rAAV Gene Therapy in a Canavan’s Disease Mouse Model Reveals Immune Impairments and an Extended Pathology Beyond the Central Nervous System
Open accessAbstract
Aspartoacylase (AspA) gene mutations cause the pediatric lethal neurodegenerative Canavan disease (CD). There is emerging promise of successful gene therapy for CD using recombinant adeno-associated viruses (rAAVs). Here, we report an intracerebroventricularly delivered AspA gene therapy regime using three serotypes of rAAVs at a 20-fold reduced dose than previously described in AspA(-/-) mice, a bona-fide mouse model of CD. Interestingly, central nervous system (CNS)-restricted therapy prolonged survival over systemic therapy in CD mice but failed to sustain motor functions seen in systemically treated mice. Importantly, we reveal through histological and functional examination of untreated CD mice that AspA deficiency in peripheral tissues causes morphological and functional abnormalities in this heretofore CNS-defined disorder. We demonstrate for the first time that AspA deficiency, possibly through excessive N-acetyl aspartic acid accumulation, elicits both a peripheral and CNS immune response in CD mice. Our data establish a role for peripheral tissues in CD pathology and serve to aid the development of more efficacious and sustained gene therapy for this disease.
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?
Published data using AAV9 in other Canavan mouse models render the possibility of unexpectedly high oligotropism in nur7 brain unlikely.
“but published data using the vector in other Canavan mouse models render this possibility unlikely.14,19”
From Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease (2021) · cites this paper as [19]
Cites
1 retracted
Foust, K. D., Wang, X., McGovern, V. L., Braun, L., Bevan, A. K., Haidet, A. M., Le, T. T., Morales, P. R., Rich, M. M., Burghes, A. H. M., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt.1610 · Cited by 688 · see citing works
Self-citationRetractedStructural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413 · see citing works
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 · see citing works
Self-citationN-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology
MOFFETT, J., Ross, B., Arun, P., Madhavarao, C. N., & Namboodiri, A. M. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2006.12.003 · Cited by 1,413 · see citing works
IL-6 in autoimmune disease and chronic inflammatory proliferative disease
Ishihara, K., & Hirano, T. (2002) · Cytokine & Growth Factor Reviews · doi:10.1016/s1359-6101(02)00027-8 · Cited by 807 · see citing works
Brain Dendritic Cells and Macrophages/Microglia in Central Nervous System Inflammation
Fischer, H., & Reichmann, G. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.4.2717 · Cited by 408 · see citing works
Aspartoacylase deficiency and N‐acetylaspartic aciduria in patients with canavan disease
Matalon, R. K., Michals, K., Sebesta, D. G., Deanching, M., Gashkoff, P., Casanova, J., Optiz, J. M., & Reynolds, J. F. (1988) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320290234 · Cited by 405 · see citing works
Self-citationIL‐1β induces COX2, MMP‐1, ‐3 and ‐13, ADAMTS‐4, IL‐1β and IL‐6 in human tendon cells
Tsuzaki, M., Guyton, G. P., Garrett, W. E. J., Archambault, J. M., Herzog, W., Almekinders, L. C., Bynum, D. K., Yang, X., & Banes, A. J. (2003) · Journal of Orthopaedic Research® · doi:10.1016/s0736-0266(02)00141-9 · Cited by 366 · see citing works
SPECIFICITY OF AMINO ACID ACYLASES
Birnbaum, S. M., Levintow, L., Kingsley, R. B., & Greenstein, J. P. (1952) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55898-1 · Cited by 350 · see citing works
Zhang, H., Yang, B., Mu, X., Ahmed, S. S., Su, Q., He, R., Wang, H., Mueller, C., Sena-Esteves, M., Brown, R., et al. (2011) · Molecular Therapy · doi:10.1038/mt.2011.98 · Cited by 291 · see citing works
Self-citationEndoplasmic reticulum stress in disorders of myelinating cells
Lin, W., & Popko, B. (2009) · Nature Neuroscience · doi:10.1038/nn.2273 · Cited by 253 · see citing works
Cloning of the human aspartoacylase cDNA and a common missense mutation in Canavan disease
Kaul, R., Ping Gao, G., Balamurugan, K., & Matalon, R. (1993) · Nature Genetics · doi:10.1038/ng1093-118 · Cited by 221 · see citing works
Self-citationYang, B., Li, S., Wang, H., Guo, Y., Gessler, D. J., Cao, C., Su, Q., Kramer, J., Zhong, L., Ahmed, S. S., et al. (2014) · Molecular Therapy · doi:10.1038/mt.2014.68 · Cited by 213 · see citing works
