The DOI matches its Crossref record; 29 of the 30 references it cites were found in a registry or an index.
Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates
Open accessAbstract
Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ∼2 × 10(12) vector genome (vg) per 3-6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The circulation of CSF delivers viral vectors to broader CNS regions when compared to IP injection [86].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [86]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“in animal models, widespread coverage can be obtained by delivering the vector into the CSF”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [83]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The Rat Brain in Stereotaxic Coordinates
Paxinos, G., & Watson, C. (1983) · Elsevier eBooks · doi:10.1016/c2009-0-63235-9 · Cited by 28,585
Intrathecal morphine in mice: A new technique
Hylden, J. L. K., & Wilcox, G. L. (1980) · European Journal of Pharmacology · doi:10.1016/0014-2999(80)90515-4 · Cited by 1,930
Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes
Foust, K. D., Nurre, E., Montgomery, C. L., Hernandez, A., Chan, C. M., & Kaspar, B. K. (2009) · Nature Biotechnology · doi:10.1038/nbt.1515 · Cited by 1,456 · cited 1×
“Recently, the adeno-associated virus (AAV) serotype 9 capsid was identified as a vector capable of transducing neurons and glia throughout the CNS following intravenous delivery in adult rodents, cats, and NHPs [1-5].”
BackgroundXiao, X., Li, J., & Samulski, R. J. (1998) · Journal of Virology · doi:10.1128/jvi.72.3.2224-2232.1998 · Cited by 1,381
Boutin, S., Monteilhet, V., Veron, P., Leborgne, C., Benveniste, O., Montus, M. F., & Masurier, C. (2010) · Human Gene Therapy · doi:10.1089/hum.2009.182 · Cited by 970
McCarty, D., Monahan, P., & Samulski, R. (2001) · Gene Therapy · doi:10.1038/sj.gt.3301514 · Cited by 735
Self-citationProduction and characterization of adeno-associated viral vectors
Grieger, J. C., Choi, V. W., & Samulski, R. J. (2006) · Nature Protocols · doi:10.1038/nprot.2006.207 · Cited by 580
McCarty, D. M., Fu, H., Monahan, P. E., Toulson, C. E., Naik, P., & Samulski, R. J. (2003) · Gene Therapy · doi:10.1038/sj.gt.3302134 · Cited by 547
Self-citationDavidson, B. L., Stein, C. S., Heth, J. A., Martins, I., Kotin, R. M., Derksen, T. A., Zabner, J., Ghodsi, A., & Chiorini, J. A. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3428 · Cited by 531
Duque, S., Joussemet, B., Riviere, C., Marais, T., Dubreil, L., Douar, A.-M., Fyfe, J., Moullier, P., Colle, M.-A., & Barkats, M. (2009) · Molecular Therapy · doi:10.1038/mt.2009.71 · Cited by 511
Flagged first, then by citations
1 of the 30 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Snyder BR, Gray SJ, Quach ET, Huang JW, Leung CH, Samulski RJ et al. Comparison of adeno-associated viral vector serotypes for spinal cord and motor neuron gene delivery. Hum Gene Ther 2011; 22: 1129–1135. · DOI
Cited by
Sorted by citations
Adeno-associated virus vector as a platform for gene therapy delivery
Wang, D., Tai, P. W. L., & Gao, G. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0012-9 · Cited by 2,444
Adeno-Associated Virus (AAV) as a Vector for Gene Therapy
Naso, M. F., Tomkowicz, B., Perry, W. L., & Strohl, W. R. (2017) · BioDrugs · doi:10.1007/s40259-017-0234-5 · Cited by 1,362
Strategies for delivering therapeutics across the blood–brain barrier
Terstappen, G. C., Meyer, A. H., Bell, R. D., & Zhang, W. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00139-y · Cited by 1,138
Hinderer, C., Katz, N., Buza, E. L., Dyer, C., Goode, T., Bell, P., Richman, L. K., & Wilson, J. M. (2018) · Human Gene Therapy · doi:10.1089/hum.2018.015 · Cited by 814
“34,35 The lesions observed in the present study consisted of degeneration of DRG sensory neuron cell bodies as well as their central and peripheral axons.”
