Delivery of bifunctional RNAs that target an intronic repressor and increase SMN levels in an animal model of spinal muscular atrophy

Human Molecular Genetics

Volumn 18, Issue 9, 2009, Pages 1600-1611

  Baughan, Travis D ^a   Dickson, Alexa ^a   Osman, Erkan Y ^a   Lorson, Christian L ^a,b  

^a University of Missouri   (United States)

^b UNIVERSITY OF MISSOURI   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2' O METHYL BIFUNCTIONAL RNA; PLASMID VECTOR; RNA; SURVIVAL MOTOR NEURON PROTEIN; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN; CONTROLLED STUDY; DOSE RESPONSE; FIBROBLAST; GENE DELIVERY SYSTEM; GENE INDUCTION; GENE SEQUENCE; GENE TARGETING; GENE THERAPY; HUMAN; HUMAN CELL; INTRON; LIFESPAN; MOUSE; NEWBORN; NONHUMAN; PRIORITY JOURNAL; SINGLE DRUG DOSE; SPINAL CORD; SPINAL MUSCULAR ATROPHY; WEIGHT GAIN;

ANIMALS; CELLS, CULTURED; DISEASE MODELS, ANIMAL; FIBROBLASTS; GENE THERAPY; HUMANS; INTRONS; MICE; MICE, TRANSGENIC; MUSCULAR ATROPHY, SPINAL; REGULATORY SEQUENCES, NUCLEIC ACID; RNA, ANTISENSE; RNA-BINDING PROTEINS; SURVIVAL OF MOTOR NEURON 2 PROTEIN;

ANIMALIA; MUS;

EID: 64549161948     PISSN: 09646906     EISSN: 14602083     Source Type: Journal    
DOI: 10.1093/hmg/ddp076     Document Type: Article

References (69)