Self-citationMadhavarao, C. N., Arun, P., Moffett, J. R., Szucs, S., Surendran, S., Matalon, R. K., Garbern, J. Y., Hristova, D. M., Johnson, T., Jiang, W., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409184102 · Cited by 213 · see citing works
Self-citationPassini, M. A., & Wolfe, J. H. (2001) · Journal of Virology · doi:10.1128/jvi.75.24.12382-12392.2001 · Cited by 185 · see citing works
Xie, J., Xie, Q., Zhang, H., Ameres, S. L., Hung, J., Su, Q., He, R., Mu, X. N., Ahmed, S. S., Park, S., et al. (2010) · Molecular Therapy · doi:10.1038/mt.2010.279 · Cited by 167 · see citing works
Self-citationN-Acetylaspartate as an acetyl source in the nervous system
Mehta, V., & Namboodiri, M. A. A. (1995) · Molecular Brain Research · doi:10.1016/0169-328x(95)00044-s · Cited by 108 · see citing works
Method for non-invasively recording electrocardiograms in conscious mice
Chu, V., Otero, J. M., López, O., Morgan, J. P., Amende, I., & Hampton, T. (2001) · BMC Physiology · doi:10.1186/1472-6793-1-6 · Cited by 102 · see citing works
Self-citationAhmed, 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 96 · see citing works
Self-citationIntroducing Genes into Mammalian Cells: Viral VectorsPreprint
Sena‐Esteves, M., & Gao, G. (2020) · Cold Spring Harbor Protocols · doi:10.1101/pdb.top095513 · Cited by 89 · see citing works
Self-citationThe Clinical Course of Canavan Disease
Traeger, E., & Rapin, I. (1998) · Pediatric Neurology · doi:10.1016/s0887-8994(97)00185-9 · Cited by 87 · see citing works
Epigenetic mechanisms facilitating oligodendrocyte development, maturation, and aging
Copray, S. C. V. M., Huynh, J. L., Sher, F., Casaccia‐Bonnefil, P., & Boddeke, E. (2009) · Glia · doi:10.1002/glia.20881 · Cited by 82 · see citing works
Bennett, J., Wu, Y.-G., Gossen, J. A., Zhou, P., & Stocco, C. O. (2012) · Endocrinology · doi:10.1210/en.2011-1969 · Cited by 78 · see citing works
Developmental increase of aspartoacylase in oligodendrocytes parallels CNS myelination
Kirmani, B. F., Jacobowitz, D. M., & Namboodiri, M. A. A. (2003) · Developmental Brain Research · doi:10.1016/s0165-3806(02)00592-8 · Cited by 71 · see citing works
Biochemistry and Molecular Biology of Canavan Disease
Matalon, R. K., & Michals‐Matalon, K. (1999) · Neurochemical Research · doi:10.1023/a:1022531829100 · Cited by 59 · see citing works
Self-citationElectron miscroscopic and enzyme histochemical studies of the cerebellum in spongy degeneration
Adachi, M., Torii, J., Schneck, L., et al. (1972) · Acta Neuropathologica · doi:10.1007/bf00687899 · Cited by 58 · see citing works
Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy
von Jonquières, G., Spencer, Z. H. T., Rowlands, B. D., Klugmann, C. B., Bongers, A., Harasta, A. E., Parley, K. E., Cederholm, J. M. E., Teahan, O., Pickford, R., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1784-9 · Cited by 57 · see citing works
Structure and Stability of Internodal Myelin in Mouse Models of Hereditary Neuropathy
Avila, R. L., Inouye, H., Baek, R. C., et al. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000186925.95957.dc · Cited by 55 · see citing works
Baslow, M. H. (1999) · Journal of Inherited Metabolic Disease · doi:10.1023/a:1005437915117 · Cited by 52 · see citing works
Epileptic seizures induced by N-acetyl-l-aspartate in rats: in vivo and in vitro studies
Akimitsu, T., Kurisu, K., Hanaya, R., et al. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02028-x · Cited by 52 · see citing works
Aspartoacylase-LacZ Knockin Mice: An Engineered Model of Canavan Disease
Mersmann, N., Tkachev, D., Jelinek, R., Röth, P. T., Möbius, W., Ruhwedel, T., Rühle, S., Weber‐Fahr, W., Sartorius, A., & Klugmann, M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020336 · Cited by 48 · see citing works
Overexpression of CART in the PVN Increases Food Intake and Weight Gain in Rats
Smith, K. L., Gardiner, J., Ward, H. L., Kong, W. M., Murphy, K. G., Martin, N. M., Ghatei, M. A., & Bloom, S. R. (2008) · Obesity · doi:10.1038/oby.2008.366 · Cited by 48 · see citing works
Karumbayaram, S., Kelly, T. K., Paucar, A. A., Roe, A. J., Umbach, J. A., Charles, A. C., Goldman, S. A., Kornblum, H. I., & Wiedau‐Pazos, M. (2009) · Disease Models & Mechanisms · doi:10.1242/dmm.002113 · Cited by 48 · see citing works
Aspartoacylase supports oxidative energy metabolism during myelination
Francis, J. S., Strande, L., Markov, V., & Leone, P. (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.66 · Cited by 41 · see citing works
METABOLISM OFN-ACETYL- L -ASPARTIC ACID IN MICE
Berlinguet, L., & Laliberté, M. (1966) · Canadian Journal of Biochemistry · doi:10.1139/o66-096 · Cited by 37 · see citing works