Current clinical applications of in vivo gene therapy with AAVs
Mendell, J. R., Al-Zaidy, S. A., Rodino-Klapac, L. R., Goodspeed, K., Gray, S. J., Kay, C. N., Boye, S. L., Boye, S. E., George, L. A., Salabarria, S., et al. (2021) · Molecular Therapy · doi:10.1016/j.ymthe.2020.12.007 · Cited by 743
Self-citationAAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer
Costa Verdera, H., Kuranda, K., & Mingozzi, F. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2019.12.010 · Cited by 641
Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain
Pardridge, W. M. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00373 · Cited by 405
Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality
Hudry, E., & Vandenberghe, L. H. (2019) · Neuron · doi:10.1016/j.neuron.2019.02.017 · Cited by 384
Various AAV Serotypes and Their Applications in Gene Therapy: An Overview
Issa, S. S., Shaimardanova, A. A., Solovyeva, V. V., & Rizvanov, A. A. (2023) · Cells · doi:10.3390/cells12050785 · Cited by 339
Gene therapy for neurological disorders: progress and prospects
Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M., & Sah, D. W. Y. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.110 · Cited by 306
Adeno-Associated Virus-Based Gene Therapy for CNS Diseases
Hocquemiller, M., Giersch, L., Audrain, M., Parker, S., & Cartier, N. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.087 · Cited by 291
“However, these strategies are associated with increased leakage of the recombinant vector into the blood circulation and with consequent off-target tissue transduction and expression in peripheral organs, particularly the liver.(18,19) Moreover, strategies will be required to reduce an immune response that may ultimat…”
BackgroundMeyer, K., Ferraiuolo, L., Schmelzer, L., Braun, L., McGovern, V., Likhite, S., Michels, O., Govoni, A., Fitzgerald, J., Morales, P., et al. (2015) · Molecular Therapy · doi:10.1038/mt.2014.210 · Cited by 286
Erratum: Gene therapy for neurological disorders: progress and prospects
Deverman, B. E., Ravina, B. M., Bankiewicz, K. S., Paul, S. M., & Sah, D. W. Y. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.158 · Cited by 248
Overcoming innate immune barriers that impede AAV gene therapy vectors
Muhuri, M., Maeda, Y., Ma, H., Ram, S., Fitzgerald, K. A., Tai, P. W. L., & Gao, G. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143780 · Cited by 212
Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy
Haurigot, V., Marcó, S., Ribera, A., Garcia, M., Ruzo, A., Villacampa, P., Ayuso, E., Añor, S., Andaluz, A., Pineda, M., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66778 · Cited by 215
“…NAb titers in the CSF did not completely block AAV vector transduction in the brain, a result in contrast to previously published results (66) and in agreement with a recent study that explored CNS transduction following intra-CSF delivery in nonhuman primates with low serum NAb titers (64).”
Adeno-Associated Virus Technologies and Methods for Targeted Neuronal Manipulation
Haery, L., Deverman, B. E., Matho, K. S., Cetin, A. H., Woodard, K., Cepko, C. L., Guerin, K. I., Rego, M. A., Ersing, I., Bächle, S. M., et al. (2019) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2019.00093 · Cited by 220
AAV-based in vivo gene therapy for neurological disorders
Ling, Q., Herstine, J. A., Bradbury, A. M., & Gray, S. J. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00766-7 · Cited by 223
Self-citationViral vectors for therapy of neurologic diseases
Choudhury, S. R., Hudry, E., Maguire, C. A., Sena-Esteves, M., Breakefield, X. O., & Grandi, P. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.013 · Cited by 190
“In higher species such as pigs and non-human primates, the spread of gene transfer after IT injection is much wider, with multiple cell populations (including neurons) in the brain and brainstem being transduced at high efficiency (Federici et al., 2012; Samaranch et al., 2012; Gray et al., 2013).”
BackgroundLipid nanoparticle-mediated drug delivery to the brain
Khare, P., Edgecomb, S. X., Hamadani, C. M., Tanner, E. E. L., & S Manickam, D. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.114861 · Cited by 187
Schuster, D. J., Dykstra, J. A., Riedl, M. S., Kitto, K. F., Belur, L. R., McIvor, R. S., Elde, R. P., Fairbanks, C. A., & Vulchanova, L. (2014) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2014.00042 · Cited by 161
“This direct CNS route of administration offers advantages such as reduction in the vector dose required for CNS transduction, and potentially restricted distribution, minimizing off-target effects (Gray et al., 2011, 2013; Snyder et al., 2011; Samaranch et al., 2013).”
BackgroundAAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease
Rosenberg, J. B., Kaplitt, M. G., De, B. P., Chen, A., Flagiello, T., Salami, C., Pey, E., Zhao, L., Ricart Arbona, R. J., Monette, S., et al. (2018) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2017.231 · Cited by 176
Lafora disease — from pathogenesis to treatment strategies
Nitschké, F., Ahonen, S., Nitschke, S., Mitra, S., & Minassian, B. A. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0057-0 · Cited by 174
Biology of adeno-associated viral vectors in the central nervous system
Murlidharan, G., Samulski, R. J., & Asokan, A. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00076 · Cited by 174
“From studies conducted in large animals like pigs and non-human primates (NHPs), a single IT injection of AAV9 has emerged as the candidate procedure for clinical correction of motor neuron disorders affecting the different regions of the spinal cord (Federici et al., 2012; Gray et al., 2013).”
