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5. MYASTHENIA & RELATED DISORDERS

Author

Bauché, S., primary, Sureau, A., additional, Sternberg, D., additional, Rendu, J., additional, Buon, C., additional, Messéant, J., additional, Boëx, M., additional, Furling, D., additional, Fauré, J., additional, Latypova, X., additional, Gelot, A. Bernabe, additional, Mayer, M., additional, Laffargue, F., additional, Nougues, M., additional, Fontaine, B., additional, Eymard, B., additional, Isapof, A., additional, and Strochlic, L., additional

Published
2020
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7. miR-7 Restores Phenotypes in Myotonic Dystrophy Muscle Cells by Repressing Hyperactivated Autophagy

Author

Sabater-Arcis M, Bargiela A, Furling D, and Artero R

Subjects
musculoskeletal diseases, CTG expansions, Muscleblind, Myotonic Dystrophy, UPS system, autophagy, miR-7, miRNA, muscle atrophy, oligonucleotide, therapy
Abstract

Unstable CTG expansions in the 3' UTR of the DMPK gene are responsible for myotonic dystrophy type 1 (DM1) condition. Muscle dysfunction is one of the main contributors to DM1 mortality and morbidity. Pathways by which mutant DMPK trigger muscle defects, however, are not fully understood. We previously reported that miR-7 was downregulated in a DM1 Drosophila model and in biopsies from patients. Here, using DM1 and normal muscle cells, we investigated whether miR-7 contributes to the muscle phenotype by studying the consequences of replenishing or blocking miR-7, respectively. Restoration of miR-7 with agomiR-7 was sufficient to rescue DM1 myoblast fusion defects and myotube growth. Conversely, oligonucleotide-mediated blocking of miR-7 in normal myoblasts led to fusion and myotube growth defects. miR-7 was found to regulate autophagy and the ubiquitin-proteasome system in human muscle cells. Thus, low levels of miR-7 promoted both processes, and high levels of miR-7 repressed them. Furthermore, we uncovered that the mechanism by which miR-7 improves atrophy-related phenotypes is independent of MBNL1, thus suggesting that miR-7 acts downstream or in parallel to MBNL1. Collectively, these results highlight an unknown function for miR-7 in muscle dysfunction through autophagy- and atrophy-related pathways and support that restoration of miR-7 levels is a candidate therapeutic target for counteracting muscle dysfunction in DM1.

Published
2020

12. Dysregulation of circular RNAs in myotonic dystrophy type 1

Author

Voellenkle, C., Perfetti, A., Carrara, M., Fuschi, P., Renna, L. V., Longo, M., Sain, S. B., Cardani, R., Valaperta, R., Silvestri, Gabriella, Legnini, I., Bozzoni, I., Furling, D., Gaetano, C., Falcone, G., Meola, G., Martelli, F., Silvestri G. (ORCID:0000-0002-1950-1468), Voellenkle, C., Perfetti, A., Carrara, M., Fuschi, P., Renna, L. V., Longo, M., Sain, S. B., Cardani, R., Valaperta, R., Silvestri, Gabriella, Legnini, I., Bozzoni, I., Furling, D., Gaetano, C., Falcone, G., Meola, G., Martelli, F., and Silvestri G. (ORCID:0000-0002-1950-1468)

Abstract

Circular RNAs (circRNAs) constitute a recently re-discovered class of non-coding RNAs functioning as sponges for miRNAs and proteins, affecting RNA splicing and regulating transcription. CircRNAs are generated by “back-splicing”, which is the linking covalently of 3′- and 5′-ends of exons. Thus, circRNA levels might be deregulated in conditions associated with altered RNA-splicing. Significantly, growing evidence indicates their role in human diseases. Specifically, myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by expanded CTG repeats in the DMPK gene which results in abnormal mRNA-splicing. In this investigation, circRNAs expressed in DM1 skeletal muscles were identified by analyzing RNA-sequencing data-sets followed by qPCR validation. In muscle biopsies, out of nine tested, four transcripts showed an increased circular fraction: CDYL, HIPK3, RTN4_03, and ZNF609. Their circular fraction values correlated with skeletal muscle strength and with splicing biomarkers of disease severity, and displayed higher values in more severely affected patients. Moreover, Receiver-Operating-Characteristics curves of these four circRNAs discriminated DM1 patients from controls. The identified circRNAs were also detectable in peripheral-blood-mononuclear-cells (PBMCs) and the plasma of DM1 patients, but they were not regulated significantly. Finally, increased circular fractions of RTN4_03 and ZNF609 were also observed in differentiated myogenic cell lines derived from DM1 patients. In conclusion, this pilot study identified circRNA dysregulation in DM1 patients.