A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis
Sun, Y., Chai, X.-Q., Kong, W., Liu, L., Yu, W., & Zhang, Z. (2014) · Neural Regeneration Research · doi:10.4103/1673-5374.135317 · Cited by 36 · see citing works
Treleaven, C. M., Tamsett, T. J., Bu, J., Fidler, J. A., Sardi, S. P., Hurlbut, G. D., Woodworth, L. A., Cheng, S. H., Passini, M. A., Shihabuddin, L. S., et al. (2012) · Molecular Therapy · doi:10.1038/mt.2012.114 · Cited by 31 · see citing works
The role of IL-6 in the inflammatory and humoral response to adenoviral vectors
Benihoud, K., Salone, B., Esselin, S., Opolon, P., Poli, V., Giovine, M. D., Perricaudet, M., & Saggio, I. (2000) · The Journal of Gene Medicine · doi:10.1002/(sici)1521-2254(200005/06)2:3 · Cited by 31 · see citing works
N‐Acetylaspartic acid promotes oxidative stress in cerebral cortex of rats
Pederzolli, C. D., Mescka, C. P., Scapin, F., et al. (2007) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2007.04.002 · Cited by 26 · see citing works
Extracellular Acidic pH Inhibits Oligodendrocyte Precursor Viability, Migration, and Differentiation
Jagielska, A., Wilhite, K. D., & Vliet, K. J. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076048 · Cited by 24 · see citing works
Neuroprotective role of lipoic acid against acute toxicity of N-acetylaspartic acid
Pederzolli, C. D., Rosa, A. P., de Oliveira, A. S., et al. (2010) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-010-0547-x · Cited by 18 · see citing works
Canavan Disease: Studies on the Knockout Mouse
Matalon, R. K., Michals‐Matalon, K., Surendran, S., et al. (2006) · Springer eBooks · doi:10.1007/0-387-30172-0_6 · Cited by 11 · see citing works
Self-citationAspartoacylase gene knockout in the mouse: Impact on reproduction
Surendran, S., Szucs, S., Tyring, S. K., et al. (2005) · Reproductive Toxicology · doi:10.1016/j.reprotox.2005.02.001 · Cited by 8 · see citing works
Upper airway abnormalities in Canavan disease
Francois, J., & Manaligod, J. M. (2002) · International Journal of Pediatric Otorhinolaryngology · doi:10.1016/s0165-5876(02)00258-6 · Cited by 6 · see citing works
Gao, S. S. A. G. (2014) · Journal of Neurological Disorders · doi:10.4172/2329-6895.1000i105 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Gessler, D. J., Li, D., Xu, H., Su, Q., Sanmiguel, J., Tuncer, S., Moore, C., King, J., Matalon, R., & Gao, G. (2017) · JCI Insight · doi:10.1172/jci.insight.90807 · Cited by 70 · see citing works
Self-citationFrancis, J. S., Wojtas, I., Markov, V., Gray, S. J., McCown, T. J., Samulski, R. J., Bilaniuk, L. T., Wang, D.-J., De Vivo, D. C., Janson, C. G., et al. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.10.001 · Cited by 49 · see citing works
Francis, J. S., Markov, V., Wojtas, I. D., Gray, S., McCown, T., Samulski, R. J., Figueroa, M., & Leone, P. (2021) · Molecular Therapy - Methods & Clinical Development · doi:10.1016/j.omtm.2021.01.009 · Cited by 41 · see citing works
“It is possible that AAV9 in the microenvironment of the nur7 brain exhibits unexpectedly high oligotropism, but published data using the vector in other Canavan mouse models render this possibility unlikely.(14,19) It would also be reasonable to ask if the use of Olig2 as a marker of oligodendrocytes exclusively is no…”
Background
- Authors
- Ahmed, S. S., Schattgen, S. A., Frakes, A. E., Sikoglu, E. M., Su, Q., Li, J., Hampton, T. G., Denninger, A. R., Kirschner, D. A., Kaspar, B., Matalon, R., & Gao, G.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Nationwide Children's Hospital (US)
- Mouse Specifics (United States) (US)
- Boston College (US)
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Gao, Guangping
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 24
- Issue
- 6
- Pages
- 1030-1041
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC4923332
- OpenAlex
- W2339223156
- Cited by
- 24
- References
- 45
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2022: 3 · 2021: 3 · 2020: 1 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 1
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (T32NS077984, R01NS076991)
- National Center for Research Resources (S10RR027897)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Canavan disease, aspartoacylase deficiency, intracerebroventricular administration, peripheral immune response, neurodegeneration, motor function
- MeSH terms
- Dependovirus, Amidohydrolases, Animals, Central Nervous System, Disease Models, Animal, Genetic Vectors, Humans, Organ Specificity, Genetic Therapy, Survival Analysis, Treatment Outcome, Canavan Disease, Mice
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
