Metabotropic glutamate receptor 5 as drug target for Fragile X syndrome
Abstract
Fragile X syndrome (FXS) is the most common monogenic form of inherited mental retardation caused by a trinucleotid repeat expansion and transcriptional shutdown of the FMR1 gene. FXS patients present a complex and often severe neuropsychiatric phenotype yet have mild somatic symptoms, normal life expectancies, and no indications of neurodegeneration. The therapeutic potential of mGlu5 inhibitors was proposed in the 'mGluR theory of FXS' based on early insights into the molecular pathophysiology of FXS. Studies in Fragile X mental retardation 1 (Fmr1) knock-out mice, a widely used disease model, demonstrated that mGlu5 inhibitors can correct a broad range of disease-related phenotypes. Recent clinical trials, however, with two different mGlu5 inhibitors (basimglurant and mavoglurant) showed no therapeutic benefit in FXS patients for reasons as yet unclear.
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Several drug development programs based on the inhibition of mGluR signaling for the treatment of FXS were recently closed because efficacy studies in adolescents and adults showed no measurable benefits.
“However, several drug development programs based on the inhibition of mGluR signaling for the treatment of FXS (Novartis and Seaside Therapeutics) were recently closed because efficacy studies in adolescents and adults showed no measurable benefits 114,115 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [115]
The observation that multiple therapeutic interventions correct the same Fmr1-knockout phenotypes supports the idea that the mouse model, the outcome measures, or both are over-predictive of clinical efficacy.
“The observations that multiple therapeutic interventions correct the same phenotypes in the Fmr1-KO mouse model (TABLE 1) further support the notion that either the Fmr1-KO mouse model, the outcome measures currently used or both factors combined are over-predictive of clinical efficacy84.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [84]
Cites
Verkerk, A. J. M. H., Pieretti, M., Sutcliffe, J. S., Fu, Y.-H., Kuhl, D. P. A., Pizzuti, A., Reiner, O., Richards, S., Victoria, M. F., Zhang, F., et al. (1991) · Cell · doi:10.1016/0092-8674(91)90397-h · Cited by 3,481 · see citing works
FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism
Darnell, J. C., Van Driesche, S. J., Zhang, C., Hung, K. Y. S., Mele, A., Fraser, C. E., Stone, E. F., Chen, C., Fak, J. J., Chi, S. W., et al. (2011) · Cell · doi:10.1016/j.cell.2011.06.013 · Cited by 2,072 · see citing works
The mGluR theory of fragile X mental retardation
Bear, M. F., Huber, K. M., & Warren, S. T. (2004) · Trends in Neurosciences · doi:10.1016/j.tins.2004.04.009 · Cited by 1,580 · see citing works
Gasparini, F., Lingenhöhl, K., Stoehr, N., Flor, P. J., Heinrich, M., Vranesic, I., Biollaz, M., Allgeier, H., Heckendorn, R., Urwyler, S., et al. (1999) · Neuropharmacology · doi:10.1016/s0028-3908(99)00082-9 · Cited by 725 · see citing works
Weiler, I. J., Irwin, S. A., Klintsova, A. Y., Spencer, C. M., Brazelton, A. D., Miyashiro, K., Comery, T. A., Patel, B., Eberwine, J., & Greenough, W. T. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5395 · Cited by 644 · see citing works
Jacquemont, S., Curie, A., des Portes, V., Torrioli, M. G., Berry-Kravis, E., Hagerman, R. J., Ramos, F. J., Cornish, K., He, Y., Paulding, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3001708 · Cited by 609 · see citing works
Bilousova, T. V., Dansie, L., Ngo, M., Aye, J., Charles, J. R., Ethell, D. W., & Ethell, I. M. (2009) · Journal of Medical Genetics · doi:10.1136/jmg.2008.061796 · Cited by 465 · see citing works
The Pathophysiology of Fragile X Syndrome
Penagarikano, O., Mulle, J. G., & Warren, S. T. (2007) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.8.080706.092249 · Cited by 420 · see citing works
The Pathophysiology of Fragile X (and What It Teaches Us about Synapses)
Bhakar, A. L., Dölen, G., & Bear, M. F. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-060909-153138 · Cited by 370 · see citing works
