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Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery
Open accessAbstract
Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of a ideal cellular target(s), available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability and most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in the context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles are discussed from the perspective of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analyses of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.
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Vos, T., Abajobir, A. A., Abate, K. H., Abbafati, C., Abbas, K. M., Abd-Allah, F., Abdulkader, R. S., Abdulle, A. M., Abebo, T. A., Abera, S. F., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)32154-2 · Cited by 13,220
Polazzi, E., Mengoni, I., Caprini, M., Peña‐Altamira, E., Kurtys, E., & Monti, B. (2012) · Neurosignals · doi:10.1159/000337115 · Cited by 9,023
Vos, T., Barber, R. M., Bell, B., Bertozzi-Villa, A., Biryukov, S., Bolliger, I., Charlson, F., Davis, A., Degenhardt, L., Dicker, D., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(15)60692-4 · Cited by 6,414
Astrocyte-endothelial interactions at the blood-brain barrier
Abbott, N. J., Rönnbäck, L., & Hansson, E. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1824 · Cited by 5,595
In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector
Naldini, L., Blömer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M., & Trono, D. (1996) · Science · doi:10.1126/science.272.5259.263 · Cited by 4,903
Microglia-mediated neurotoxicity: uncovering the molecular mechanisms
Block, M. L., Zecca, L., & Hong, J.-S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2038 · Cited by 4,110
ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering
Gaj, T., Gersbach, C. A., & Barbas, C. F. (2013) · Trends in Biotechnology · doi:10.1016/j.tibtech.2013.04.004 · Cited by 3,820
Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain
DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P., & Aronin, N. (1997) · Science · doi:10.1126/science.277.5334.1990 · Cited by 2,439
Bellini, M., Charalampidis, S., Herbert, P., Bonatsos, V., Crane, J., Muthusamy, A., Dor, F., & Papalois, V. E. (2022) · BioMed Research International · doi:10.1155/2738 · Cited by 2,431
Neuroinflammation in Parkinson’s disease: A target for neuroprotection?
Hirsch, E. C., & Hunot, S. (2009) · The Lancet Neurology · doi:10.1016/s1474-4422(09)70062-6 · Cited by 1,984
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Peña, S., Iyengar, R., Eshraghi, R. S., Bencie, N., Mittal, J., Aljohani, A., Mittal, R., & Eshraghi, A. A. (2019) · Journal of drug targeting · doi:10.1080/1061186x.2019.1630415 · Cited by 116
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Wu, J., Ji, A., Wang, Z., Qiang, G.-H., Qu, Z., Wu, J., & Jiang, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-20505-y · Cited by 92
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Moradi, S. Z., Jalili, F., Farhadian, N., Joshi, T., Wang, M., Zou, L., Cao, H., Farzaei, M. H., & Xiao, J. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2020.1865870 · Cited by 62
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Abdallah, K., Nadeau, F., Bergeron, F., Blouin, S., Blais, V., Bradbury, K. M., Lavoie, C. L., Parent, J., & Gendron, L. (2018) · Scientific Reports · doi:10.1038/s41598-018-25626-y · Cited by 8
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Zorzi, A. R., & de Miranda, J. B. (2018) · InTech eBooks · doi:10.5772/67903 · Cited by 7
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Metadata
- Authors
- Joshi, C. R., Labhasetwar, V., & Ghorpade, A.
- Affiliations
- University of North Texas Health Science Center (US)
- Cleveland Clinic (US)
- Corresponding author
- Ghorpade, Anuja
- Venue
- Journal of Neuroimmune Pharmacology
- Published
- 2017-02-03
- Volume
- 12
- Issue
- 1
- Pages
- 51-83
- ISSN
- 1557-1890 (ISSN-L)
- 1557-1904
- PMC
- PMC5393046
- OpenAlex
- W2585557706
- Cited by
- 55
- References
- 259
- Citations by year
- 2025: 4 · 2024: 8 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 10 · 2019: 5 · 2018: 10 · 2017: 7
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Neuroimmune Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS048837, NS070896)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- gene therapy, gene delivery to the brain, central nervous system, neurological disorders, blood-brain barrier, viral vectors, nanoparticles, RNA interference, genome editing, cell-specific promoters, clinical trials, translational medicine, neuropathogenesis
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Forecasting, Humans, Genetic Therapy, Gene Transfer Techniques, Neurodegenerative Diseases
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