Abstract
The ability to directly modulate intracellular processes through genetic manipulation has long been felt to have great potential for treating intractable neurological and psychiatric diseases. To date, the largest number of clinical trials of central nervous system gene therapy has been in patients with Parkinson’s disease (PD). Most of these have used adeno-associated virus (AAV) as a vehicle, which we demonstrated to be safe and effective for stable gene therapy in the brain more than 20 years ago. Here, we describe the development and results of the first human gene therapy for PD, which used AAV to transfer the gene for glutamic acid decarboxylase (GAD) into the subthalamic nucleus (STN). The STN is in the basal ganglia circuitry which is dysfunctional in PD, and human therapy for drug resistant PD has focused upon either lesioning or electrical stimulation of the STN for many years. In an initial open label pilot study, unilateral injection of AAV-STN into the STN of the more symptomatic hemisphere demonstrated safety and suggested evidence of efficacy based upon both motor improvements and reversal of functional imaging abnormalities up to 1 year. This led to a randomized, double-blind phase II clinical trial of bilateral AAV-GAD into the STN compared with patients receiving bilateral sham surgery. This confirmed the effectiveness of AAV-GAD, as the treated patients showed significantly greater improvements than the sham patients throughout both the 6-month blinded phase and full 12-month study phase, again with a very good safety profile. Functional imaging further supported these findings and identified a pattern of changes unique to the sham patients with improvement which was not seen in either the AAV-GAD patients or sham non-responders. These combined data support ongoing development of AAV-GAD as the only gene therapy in the CNS to date to demonstrate efficacy compared with contemporaneous sham controls and provide a stronger foundation for the further development of CNS gene therapy for a variety of disorders.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Walter BL, Vitek JL. Surgical treatment for Parkinson’s disease. Lancet Neurol. 2004;3(12):719–28.
Kumar R, et al. Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson’s disease. Neurology. 1998;51(3):850–5.
Fink DJ, et al. In vivo expression of beta-galactosidase in hippocampal neurons by HSV-mediated gene transfer. Hum Gene Ther. 1992;3(1):11–9.
Kaplitt MG, et al. Expression of a functional foreign gene in adult mammalian brain following in vivo transfer via a herpes simplex virus type 1 defective viral vector. Mol Cell Neurosci. 1991;2(4):320–30.
Mastrangeli A, et al. Diversity of airway epithelial cell targets for in vivo recombinant adenovirus-mediated gene transfer. J Clin Invest. 1993;91(1):225–34.
During MJ, et al. Long-term behavioral recovery in parkinsonian rats by an HSV vector expressing tyrosine hydroxylase. Science. 1994;266:1399–403.
Kaplitt MG, et al. Long-term gene expression and phenotypic correction using adeno-associated virus vectors in the mammalian brain. Nat Genet. 1994;8(2):148–54.
Freed CR, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med. 2001;344(10):710–9.
Gross RE, et al. Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2011;10(6):509–19.
Ma Y, et al. Dyskinesia after fetal cell transplantation for parkinsonism: a PET study. Ann Neurol. 2002;52(5):628–34.
Olanow CW, et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol. 2003;54(3):403–14.
Deuschl G, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2006;355(9):896–908.
Weaver FM, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009;301(1):63–73.
Hamani C, et al. The subthalamic nucleus in the context of movement disorders. Brain. 2004;127(Pt 1):4–20.
Patel NK, et al. Unilateral subthalamotomy in the treatment of Parkinson’s disease. Brain. 2003;126(Pt 5):1136–45.
Su PC, et al. Treatment of advanced Parkinson’s disease by subthalamotomy: one-year results. Mov Disord. 2003;18(5):531–8.
Hutchison WD, et al. Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson’s disease. Ann Neurol. 1998;44(4):622–8.
Levy R, et al. Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms. Brain. 2001;124(Pt 10):2105–18.
Petri D, et al. GABAA-receptor activation in the subthalamic nucleus compensates behavioral asymmetries in the hemiparkinsonian rat. Behav Brain Res. 2013;252:58–67.
Luo J, et al. Subthalamic GAD gene therapy in a Parkinson’s disease rat model. Science. 2002;298:425–9.
Lee B, et al. Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models. Gene Ther. 2005;12(15):1215–22.
Emborg ME, et al. Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism. J Cereb Blood Flow Metab. 2007;27(3):501–9.
Kaplitt MG, et al. Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’s disease: an open label, phase I trial. Lancet. 2007;369(9579):2097–105.
Feigin A, et al. Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson’s disease. Proc Natl Acad Sci U S A. 2007;104(49):19559–64.
Asanuma K, et al. Network modulation in the treatment of Parkinson’s disease. Brain. 2006;129(Pt 10):2667–78.
Lang AE, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59(3):459–66.
Marks Jr WJ, et al. Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2010;9(12):1164–72.
Nutt JG, et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology. 2003;60(1):69–73.
Ma Y, et al. Abnormal metabolic network activity in Parkinson’s disease: test-retest reproducibility. J Cereb Blood Flow Metab. 2007;27(3):597–605.
Pourfar M, et al. Assessing the microlesion effect of subthalamic deep brain stimulation surgery with FDG PET. J Neurosurg. 2009;110(6):1278–82.
LeWitt PA, 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.
Ko JH, et al. Network modulation following sham surgery in Parkinson’s disease. J Clin Invest. 2014;124(8):3656–66.
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
Kaplitt, M.G., During, M.J. (2016). GAD 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_5
Download citation
DOI: https://doi.org/10.1007/978-1-4899-7654-3_5
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)