Dolan, B. M., Duron, S. G., Campbell, D. A., Vollrath, B., Rao, B. S. S., Ko, H.-Y., Lin, G. G., Govindarajan, A., Choi, S.-Y., & Tonegawa, S. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1219383110 · Cited by 260 · see citing works
The fragile X mental retardation protein is associated with ribosomes
Khandjian, E. W., Corbin, F., Woerly, S., & Rousseau, F. (1996) · Nature Genetics · doi:10.1038/ng0196-91 · Cited by 251 · see citing works
Henderson, C., Wijetunge, L., Kinoshita, M. N., Shumway, M., Hammond, R. S., Postma, F. R., Brynczka, C., Rush, R., Thomas, A., Paylor, R., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004218 · Cited by 249 · see citing works
Osterweil, E. K., Chuang, S.-C., Chubykin, A. A., Sidorov, M., Bianchi, R., Wong, R. K. S., & Bear, M. F. (2013) · Neuron · doi:10.1016/j.neuron.2012.01.034 · Cited by 230 · see citing works
Sidhu, H., Dansie, L. E., Hickmott, P. W., Ethell, D. W., & Ethell, I. M. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.1162-14.2014 · Cited by 155 · see citing works
Spooren, W., Lindemann, L., Ghosh, A., & Santarelli, L. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.09.004 · Cited by 119 · see citing works
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Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome
Berry-Kravis, E. M., Lindemann, L., Jønch, A. E., Apostol, G., Bear, M. F., Carpenter, R. L., Crawley, J. N., Curie, A., Des Portes, V., Hossain, F., et al. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.221 · Cited by 336 · see citing works
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Sahin, M., & Sur, M. (2015) · Science · doi:10.1126/science.aab3897 · Cited by 295 · see citing works
Outcome Measures for Clinical Trials in Down Syndrome
Esbensen, A. J., Hooper, S. R., Fidler, D., Hartley, S. L., Edgin, J., d'Ardhuy, X. L., Capone, G., Conners, F. A., Mervis, C. B., Abbeduto, L., et al. (2017) · American Journal on Intellectual and Developmental Disabilities · doi:10.1352/1944-7558-122.3.247 · Cited by 153 · see citing works
FragXis Study Group, Youssef, E. A., Berry-Kravis, E., Czech, C., Hagerman, R. J., Hessl, D., Wong, C. Y., Rabbia, M., Deptula, D., John, A., et al. (2018) · Neuropsychopharmacology · doi:10.1038/npp.2017.177 · Cited by 133 · see citing works
Self-citationGreiss Hess, L., Fitzpatrick, S. E., Nguyen, D. V., Chen, Y., Gaul, K. N., Schneider, A., Lemons Chitwood, K., Eldeeb, M. A. A. A., Polussa, J., Hessl, D., et al. (2016) · Journal of Developmental & Behavioral Pediatrics · doi:10.1097/dbp.0000000000000334 · Cited by 122 · see citing works
Lindemann, L., Porter, R. H., Scharf, S. H., Kuennecke, B., Bruns, A., von Kienlin, M., Harrison, A. C., Paehler, A., Funk, C., Gloge, A., et al. (2015) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.222463 · Cited by 107 · see citing works
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Gross, C., Hoffmann, A., Bassell, G. J., & Berry-Kravis, E. M. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0355-9 · Cited by 105 · see citing works
Fuxe, K., & Borroto-Escuela, D. O. (2015) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.1074175 · Cited by 43 · see citing works
- Authors
- Scharf, S. H., Jaeschke, G., Wettstein, J. G., & Lindemann, L.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Lindemann, Lothar
- Venue
- Current Opinion in Pharmacology
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 20
- Pages
- 124-134
- ISSN
- 1471-4892 (ISSN-L)
- OpenAlex
- W2018457010
- Cited by
- 106
- References
- 15
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 8 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 13 · 2017: 24 · 2016: 15 · 2015: 20 · 2012: 1
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Opinion in Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- fragile X syndrome, metabotropic glutamate receptor 5, FMR1 gene, trinucleotide repeat expansion, Fmr1 knockout mice, intellectual disability, therapeutic target
- MeSH terms
- Animals, Disease Models, Animal, Fragile X Syndrome, Humans, Imidazoles, Indoles, Phenotype, Pyridines, Mice, Knockout, Excitatory Amino Acid Antagonists, Mice, Molecular Targeted Therapy, Receptor, Metabotropic Glutamate 5
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