BackgroundSamaranch, L., Sebastian, W. S., Kells, A. P., Salegio, E. A., Heller, G., Bringas, J. R., Pivirotto, P., DeArmond, S., Forsayeth, J., & Bankiewicz, K. S. (2014) · Molecular Therapy · doi:10.1038/mt.2013.266 · Cited by 142
Liguore, W. A., Domire, J. S., Button, D. A., Wang, Y., Dufour, B. D., Srinivasan, S., & McBride, J. L. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.07.017 · Cited by 158
“B in the liver and spleen compared with other peripheral organs including the kidney and gastrocnemius muscle following intrathecal or intravascular infusion, which has also been reported for AAV9.(35,65)”
BackgroundInfluentialControlling AAV Tropism in the Nervous System with Natural and Engineered Capsids
Castle, M. J., Turunen, H. T., Vandenberghe, L. H., & Wolfe, J. H. (2016) · Methods in Molecular Biology · doi:10.1007/978-1-4939-3271-9_10 · Cited by 151
“In contrast, AAV7 and AAV9 can bypass the ependymal layer following intrathecal injection, penetrating the parenchyma and transducing neurons throughout the cortex, cerebellum, and spinal cord [37, 38].”
BackgroundAdeno-Associated Virus Toolkit to Target Diverse Brain Cells
Challis, R. C., Ravindra Kumar, S., Chen, X., Goertsen, D., Coughlin, G. M., Hori, A. M., Chuapoco, M. R., Otis, T. S., Miles, T. F., & Gradinaru, V. (2022) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-111020-100834 · Cited by 148
“Wegmann et al. (2021) delivered gene-silencing zinc finger protein transcription factors, either locally into the hippocampus with AAV9 or brain-wide with AAV-PHP.”
BackgroundInfluentialRecent progress and considerations for AAV gene therapies targeting the central nervous system
Lykken, E. A., Shyng, C., Edwards, R. J., Rozenberg, A. J., & Gray, S. J. (2018) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-018-9234-0 · Cited by 144
“However, following the observation of an obvious immune response to AAV-based gene therapies during clinical trials [78], studies have begun to evaluate the immune response to AAV-mediated gene therapy in both pre-clinical models [18, 79, 80] and human patients [78, 81].”
BackgroundSelf-citationAAV gene therapy for Tay-Sachs disease
Flotte, T. R., Cataltepe, O., Puri, A., Batista, A. R., Moser, R., McKenna-Yasek, D., Douthwright, C., Gernoux, G., Blackwood, M., Mueller, C., et al. (2022) · Nature Medicine · doi:10.1038/s41591-021-01664-4 · Cited by 143
Hinderer, C., Bell, P., Katz, N., Vite, C. H., Louboutin, J.-P., Bote, E., Yu, H., Zhu, Y., Casal, M. L., Bagel, J., et al. (2018) · Human Gene Therapy · doi:10.1089/hum.2017.026 · Cited by 141
“Consistent with previous results, preexisting antibodies blocked liver transduction, and resulted in increased vector distribution to the spleen,(17) but had no impact on CNS transduction.(7,14)”
ResultSpinal muscular atrophy—recent therapeutic advances for an old challenge
Faravelli, I., Nizzardo, M., Comi, G. P., & Corti, S. (2015) · Nature Reviews Neurology · doi:10.1038/nrneurol.2015.77 · Cited by 138
AAV vectors applied to the treatment of CNS disorders: Clinical status and challenges
Kang, L., Jin, S., Wang, J., Lv, Z., Xin, C., Tan, C., Zhao, M., Wang, L., & Liu, J. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.01.067 · Cited by 131
Long-lasting analgesia via targeted in situ repression of Na V 1.7 in mice
Moreno, A. M., Alemán, F., Catroli, G. F., Hunt, M. A., Hu, M. Y., Dailamy, A., Pla, A., Woller, S. A., Palmer, N. D., Parekh, U., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aay9056 · Cited by 143
Adeno-Associated Virus Vectors and Neurological Gene Therapy
Ojala, D. S., Amara, D. P., & Schaffer, D. V. (2014) · The Neuroscientist · doi:10.1177/1073858414521870 · Cited by 143
A large animal model of spinal muscular atrophy and correction of phenotype
Duqué, S. I., Arnold, W. D., Odermatt, P., Li, X., Porensky, P. N., Schmelzer, L., Meyer, K., Kolb, S. J., Schümperli, D., Kaspar, B. K., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24332 · Cited by 148
Chuapoco, M. R., Flytzanis, N. C., Goeden, N., Octeau, J. C., Roxas, K. M., Chan, K. Y., Scherrer, J., Winchester, J., Blackburn, R. J., Campos, L., et al. (2023) · Nature Nanotechnology · doi:10.1038/s41565-023-01419-x · Cited by 141
“Several groups have attempted to circumvent the BBB via lumbar puncture 26 or intra-cisterna magna (ICM) 27 injections to access the cerebral spinal fluid.”