Published
2019

14. CRISPR/Cas9-mediated editing for dominant genetic disorders: efficient excision of trinucleotide repeat expansion in myotonic dystrophy

Author

Dastidar, S., Ardui, S., Singh, K., Nair, N., Fu, Y., Reyon, D., Samara, E., Gerli, M. F. M., Klein, A. F., DeSchrijver, W., Majumdar, D., Tipanee, J., Seneca, S., Tulalamba, W., Wang, H., Chai, Y. C., In't Veld, P., Furling, D., Tedesco, F. S., Vermeesch, J. R., Joung, J. K., Chuah, M. K., VandenDriessche, T., Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, Division of Gene Therapy & Regenerative Medicine, Physics, Medicine and Pharmacy academic/administration, Faculty of Sciences and Bioengineering Sciences, Clinical sciences, Medical Genetics, Reproduction and Genetics, Experimental Pathology, Pathology/molecular and cellular medicine, Diabetes Pathology & Therapy, and Vrije Universiteit Brussel

Published
2017

15. Downregulation of the Glial GLT1 Glutamate Transporter and Purkinje Cell Dysfunction in a Mouse Model of Myotonic Dystrophy

Author

Sicot, G, Servais, L, Dinca, DM, Leroy, A, Prigogine, C, Medja, F, Braz, SO, Huguet-Lachon, A, Chhuon, C, Nicole, A, Gueriba, N, Oliveira, R, Dan, B, Furling, D, Swanson, MS, Guerrera, IC, Cheron, G, Gourdon, G, Gomes-Pereira, M, Gomes-Pereira, Mario, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, BLANC - Anomalies précoces dans un modèle murin de la dystrophie myotonique de Steinert : un modèle de la forme congénitale ? - - MODELCDM2010 - ANR-10-BLAN-1121 - BLANC - VALID, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of Neurophysiology and Biomechanics of Movement (LNBM), Université libre de Bruxelles (ULB), Université Sorbonne Paris Cité (USPC), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Florida [Gainesville] (UF), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-BLAN-1121,MODELCDM,Anomalies précoces dans un modèle murin de la dystrophie myotonique de Steinert : un modèle de la forme congénitale ?(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service of Clinical Trials and Databases, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Laboratory of Electrophysiology, University of Mons, 7000 Mons, and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, Bergmann glia, cerebellum, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, brain, Down-Regulation, neurons, Mice, Transgenic, glutamate, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, transgenic mice, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sciences de l'ingénieur, Article, Glutamate Plasma Membrane Transport Proteins, Mice, Purkinje Cells, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, lcsh:QH301-705.5, myotonic dystrophy, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, astrocytes, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, ceftriaxone, Disease Models, Animal, Excitatory Amino Acid Transporter 2, lcsh:Biology (General), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, nervous system, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], GLT1, unstable microsatellite repeats
Abstract

SUMMARY Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels., Graphical Abstract, In Brief Neural dysfunction in myotonic dystrophy is not fully understood. Using a transgenic mouse model of the disease, Sicot et al. find electrophysiological and motor evidence for cerebellar dysfunction in association with pronounced signs of RNA toxicity in Bergmann glia. Upregulation of a defective glial-specific glutamate transporter corrects cerebellum phenotypes.

Published
2017
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18. Incidence and predictors of venous thromboembolism in inherited myopathies: A higher risk in myotonic dystrophy

Author

Sochala, M., primary, Porcher, R., additional, Laforet, P., additional, Fayssoil, A., additional, Becane, H.M., additional, Lazarus, A., additional, Stojkovic, T., additional, Behin, A., additional, Leonard-Louis, S., additional, Arnaud, P., additional, Furling, D., additional, Bassez, G., additional, Eymard, B., additional, Duboc, D., additional, and Wahbi, K., additional

Published
2018
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19. Survival in myotonic dystrophy type 1 predicted by the new DM1 survival risk score

