Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat Model
Abstract
The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector–mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Induction of glutamic acid decarboxylase enzyme as a neuromodulator can evoke synthesis of GABA to perform inhibitory modulation of neuronal activities in the subthalamic nucleus.
“Induction of glutamic acid decarboxylase enzyme as a neuromodulator that can evoke the synthesis of a neurotransmitter Gamma-aminobutyric acid (GABA) to perform inhibitory modulation of neuronal activities in the subthalamic nucleus [162, 163].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [163]
Cites
Woodchuck hepatitis virus contains a tripartite posttranscriptional regulatory element
Donello, J. E., Loeb, J. E., & Hope, T. J. (1998) · Journal of Virology · doi:10.1128/jvi.72.6.5085-5092.1998 · Cited by 350 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease
Benabid, A. L., Chabardes, S., Mitrofanis, J., & Pollak, P. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70291-6 · Cited by 1,285 · see citing works
Kaplitt, M. G., Feigin, A., Tang, C., Fitzsimons, H. L., Mattis, P., Lawlor, P. A., Bland, R. J., Young, D., Strybing, K., Eidelberg, D., et al. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60982-9 · Cited by 1,067 · see citing works
Self-citationLeWitt, P. A., Rezai, A. R., Leehey, M. A., Ojemann, S. G., Flaherty, A. W., Eskandar, E. N., Kostyk, S. K., Thomas, K., Sarkar, A., Siddiqui, M. S., et al. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70039-4 · Cited by 681 · see citing works
Self-citationPeden, C. S., Burger, C., Muzyczka, N., & Mandel, R. J. (2004) · Journal of Virology · doi:10.1128/jvi.78.12.6344-6359.2004 · Cited by 222 · see citing works
Clinical Applications Involving CNS Gene Transfer
Kantor, B., McCown, T., Leone, P., & Gray, S. J. (2014) · Advances in Genetics · doi:10.1016/b978-0-12-800149-3.00002-0 · Cited by 74 · see citing works
Heusner, C. L., Hnasko, T. S., Szczypka, M. S., Liu, Y., During, M. J., & Palmiter, R. D. (2003) · Brain Research · doi:10.1016/s0006-8993(03)02986-x · Cited by 48 · see citing works
Xu, L., Yao, S., Ding, Y. E., Xie, M., Feng, D., Sha, P., Tan, L., Bei, F., & Yao, Y. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05661-2 · Cited by 48 · see citing works
Harding, T. C., Dickinson, P. J., Roberts, B. N., Yendluri, S., Gonzalez-Edick, M., Lecouteur, R. A., & Jooss, K. U. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.807 · Cited by 45 · see citing works
- Authors
- Luo, J., Kaplitt, M. G., Fitzsimons, H. L., Zuzga, D. S., Liu, Y., Oshinsky, M. L., & During, M. J.
- Affiliations
- University of Auckland (NZ)
- Cornell University (US)
- CNS Gene Therapy Center, Jefferson Medical College, Philadelphia, PA 19107, USA.
- Corresponding author
- Fitzsimons, Helen L.
- During, Matthew J.
- Venue
- Science
- Published
- 2002-10-11
- Volume
- 298
- Issue
- 5592
- Pages
- 425-429
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2005646823
- Cited by
- 325
- References
- 1
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 10 · 2023: 4 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 7 · 2016: 11 · 2015: 11 · 2014: 12 · 2013: 16 · 2012: 17
- FWCI
- 17.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- Parkinson's disease, subthalamic nucleus, glutamic acid decarboxylase, gene therapy, adeno-associated virus vectors, GABAergic neurons, basal ganglia, disinhibition, neuroprotection, dopaminergic neurons, electrical stimulation
- MeSH terms
- Dependovirus, Animals, Disease Models, Animal, Dopamine, Electric Stimulation, Electrophysiology, gamma-Aminobutyric Acid, Genetic Vectors, Glutamate Decarboxylase, Humans, Ibotenic Acid, Isoenzymes, Male, Mesencephalon, Motor Activity, Nerve Degeneration, Synaptic Transmission, Neurons, Phenotype, Stem Cells, Substantia Nigra, Genetic Therapy, Oxidopamine, Glutamic Acid, Transgenes, Subthalamic Nucleus, Parkinsonian Disorders, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