Hinderer, C. J., Bell, P. L., Vite, C. H., Louboutin, J., Grant, R. L., Bote, E., Yu, H., Pukenas, B. A., Hurst, R. W., & Wilson, J. M. (2014) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2014.51 · Cited by 134
Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy
Bailey, R. M., Armao, D. M., Kalburgi, S. N., & Gray, S. J. (2018) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2018.02.005 · Cited by 132
Self-citationSchulz, M., Lévy, D., Petropoulos, C. J., Bashirians, G., Winburn, I. C., Mahn, M., Somanathan, S., Cheng, S. H., & Byrne, B. J. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.01.010 · Cited by 134
Current clinical applications of AAV-mediated gene therapy
Byrne, B. J., Flanigan, K. M., Matesanz, S. E., Finkel, R. S., Waldrop, M. A., D'Ambrosio, E. S., Johnson, N. E., Smith, B. K., Bönnemann, C. G., Carrig, S., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.04.045 · Cited by 152
Castle, M. J., Baltanás, F. C., Kovács, I., Nagahara, A. H., Barba, D., & Tuszynski, M. H. (2020) · Human Gene Therapy · doi:10.1089/hum.2019.367 · Cited by 117
Bey, K., Deniaud, J., Dubreil, L., Joussemet, B., Cristini, J., Ciron, C., Hordeaux, J., Boulc’h, M. L., Marche, K., Maquigneau, M., et al. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.04.001 · Cited by 120
“In the brain, GFP expression mapping results are in line with previous studies that used intra-CSF delivery coupled to an AAV9-GFP vector in large animal models.(22,23,28,29,31,46)”
Therapeutic rAAVrh10 Mediated SOD1 Silencing in Adult SOD1 G93A Mice and Nonhuman Primates
Borel, F., Gernoux, G., Cardozo, B. H., Metterville, J., Cabrera, G. T., Song, L., Su, Q., Gao, G. P., ElMallah, M. K., Brown, R. H., et al. (2015) · Human Gene Therapy · doi:10.1089/hum.2015.122 · Cited by 116
A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna
Taghian, T., Marosfoi, M. G., Puri, A. S., Cataltepe, O. I., King, R. M., Diffie, E. B., Maguire, A. S., Martin, D. R., Fernau, D., Batista, A. R., et al. (2019) · Molecular Therapy · doi:10.1016/j.ymthe.2019.11.012 · Cited by 111
“In agreement with previous studies, vector delivery solely to the cisterna magna results in robust transduction of the entire spinal cord.(21,28,29) However, our results show that motor neuron transduction in the lumbar region was reduced as compared to the cervical region.”
BackgroundResultInfluentialHordeaux, J., Hinderer, C., Goode, T., Katz, N., Buza, E. L., Bell, P., Calcedo, R., Richman, L. K., & Wilson, J. M. (2018) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2018.06.003 · Cited by 105
Methods for Gene Transfer to the Central Nervous System
Kantor, B., Bailey, R. M., Wimberly, K., Kalburgi, S. N., & Gray, S. J. (2014) · Advances in Genetics · doi:10.1016/b978-0-12-800149-3.00003-2 · Cited by 109
“In a second study by Gray et al. (2013), intra-CSF delivery via intrathecal or intracisternal injections were compared in nonhuman primates.”