Author

Wahbi, K., primary, Porcher, R., additional, Laforêt, P., additional, Fayssoil, A., additional, Stojkovic, T., additional, Leonard Louis, S., additional, Behin, A., additional, Furling, D., additional, Arnaud, P., additional, Sochala, M., additional, Probst, V., additional, Babuty, D., additional, Pellieux, S., additional, Bassez, G., additional, Pereon, Y., additional, Eymard, B., additional, and Duboc, D., additional

Published
2017
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21. Association between mutation size and cardiac involvement in myotonic dystrophy type 1: an analysis of the DM1-heart registry

Author

Wahbi, K., primary, Chong-Nguyen, C., additional, Algalarrondo, V., additional, Becane, H., additional, Arnaud, P., additional, Furling, D., additional, Bassez, G., additional, Behin, A., additional, Fayssoil, A., additional, Laforêt, P., additional, Stojkovic, T., additional, Eymard, B., additional, and Duboc, D., additional

Published
2017
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23. Therapeutic Approaches for Dominant Muscle Diseases

Author

Klein, A F, Dastidar, S, Furling, D, Chuah, M K, Basic (bio-) Medical Sciences, and Division of Gene Therapy & Regenerative Medicine

Subjects
Medicine(all), myotonic dystrophy
Abstract

Myotonic Dystrophy (DM), one of the most common neuromuscular disorders in adults, comprises two genetically distinct forms triggered by unstable expanded repeats in non-coding regions. The most common DM1 is caused by expanded CTG repeats in the 3'UTR of the DMPK gene, whereas DM2 is due to large expanded CCTG repeats in the first intron of the CNBP gene. Both mutations induce a pathogenic RNA gain-of-function mechanism. Mutant RNAs containing CUG or CCUG expanded repeats, which are retained in the nuclei as aggregates alter activities of alternative splicing regulators such as MBNL proteins and CELF1. As a consequence, alternative splicing misregulations of several pre-mRNAs have been associated with DM clinical symptoms. Currently, there is no available cure for this dominant neuromuscular disease. Nevertheless, promising therapeutic strategies have been developed for the last decade. Preclinical progress in DM research prompted the first DM1 clinical trial based on antisense oligonucleotides promoting a RNase-H-mediated degradation of the expanded CUG transcripts. The ongoing Phase 1/2a clinical trial will hopefully give further insights into the quest to find a bona fide cure for DM1. In this review, we will provide an overview of the different strategies that were developed to neutralize the RNA toxicity in DM1. Different approaches including antisense oligonucleotide technologies, gene therapies or small molecules have been tested and validated in cellular and animal models. Remaining challenges and additional avenues to explore will be discussed.

Published
2015

24. CRISPR/Cas9-Induced (CTGCAG)n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing

Author

Agtmaal, E.L. van, Andre, L.M., Willemse, M.P., Cumming, S.A., Kessel, I.D.G. van, Broek, W.J.A.A. van den, Gourdon, G., Furling, D., Mouly, V., Monckton, D.G., Wansink, D.G., Wieringa, B., Agtmaal, E.L. van, Andre, L.M., Willemse, M.P., Cumming, S.A., Kessel, I.D.G. van, Broek, W.J.A.A. van den, Gourdon, G., Furling, D., Mouly, V., Monckton, D.G., Wansink, D.G., and Wieringa, B.

Abstract

Contains fulltext : 174401.pdf (publisher's version ) (Closed access), Myotonic dystrophy type 1 (DM1) is caused by (CTGCAG)n-repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5' or 3' unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTGCAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTGCAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1.

Published
2017

25. Association between mutation size and cardiac involvement in myotonic dystrophy type 1: when size matters

Author

Chong-Nguyen, C., primary, Wahbi, K., additional, Algalarrondo, V., additional, Bécane, H.M., additional, Radvanyi-Hoffman, H., additional, Arnaud, P., additional, Furling, D., additional, Bassez, G., additional, Lazarus, A., additional, Laforet, P., additional, Stojkovic, T., additional, Behin, A., additional, Fayssoil, A., additional, Eymard, B., additional, and Duboc, D., additional

Published
2017
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35. P22 High content screening identifies small molecules that remove nuclear foci, affect MBNL distribution and CELF1 protein levels via a PKC independent pathway in myotonic dystrophy cell lines

