83.
Marks Jr WJ, Ostrem JL, Verhagen L, Starr PA, Larson PS, Bakay RA, et al. Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol. 2008;7(5):400–8.
Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K, et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther. 2010;18(9):1731–5.
LeWitt PA, Rezai AR, Leehey MA, Ojemann SG, Flaherty AW, Eskandar EN, et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011;10(4):309–19.
Bartus RT, Weinberg MS, Samulski RJ. Parkinson’s disease gene therapy: success by design meets failure by efficacy. Mol Ther. 2014;22(3):487–97.
Yin D, Valles FE, Fiandaca MS, Forsayeth J, Larson P, Starr P, et al. Striatal volume differences between non-human and human primates. J Neurosci Methods. 2009;176(2):200–5.
Bankiewicz KS, Forsayeth J, Eberling JL, Sanchez-Pernaute R, Pivirotto P, Bringas J, et al. Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC. Mol Ther. 2006;14(4):564–70.
Hadaczek P, Eberling JL, Pivirotto P, Bringas J, Forsayeth J, Bankiewicz KS. Eight years of clinical improvement in MPTP-lesioned primates after gene therapy with AAV2-hAADC. Mol Ther. 2010;18(8):1458–61.
Forsayeth JR, Eberling JL, Sanftner LM, Zhen Z, Pivirotto P, Bringas J, et al. A dose-ranging study of AAV-hAADC therapy in parkinsonian monkeys. Mol Ther. 2006;14(4):571–7.
Bankiewicz KS, Eberling JL, Kohutnicka M, Jagust W, Pivirotto P, Bringas J, et al. 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(1):2–14.
Mittermeyer G, Christine CW, Rosenbluth KH, Baker SL, Starr P, Larson P, et al. Long-term evaluation of a Phase 1 study of AADC gene therapy for Parkinson’s disease. Hum Gene Ther. 2012;23(4):377–81.
Engele J, Schubert D, Bohn MC. Conditioned media derived from glial cell lines promote survival and differentiation of dopaminergic neurons in vitro: role of mesencephalic glia. J Neurosci Res. 1991;30:359–71.
Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993;260(5111):1130–2.
Lin LF, Zhang TJ, Collins F, Armes LG. Purification and initial characterization of rat B49 glial cell line- derived neurotrophic factor. J Neurochem. 1994;63(2):758–68.
Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci. 2002;3(5):383–94.
Grondin R, Zhang Z, Ai Y, Gash DM, Gerhardt GA. Intracranial delivery of proteins and peptides as a therapy for neurodegenerative diseases. Prog Drug Res. 2003;61:101–23.
Bjorklund A, Kirik D, Rosenblad C, Georgievska B, Lundberg C, Mandel RJ. 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. Brain Res. 2000;886:82–98.
Choi-Lundberg DL. An adenoviral vector encoding glial cell line-derived neurotrophic factor (GDNF) protects rat dopaminergic neurons from degeneration. Ph.D. thesis, University of Rochester, Rochester, NY; 1997.
Connor B, Kozlowski DA, Schallert T, Tillerson JL, Davidson BL, Bohn MC. Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat. Gene Ther. 1999;6:1936–51.
Kirik D, Rosenblad C, Bjorklund A, Mandel RJ. Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson’s model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system. J Neurosci. 2000;20(12):4686–700.
Kirik D, Rosenblad C, Bjorklund A. Preservation of a functional nigrostriatal dopamine pathway by GDNF in the intrastriatal 6-OHDA lesion model depends on the site of administration of the trophic factor. Eur J Neurosci. 2000;12(11):3871–82.
Eslamboli A, Georgievska B, Ridley RM, Baker HF, Muzyczka N, Burger C, et al. Continuous low-level glial cell line-derived neurotrophic factor delivery using recombinant adeno-associated viral vectors provides neuroprotection and induces behavioral recovery in a primate model of Parkinson’s disease. J Neurosci. 2005;25(4):769–77.
Johnston LC, Eberling J, Pivirotto P, Hadaczek P, Federoff HJ, Forsayeth J, et al. Clinically relevant effects of convection-enhanced delivery of AAV2-GDNF on the dopaminergic nigrostriatal pathway in aged rhesus monkeys. Hum Gene Ther. 2009;20(5):497–510.
Su X, Kells AP, Huang EJ, Lee HS, Hadaczek P, Beyer J, et al. Safety evaluation of AAV2-GDNF gene transfer into the dopaminergic nigrostriatal pathway in aged and parkinsonian rhesus monkeys. Hum Gene Ther. 2009;20(12):1627–40.
Kells AP, Eberling J, Su X, Pivirotto P, Bringas J, Hadaczek P, et al. Regeneration of the MPTP-lesioned dopaminergic system after convection-enhanced delivery of AAV2-GDNF. J Neurosci. 2010;30(28):9567–77.
Eberling JL, Bankiewicz KS, Jordan S, VanBrocklin HF, Jagust WJ. PET studies of functional compensation in a primate model of Parkinson’s disease. Neuroreport. 1997;8(12):2727–33.
Bartus RT, Baumann TL, Siffert J, Herzog CD, Alterman R, Boulis N, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology. 2013;80(18):1698–701.
Hadaczek P, Wu G, Sharma N, Cieselska A, Bankiewicz K, Davidow AL, et al. GDNF signaling implemented by GM1 ganglioside; failure in Parkinson’s disease and GM1-deficient murine model. Exp Neurol. 2014;263:177–89.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this chapter
Cite this chapter
Bankiewicz, K., Sebastian, W.S., Samaranch, L., Forsayeth, J. (2016). GDNF and AADC Gene Therapy for Parkinson’s Disease. In: Tuszynski, M. (eds) Translational Neuroscience. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-7654-3_4
Download citation
DOI: https://doi.org/10.1007/978-1-4899-7654-3_4
Published:
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-7652-9
Online ISBN: 978-1-4899-7654-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)