BackgroundSelf-citationIntrathecal Gene Therapy Corrects CNS Pathology in a Feline Model of Mucopolysaccharidosis I
Hinderer, C. J., Bell, P. L., Gurda, B. L., Wang, Q., Louboutin, J., Zhu, Y., Bagel, J. H., O’Donnell, P., Sikora, T. U., Ruane, T., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.135 · Cited by 108
Grimm, D., & Zolotukhin, S. (2015) · Molecular Therapy · doi:10.1038/mt.2015.173 · Cited by 108
Engineering the AAV capsid to evade immune responses
Barnes, C., Scheideler, O. J., & Schaffer, D. V. (2019) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2019.01.002 · Cited by 109
Ahmed, S. S., Li, H., Cao, C., Şıkoğlu, E. M., Denninger, A. R., Su, Q., Eaton, S. C., Navarro, A. A. L., Xie, J., Szucs, S., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2013.138 · Cited by 97
Gene Therapy for the Nervous System: Challenges and New Strategies
Maguire, C. A., Ramirez, S. H., Merkel, S. F., Sena‐Esteves, M., & Breakefield, X. O. (2014) · Neurotherapeutics · doi:10.1007/s13311-014-0299-5 · Cited by 99
“Transduction can be improved using convection-enhanced delivery [12, 13], viruses that move by retrograde or anterograde transport within neuronal processes or use of cerebrospinal fluid (CSF) flow to transduce neuronal bodies in distant structures [14, 15], and alternate vector serotypes [16] to give high, yet focal…”
BackgroundInfluentialAdeno-Associated Virus Gene Therapy in a Sheep Model of Tay–Sachs Disease
Gray‐Edwards, H. L., Randle, A. N., Maitland, S. A., Benatti, H. R., Hubbard, S. M., Canning, P. F., Vogel, M. B., Brunson, B. L., Hwang, M., Ellis, L. E., et al. (2017) · Human Gene Therapy · doi:10.1089/hum.2017.163 · Cited by 96
Wang, H., Yang, B., Qiu, L., Yang, C., Kramer, J. A., Su, Q., Guo, Y., Brown, R. H., Gao, G., & Xu, Z. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt454 · Cited by 99
“Samulski and colleagues have reported the construction of a new promoter called CBh, which they demonstrated to be capable of driving transgene expression in both glia and motor neurons in the spinal cord (32,47).”
BackgroundResultInfluentialCharacterization of a novel adeno-associated viral vector with preferential oligodendrocyte tropism
Powell, S. K., Khan, N., Parker, C. L., Samulski, R. J., Matsushima, G., Gray, S. J., & McCown, T. J. (2016) · Gene Therapy · doi:10.1038/gt.2016.62 · Cited by 92
Self-citationHarnessing cerebrospinal fluid circulation for drug delivery to brain tissues
Naseri Kouzehgarani, G., Feldsien, T., Engelhard, H. H., Mirakhur, K. K., Phipps, C., Nimmrich, V., Clausznitzer, D., & Lefebvre, D. R. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.03.002 · Cited by 95
Passini, M. A., Bu, J., Richards, A. M., Treleaven, C. M., Sullivan, J. A., O’Riordan, C. R., Scaria, A., Kells, A. P., Samaranch, L., Sebastián, W. S., et al. (2014) · Human Gene Therapy · doi:10.1089/hum.2014.011 · Cited by 101
Spinal muscular atrophy: Development and implementation of potential treatments
Arnold, W. D., & Burghes, A. H. M. (2013) · Annals of Neurology · doi:10.1002/ana.23995 · Cited by 85
Govoni, A., Gagliardi, D., Comi, G. P., & Corti, S. P. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0831-9 · Cited by 87
Chen, W., Yao, S., Wan, J., Tian, Y., Huang, L., Wang, S., Akter, F., Wu, Y., Yao, Y., & Zhang, X. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.03.029 · Cited by 81
Bailey, R. M., Rozenberg, A., & Gray, S. J. (2020) · Brain Research · doi:10.1016/j.brainres.2020.146832 · Cited by 83
“This study expands our previous findings in non-human primates (8) and work by others by using a 10X higher vector dose in mice and reporting a detailed analysis of biodistribution to the CNS, PNS and ANS.”
BackgroundResultSelf-citationTherapeutic Options for Mucopolysaccharidoses: Current and Emerging Treatments
Sawamoto, K., Stapleton, M., Alméciga-Díaz, C. J., Espejo-Mojica, A. J., Losada, J. C., Súarez, D. A., & Tomatsu, S. (2019) · Drugs · doi:10.1007/s40265-019-01147-4 · Cited by 86
Hordeaux, J., Hinderer, C., Goode, T., Buza, E. L., Bell, P., Calcedo, R., Richman, L. K., & Wilson, J. M. (2018) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2018.06.004 · Cited by 81
“This is likely due to asymmetric distribution of NAbs between the systemic and CNS compartments observed by us and others.(24,25) The fact that DRG transduction was also not impacted suggests that AAV particles gained entry via the CSF rather than the fenestrated endothelium of the DRG.”