Author

Ketley, A., primary, Chen, C.Z., additional, Li, X., additional, Arya, S., additional, Robinson, T., additional, Granados-Riveron, J., additional, Udosen, I., additional, Morris, G.E., additional, Holt, I., additional, Furling, D., additional, Chaouch, S., additional, Haworth, B., additional, Southall, N., additional, Shinn, P., additional, Zheng, W., additional, Austin, C., additional, Hayes, C., additional, and Brook, J.D., additional

Published
2014
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36. New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1). The International Myotonic Dystrophy Consortium (IDMC)

Author

Ashizawa, T, Gonzales, I, Ohsawa, N, Singer, RH, Devillers, M, Balasubramanyam, A, Cooper, TA, Khajavi, M, Lia-Baldini, A-S, Miller, G, Philips, AV, Timchenko, LT, Waring, J, Yamagata, H, Barbet, JP, Klesert, TR, Tapscott, SJ, Roses, AD, Wagner, M, Baiget, M, Martorell, L, Browne, GB, Eymard, B, Gourdon, G, Junien, C, Seznec, H, Carey, N, Gosling, M, Maire, P, Gennarelli, M, Sato, S, Ansved, T, Kvist, U, Eriksson, M, Furling, D, Chen, EJ, Housman, DE, Luciano, B, Siciliano, M, Spring, N, Shimizu, M, Eddy, E, Morris, GE, Krahe, R, Furuya, H, Adelman, J, Pribnow, D, Furutama, D, Mathieu, J, Hilton-Jones, D, Kinoshita, M, Abbruzzese, C, Sinden, RR, Wells, RD, Pearson, CE, Kobayashi, T, Johansson, A, Salvatori, S, Perryman, B, Swanson, M, Gould, FK, Harris, SE, Johnson, K, Mitchell, AM, Monckton, DG, Winchester, CL, Antonini, G, Day, JW, Liquori, C, Ranum, LPW, Westerlaken, J, Wieringa, B, Griffith, JD, Michalowski, S, Moore, H, Hamshere, M, Korade, Z, Thornton, CA, Jaeger, H, Lehmann, F, Moorman, JR, Mounsey, JP, and Mahadevan, MS

Published
2000

37. New nomenclature and DNA testing guidelines for myotonic dystrophy type 1(DM1)

Author

Gonzalez, I, Ohsawa, N, Singer, Rh, Devillers, M, Ashizawa, T, Balasubramanyam, A, Cooper, Ta, Khajavi, M, LIA BALDINI AS, Miller, G, Philips, Av, Timchenko, Lt, Waring, J, Yamagata, H, Barbet, Jp, Klesert, Tr, Tapscott, Sj, Roses, Ad, Wagner, M, Baiget, M, Martorell, L, Browne, Gb, Eymard, B, Gourdon, G, Junien, C, Seznec, H, Carey, N, Gosling, M, Maire, P, Gennarelli, M, Sato, S, Ansved, T, Kvist, U, Eriksson, M, Furling, D, Chen, Ej, Housman, De, Luciano, B, Siciliano, M, Spring, N, Shimizu, M, Eddy, E, Morris, Ge, Krahe, R, Furuya, H, Adelman, J, Pribnow, D, Furutama, D, Mathieu, J, HILTON JONES, D, Kinoshita, M, Abbruzzese, C, Sinden, Rr, Wells, Rd, Pearson, Ce, Kobayashi, T, Johansson, A, Salvatori, Sergio, Perryman, B, Swanson, Ms, Gould, Fk, Harris, Se, Johnson, K, Mitchell, Am, Monckton, Dg, Winchester, Cl, Antonini, G, Day, Jw, Liquori, C, Ranum, Lpw, Westerlaken, J, Wieringa, B, Griffith, Jd, Michalowski, S, Moore, H, Hamshere, M, Korade, Z, Thornton, Ca, Jaeger, H, Lehmann, F, Moorman, Jr, Mounsey, Jp, and Mahadevan, Ms