BackgroundPrasad, S., Dimmock, D. P., Greenberg, B., Walia, J. S., Sadhu, C., Tavakkoli, F., & Lipshutz, G. S. (2022) · Human Gene Therapy · doi:10.1089/hum.2022.138 · Cited by 81
Gurda, B. L., de Lataillade, A. D. G., Bell, P. L., Zhu, Y., Yu, H., Wang, P., Bagel, J. H., Vite, C. H., Sikora, T. U., Hinderer, C. J., et al. (2015) · Molecular Therapy · doi:10.1038/mt.2015.189 · Cited by 82
Gene Therapy for Parkinson’s Disease Associated with GBA1 Mutations
Abeliovich, A., Hefti, F. F., & Sevigny, J. (2021) · Journal of Parkinson s Disease · doi:10.3233/jpd-212739 · Cited by 82
McCurdy, V. J., Rockwell, H. E., Arthur, J. R., Bradbury, A. M., Johnson, A. K., Randle, A. N., Brunson, B. L., Hwang, M., Gray‐Edwards, H. L., Morrison, N. E., et al. (2014) · Gene Therapy · doi:10.1038/gt.2014.108 · Cited by 79
Sinnett, S. E., Hector, R. D., Gadalla, K. K. E., Heindel, C., Chen, D., Zaric, V., Bailey, M. E. S., Cobb, S., & Gray, S. J. (2017) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2017.04.006 · Cited by 84
“This observation is consistent with published data demonstrating peripheral transgene biodistribution after intraCSF administration of AAV.13,17 In general, one or more viral genome copies were present per cell across multiple organs (Figure 2A).”
ResultSelf-citationChowdhury, E. A., Meno‐Tetang, G. M. L., Chang, H. Y., Wu, S., Huang, H. W., Jamier, T., Chandran, J. S., & Shah, D. K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.01.017 · Cited by 80
Ayers, J. I., Fromholt, S., Sinyavskaya, O., Siemienski, Z. B., Rosario, A. M., Li, A., Crosby, K. W., Cruz, P. E., DiNunno, N., Janus, C., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.180 · Cited by 83
Thwaite, R., Pagès, G., Chillón, M., & Bosch, A. (2015) · Gene Therapy · doi:10.1038/gt.2014.103 · Cited by 76
Gene therapy for Mucopolysaccharidoses
Sawamoto, K., Chen, H.-H., Alméciga-Díaz, C. J., Mason, R. W., & Tomatsu, S. (2017) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2017.12.434 · Cited by 78
Advances in optogenetic and chemogenetic methods to study brain circuits in non-human primates
Galván, A., Caiola, M. J., & Albaugh, D. L. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1697-8 · Cited by 75
“…of animals based on screening for neutralizing antibodies could minimize this problem (Bevan et al. 2011; Samaranch et al. 2013), immunity could develop after an initial AAV injection (Gray et al. 2013; Kotterman et al. 2015), ultimately limiting the time window to perform multiple AAV injections.”
BackgroundInfluentialCurrent and potential new treatment strategies for creatine deficiency syndromes
Fernandes‐Pires, G., & Braissant, O. (2021) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2021.12.005 · Cited by 77
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
Self-citationCurrent Gene Therapy using Viral Vectors for Chronic Pain
Guedon, J.-M. G., Wu, S., Zheng, X., Churchill, C. C., Glorioso, J. C., Liu, C.-H., Liu, S., Vulchanova, L., Bekker, A., Tao, Y., et al. (2015) · Molecular Pain · doi:10.1186/s12990-015-0018-1 · Cited by 74
“Direct delivery to the CNS through a spinal or intracerebroventricular route presents an opportunity to partially overcome these barriers as it has yielded higher levels of expression with lower viral titers compared to vascular routes of administration and it takes advantage of the relatively immuno-privileged status…”
BackgroundAdenoassociated virus serotype 9-mediated gene therapy for x-linked adrenoleukodystrophy
Gong, Y., Mu, D., Prabhakar, S., Moser, A., Musolino, P., Ren, J., Breakefield, X. O., Maguire, C. A., & Eichler, F. S. (2015) · Molecular Therapy · doi:10.1038/mt.2015.6 · Cited by 74
Challenges of gene delivery to the central nervous system and the growing use of biomaterial vectors
Puhl, D. L., D’Amato, A. R., & Gilbert, R. J. (2019) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2019.05.024 · Cited by 74
“Approaches that deliver vectors via the CSF, by either intracerebroventricular or intrathecal injection, can result in widespread delivery of the vector system throughout the CNS (Bergen and Pun, 2008; Goula et al., 1998; Gray et al., 2013; Meyer et al., 2015).”