Published
2000

38. New nomenclature and DNA testing guidelines for myotonic dystrophy type 1 (DM1)

Author

Ashizawa, T., Gonzales, I., Ohsawa, N., Singer, R. H., Devillers, M., Balasubramanyam, A., Cooper, T. A., Khajavi, M., Lia Baldini, A. S., Miller, G., Philips, A. V., Timchenko, L. T., Waring, J., Yamagata, H., Barbet, J. P., Klesert, T. R., Tapscott, S. J., Roses, A. D., Wagner, M., Baiget, M., Martorell, L., Browne, G. B., Eymard, B., Gourdon, G., Junien, C., Seznec, H., Carey, N., Gosling, M., Maire, P., Gennarelli, M., Sato, S., Ansved, T., Kvist, U., Eriksson, M., Furling, D., Chen, E. J., Housman, D. E., Luciano, B., Siciliano, M., Spring, N., Shimizu, M., Eddy, E., Morris, G. E., Krahe, R., Furuya, H., Adelman, J., Pribnow, D., Furutama, D., Mathieu, J., Hilton, Jones, Kinoshita, D., Abbruzzese, M., Sinden, C., R. R., Wells, R. D., Pearson, C. E., Kobayashi, Johansson, T., Salvatori, A., Perryman, S., Swanson, B., Gould, M., F. K., Harris, S. E., Johnson, Mitchell, K., A. M., Monckton, D. G., Winchester, C. L., Antonini, Giovanni, Day, J. W., Liquori, C., Ranum, L. P. W., Westerlaken, J., Wieringa, B., Griffith, J. D., Michalowski, S., Moore, H., Hamshere, M., Korade, Z., Thornton, C. A., Jaeger, H., Lehmann, F., Moorman, J. R., Mounsey, J. P., and Mahadevan, M. S.

Published
2000

40. Triplet-repeat oligonucleotide-mediated reversal of RNA toxicity in myotonic dystrophy.

Author

Mulders, S.A.M., Broek, W.J.A.A. van den, Wheeler, T.M., Croes, H.J.E., Kuik-Romeijn, P. van, Kimpe, S.J. de, Furling, D., Platenburg, G.J., Gourdon, G., Thornton, C.A., Wieringa, B., Wansink, D.G., Mulders, S.A.M., Broek, W.J.A.A. van den, Wheeler, T.M., Croes, H.J.E., Kuik-Romeijn, P. van, Kimpe, S.J. de, Furling, D., Platenburg, G.J., Gourdon, G., Thornton, C.A., Wieringa, B., and Wansink, D.G.

Abstract

Contains fulltext : 81075.pdf (publisher's version ) (Closed access), Myotonic dystrophy type 1 (DM1) is caused by toxicity of an expanded, noncoding (CUG)n tract in DM protein kinase (DMPK) transcripts. According to current evidence the long (CUG)n segment is involved in entrapment of muscleblind (Mbnl) proteins in ribonuclear aggregates and stabilized expression of CUG binding protein 1 (CUGBP1), causing aberrant premRNA splicing and associated pathogenesis in DM1 patients. Here, we report on the use of antisense oligonucleotides (AONs) in a therapeutic strategy for reversal of RNA-gain-of-function toxicity. Using a previously undescribed mouse DM1 myoblast-myotube cell model and DM1 patient cells as screening tools, we have identified a fully 2'-O-methyl-phosphorothioate-modified (CAG)7 AON that silences mutant DMPK RNA expression and reduces the number of ribonuclear aggregates in a selective and (CUG)n-length-dependent manner. Direct administration of this AON in muscle of DM1 mouse models in vivo caused a significant reduction in the level of toxic (CUG)n RNA and a normalizing effect on aberrant premRNA splicing. Our data demonstrate proof of principle for therapeutic use of simple sequence AONs in DM1 and potentially other unstable microsatellite diseases.

Published
2009

42. P81 Compound screening in myotonic dystrophy

Author

Arya, S., primary, Li, X., additional, Robinson, T.E., additional, Udosen, I., additional, Chen, C., additional, Austin, C., additional, Furling, D., additional, Hayes, C., additional, Brook, J.D., additional, and Ketley, A., additional

Published
2012
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44. P1-19 Dérégulation de l’épissage de Tau par MBNL1 dans une Tauopathie

Author

Tran, H., primary, Dhaenens, C.-M., additional, Trollet, C., additional, Obriot, H., additional, Ghanem, D., additional, Hammer, C., additional, Vanbrussels, E., additional, Charlet, N., additional, Gourdon, G., additional, Furling, D., additional, Buée, L., additional, Caillet-Boudin, M.-L., additional, Schraen-Maschke, S., additional, and Sergeant, N., additional

Published
2009
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