BackgroundBey, K., Ciron, C., Dubreil, L., Deniaud, J., Ledevin, M., Cristini, J., Blouin, V., Aubourg, P. R., & Colle, M.-A. (2017) · Gene Therapy · doi:10.1038/gt.2017.18 · Cited by 74
Sondhi, D., Kaminsky, S. M., Hackett, N. R., Pagovich, O. E., Rosenberg, J. B., De, B. P., Chen, A., Van de Graaf, B., Mezey, J. G., Mammen, G. W., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.abb5413 · Cited by 72
Ohno, K., Samaranch, L., Hadaczek, P., Bringas, J. R., Allen, P. C., Sudhakar, V., Stockinger, D. E., Snieckus, C., Campagna, M. V., San Sebastian, W., et al. (2019) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2018.12.001 · Cited by 85
Oligonucleotide therapeutics in neurodegenerative diseases
Scoles, D. R., & Pulst, S. M. (2018) · RNA Biology · doi:10.1080/15476286.2018.1454812 · Cited by 72
“the CSF were able to reach CNS targets in non-human primates [11].”
BackgroundSevigny, J., Uspenskaya, O., Heckman, L. D., Wong, L. C., Hatch, D. A., Tewari, A., Vandenberghe, R. R., Irwin, D. J., Saracino, D., Ber, I. L., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-02973-0 · Cited by 87
Adeno-Associated Viruses (AAV) and Host Immunity – A Race Between the Hare and the Hedgehog
Rapti, K., & Grimm, D. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.753467 · Cited by 73
“While these concepts have been challenged (189), CNS gene transfer, either to the cerebrospinal fluid (CSF) (75, 190) and, to a lesser extent, after intraparenchymal injection (191–193), remains comparatively successful notwithstanding the presence of circulating nAbs.”
BackgroundSustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model
McCurdy, V. J., Johnson, A. K., Gray‐Edwards, H. L., Randle, A. N., Brunson, B. L., Morrison, N. E., Salibi, N., Johnson, J. A., Hwang, M., Beyers, R. J., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007733 · Cited by 67
AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials
Hardcastle, N., Boulis, N. M., & Federici, T. (2017) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2018.1416089 · Cited by 70
“Other groups have also reported highly reduced to no off-target gene expression when compared with IV delivery [45,56,57].”
BackgroundMethodParambi, D. G. T., Alharbi, K. S., Kumar, R., Harilal, S., Batiha, G. E., Martins, N. A., Hendawy, O. M., Musa, A., Panda, D. S., & Mathew, B. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02555-y · Cited by 76
Chen, X., Lim, D. A., Lawlor, M. W., Dimmock, D., Vite, C. H., Lester, T. L., Tavakkoli, F., Sadhu, C., Prasad, S., & Gray, S. J. (2023) · Human Gene Therapy · doi:10.1089/hum.2022.163 · Cited by 70
“1,82 DRG anatomy allows for exposure to vector in the CSF through nerve roots and ascending spinal cord tracts that are connected to these neurons.”
InfluentialSelf-citationUpright, N. A., Brookshire, S. W., Schnebelen, W., Damatac, C. G., Hof, P. R., Browning, P. G. F., Croxson, P. L., Rudebeck, P. H., & Baxter, M. G. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.1422-18.2018 · Cited by 65
“, 2017), although it is not clear whether the presence of neutralizing antibodies would impede transduction by AAV (Gray et al., 2013).”
BackgroundKrabbe disease successfully treated via monotherapy of intrathecal gene therapy
Bradbury, A. M., Bagel, J. H., Nguyen, D. A., Lykken, E. A., Pesayco, J. P., Jiang, X., Swain, G. P., Assenmacher, C., Hendricks, I. J., Miyadera, K., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133953 · Cited by 68
“However, intrathecal administration has many advantages, including higher transduction efficiency of the CNS (20); sustained expression with the absence of toxicity (21) seen with systemic delivery (22); evasion of anti-AAV neutralizing antibodies (23), which have been shown to be detrimental to systemic delivery (24)…”
BackgroundSelf-citationIntrathecal Gene Therapy for Giant Axonal Neuropathy
Bharucha-Goebel, D. X., Todd, J. J., Saade, D. N., Norato, G., Jain, M., Lehky, T., Bailey, R. M., Chichester, J. A., Calcedo, R., Armao, D. M., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2307952 · Cited by 67
Self-citationAAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy
Kagiava, A., Karaiskos, C., Richter, J., Tryfonos, C., Jennings, M. J., Heslegrave, A., Sargiannidou, I., Stavrou, M., Zetterberg, H., Reilly, M. M., et al. (2021) · Gene Therapy · doi:10.1038/s41434-021-00250-0 · Cited by 65
Motas, S., Haurigot, V., Garcia, M., Marcó, S., Ribera, A., Roca, C., Sánchez, X., Sánchez, V., Molas, M., Bertolin, J., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.86696 · Cited by 63
Preclinical testing of AAV9-PHP.B for transgene expression in the non-human primate cochlea
Ivanchenko, M. V., Hanlon, K. S., Devine, M. K., Tenneson, K., Émond, F., Lafond, J.-F., Kenna, M. A., Corey, D. P., & Maguire, C. A. (2020) · Hearing Research · doi:10.1016/j.heares.2020.107930 · Cited by 62
Woodard, K. T., Liang, K. J., Bennett, W. C., & Samulski, R. J. (2016) · Journal of Virology · doi:10.1128/jvi.01568-16 · Cited by 59
“The CBh promoter has shown exceptional activity in other neuronal tissue compared to CMV or CBA promoter activity (31) without potential silencing issues, and its small size is beneficial for maximizing the limited transgene capacity of rAAV.”
BackgroundGene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development
Massaro, G., Geard, A. F., Liu, W., Coombe-Tennant, O., Waddington, S. N., Baruteau, J., Gissen, P., & Rahim, A. A. (2021) · Biomolecules · doi:10.3390/biom11040611 · Cited by 64
Lysosomal storage disease: Gene therapy on both sides of the blood–brain barrier
Aronovich, E. L., & Hackett, P. B. (2014) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2014.09.011 · Cited by 63
“Neutralizing antibodies to either the viral capsid [103] or the expressed therapeutic protein may block transduction of peripheral organs, although are not necessarily associated with adverse clinical consequences or loss of efficacy, particularly, when “self” enzyme is expressed [78,86, 104,105].”
BackgroundLong-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease
Hordeaux, J., Dubreil, L., Robveille, C., Deniaud, J., Pascal, Q., Déqueant, B., Pailloux, J., Lagalice, L., Ledevin, M., Babarit, C., et al. (2017) · Acta Neuropathologica Communications · doi:10.1186/s40478-017-0464-2 · Cited by 59
“The feasibility of AAV-mediated gene transfer via the CSF in large animal models and non-human primates has been largely demonstrated by we [3, 4], and others [19, 25, 27, 28, 41, 42, 49, 50].”
BackgroundLópez-Gordo, E., Chamberlain, K., Riyad, J. M., Kohlbrenner, E., & Weber, T. (2024) · Viruses · doi:10.3390/v16030442 · Cited by 68
“In rats, substantial transduction was found in the CNS upon delivery through the CSF [208].”
BackgroundIntraventricular Delivery of siRNA Nanoparticles to the Central Nervous System
Shyam, R., Ren, Y., Lee, J., Braunstein, K. E., Mao, H.-Q., & Wong, P. C. (2015) · Molecular Therapy - Nucleic Acids · doi:10.1038/mtna.2015.15 · Cited by 58
AAV9-mediated central nervous system–targeted gene delivery via cisterna magna route in mice
Lukashchuk, V., Lewis, K. E. A., Coldicott, I., Grierson, A. J., & Azzouz, M. (2016) · Molecular Therapy — Methods & Clinical Development · doi:10.1038/mtm.2015.55 · Cited by 60
Metadata
- Authors
- Gray, S. J., Nagabhushan Kalburgi, S., McCown, T. J., & Jude Samulski, R.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Gene Therapy
- Published
- 2013-01-10
- Volume
- 20
- Issue
- 4
- Pages
- 450-459
- ISSN
- 0969-7128 (ISSN-L)
- 1476-5462
- PMC
- PMC3618620
- OpenAlex
- W2092757238
- Cited by
- 377
- References
- 30
- Citations by year
- 2026: 17 · 2025: 37 · 2024: 31 · 2023: 30 · 2022: 30 · 2021: 43 · 2020: 32 · 2019: 19 · 2018: 27 · 2017: 16 · 2016: 21 · 2015: 23 · 2014: 37 · 2013: 14
- FWCI
- 20.99
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-04-04)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gene Therapy (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institutes of Health (5u54ar056953-05)
- National Institute of Allergy and Infectious Diseases (R01AI072176)
- National Institute of Neurological Disorders and Stroke (NS 35633, R43NS063611, R01NS035633)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54-AR056953)
- National Center for Research Resources (UL1RR025747)
- 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
- Health Sciences › Medicine › Genetics (clinical) › Neurogenetic and Muscular Disorders Research
- Keywords
- adeno-associated virus, AAV9, intrathecal gene delivery, cerebrospinal fluid injection, antibody escape, spinal cord, non-human primates, lysosomal storage disease, motor neuron disease, vector biodistribution
- MeSH terms
- Dependovirus, Animals, Blood Vessels, Brain, Genetic Vectors, Injections, Spinal, Macaca fascicularis, Mice, Inbred BALB C, Motor Neurons, Spinal Cord, Tissue Distribution, Transduction, Genetic, Rats, Sprague-Dawley, Mice, Rats, Antibodies, Neutralizing
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