1. Crawford, T.O. and Pardo, C.A. (1996) The neurobiology of childhood spinal muscular atrophy. Neurobiol. Dis., 3, 97-110.
2. Feldkotter, M., Schwarzer, V., Wirth, R., Wienker, T.F. and Wirth, B. (2002) Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: Fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am. J. Hum. Genet., 2 358-368.
3. Meister, G. and Fischer, U. (2002) Assisted RNP assembly: SMN and PRMT5 complexes cooperate in the formation of spliceosomal UsnRNPs. EMBO J. 21, 5853-5863.
4. Lorson, C.L., Hahnen, E., Androphy, E.J. and Wirth, B. (1999) A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA, 96, 6307-6311.
5. Cartegni, L. and Krainer, A.R. (2002) Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat. Genet., 30, 377-384.
6. Lorson, C.L. and Androphy, E.J. (2000) An exonic enhancer is required for inclusion of an essential exon in the SMA-determining gene SMN. Hum. Mol. Genet., 9, 259-265.
7. Kashima, T., Rao, N. and Manley, J.L. (2007) An intronic element contributes to splicing repression in spinal muscular atrophy. Proc. Natl Acad. Sci. USA, 104, 3426-3431.
8. Hofmann, Y., Lorson, C.L., Stamm, S., Androphy, E.J. and Wirth, B. (2000) Htra2-beta 1 stimulates an exonic splicing enhancer and can restore full-length SMN expression to survival motor neuron 2 (SMN2). Proc. Natl Acad. Sci. USA, 97, 9618-9623.
9. Hofmann, Y. and Wirth, B. (2002) hnRNP-G promotes exon 7 inclusion of survival motor neuron (SMN) via direct interaction with Htra2-beta1. Hum. Mol. Genet., 11, 2037-2049.
10. Young, P.J., DiDonato, C.J., Hu, D., Kothary, R., Androphy, E.J. and Lorson, C.L. (2002) SRp30c-dependent stimulation of survival motor neuron (SMN) exon 7 inclusion is facilitated by a direct interaction with hTra2beta1. Hum. Mol. Genet., 11, 577-587.
11. Miyajima, H., Miyaso, H., Okumura, M., Kurisu, J. and Imaizumi, K. (2002) Identification of a cis-acting element for the regulation of SMN exon 7 splicing. J. Biol. Chem., 277, 23271-23277.
12. Singh, N.N., Androphy, E.J. and Singh, R.N. (2004) The regulation and regulatory activities of alternative splicing of the SMN gene. Crit. Rev. Eukaryot. Gene Expr., 14, 271-285.
13. Singh, N.N., Androphy, E.J. and Singh, R.N. (2004) In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes. RNA, 10, 1291-1305.
14. Singh, N.N., Androphy, E.J. and Singh, R.N. (2004) An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy. Biochem. Biophys. Res. Commun., 315, 381-388.
15. Singh, N.N., Singh, R.N. and Androphy, E.J. (2007) Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Res., 35, 371-389.
16. Kernochan, L.E., Russo, M.L., Woodling, N.S., Huynh, T.N., Avila, A.M., Fischbeck, K.H. and Sumner, C.J. (2005) The role of histone acetylation in SMN gene expression. Hum Mol. Genet., 14, 1171-1182.
17. Wolstencroft, E.C., Mattis, V., Bajer, A.A., Young, P.J. and Lorson, C.L. (2005) A non-sequence-specific requirement for SMN protein activity: The role of aminoglycosides in inducing elevated SMN protein levels. Hum. Mol. Genet., 14, 1199-1210.
18. Mattis, V.B., Rai, R., Wang, J., Chang, C.W., Coady, T. and Lorson, C.L. (2006) Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts. Hum. Genet., 120, 589-601.
19. Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F.A., Raschke, H., Blumcke, I., Eyupoglu, I.Y. and Wirth, B. (2003) Valproic acid increases the SMN2 protein level: A well-known drug as a potential therapy for spinal muscular atrophy. Hum. Mol. Genet., 12, 2481-2489.
20. Riessland, M., Brichta, L., Hahnen, E. and Wirth, B. (2006) The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells. Hum. Genet., 120, 101-110.
21. Sakla, M.S. and Lorson, C.L. (2008) Induction of full-length survival motor neuron by polyphenol botanical compounds. Hum. Genet., 122, 635-643.
22. Hua, Y., Vickers, T.A., Baker, B.F., Bennett, C.F. and Krainer, A.R. (2007) Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol., 5, e73.
23. Hua, Y., Vickers, T.A., Okunola, H.L., Bennett, C.F. and Krainer, A.R. (2008) Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am. J. Hum. Genet., 82, 834-848.
24. Cartegni, L. and Krainer, A.R. (2003) Correction of disease-associated exon skipping by synthetic exon-specific activators. Nat. Struct. Biol., 10, 120-125.
25. Madocsai, C., Lim, S.R., Geib, T., Lam, B.J. and Hertel, K.J. (2005) Correction of SMN2 pre-mRNA splicing by antisense U7 small nuclear RNAs. Mol. Ther., 12, 1013-1022.
26. Singh, N.K., Singh, N.N., Androphy, E.J. and Singh, R.N. (2006) Splicing of a critical exon of human survival motor neuron is regulated by a unique silencer element located in the last intron. Mol. Cell. Biol. 26, 1333-1346.
27. Coady, T.H., Shababi, M., Tullis, G.E. and Lorson, C.L. (2007) Restoration of SMN function: Delivery of a trans-splicing RNA re-directs SMN2 pre-mRNA splicing. Mol. Ther., 15, 1471-1478.
28. Marquis, J., Meyer, K., Angehrn, L., Kampfer, S.S., Rothen-Rutishauser, B. and Schumperli, D. (2007) Spinal muscular atrophy: SMN2 pre-mRNA splicing corrected by a U7 snRNA derivative carrying a splicing enhancer sequence. Mol. Ther., 15, 1479-1486.
29. Lim, S.R. and Hertel, K.J. (2001) Modulation of survival motor neuron pre-mRNA splicing by inhibition of alternative 3′ splice site pairing. J. Biol. Chem., 276, 45476-45483.
30. Dickson, A., Osman, E. and Lorson, C. (2008) A negatively-acting bifunctional RNA increases survival motor neuron in vitro and in vivo. Hum. Gene Ther. August 25. [Epub ahead of print].
31. Baughan, T., Shababi, M., Coady, T.H., Dickson, A.M., Tullis, G.E. and Lorson, C.L. (2006) Stimulating full-length SMN2 expression by delivering bifunctional RNAs via a viral vector. Mol. Ther., 14 54-62.
32. Skordis, L.A., Dunckley, M.G., Yue, B., Eperon, I.C. and Muntoni, F. (2003) Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts. Proc. Natl Acad. Sci. USA, 100, 4114-4119.
33. Gendron, D., Carriero, S., Garneau, D., Villemaire, J., Klinck, R., Elela, S.A., Damha, M.J. and Chabot, B. (2006) Modulation of 5′ splice site selection using tailed oligonucleotides carrying splicing signals. BMC Biotechnol., 6, 5.
34. Villemaire, J., Dion, I., Elela, S.A. and Chabot, B. (2003) Reprogramming alternative pre-messenger RNA splicing through the use of protein-binding antisense oligonucleotides. J. Biol. Chem., 278 50031-50039.
35. Ashiya, M. and Grabowski, P.J. (1997) A neuron-specific splicing switch mediated by an array of pre-mRNA repressor sites: Evidence of a regulatory role for the polypyrimidine tract binding protein and a brain-specific PTB counterpart. RNA, 3, 996-1015.
36. Carstens, R.P., Wagner, E.J. and Garcia-Blanco, M.A. (2000) An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein. Mol. Cell. Biol., 20, 7388-7400.
37. Chan, R.C. and Black, D.L. (1997) The polypyrimidine tract binding protein binds upstream of neural cell-specific c-src exon N1 to repress the splicing of the intron downstream. Mol. Cell. Biol., 17, 4667-4676.
38. Irwin, N., Baekelandt, V., Goritchenko, L. and Benowitz, L.I. (1997) Identification of two proteins that bind to a pyrimidine-rich sequence in the 3′-untranslated region of GAP-43 mRNA. Nucleic Acids Res. 25, 1281-1288.
39. Grossman, J.S., Meyer, M.I., Wang, Y.C., Mulligan, G.J., Kobayashi, R. and Helfman, D.M. (1998) The use of antibodies to the polypyrimidine tract binding protein (PTB) to analyze the protein components that assemble on alternatively spliced pre-mRNAs that use distant branch points. RNA, 4, 613-625.
40. Zhang, L., Liu, W. and Grabowski, P.J. (1999) Coordinate repression of a trio of neuron-specific splicing events by the splicing regulator PTB. RNA, 5, 117-130.
41. Hao, Y.H., Lai, L.X., Liu, Z.H., Im, G.S., Wax, D., Samuel, M., Murphy, C.N., Sutovsky, P. and Prather, R.S. (2006) Developmental competence of porcine parthenogenetic embryos relative to embryonic chromosomal abnormalities. Mol. Reprod. Dev., 73, 77-82.
42. Liu, J., He, L., Collins, I., Ge, H., Libutti, D., Li, J., Egly, J.M. and Levens, D. (2000) The FBP interacting repressor targets TFIIH to inhibit activated transcription. Mol. Cell, 5, 331-341.
43. He, L., Liu, J., Collins, I., Sanford, S., O'Connell, B., Benham, C.J. and Levens, D. (2000) Loss of FBP function arrests cellular proliferation and extinguishes c-myc expression. EMBO J., 19 1034-1044.
44. Goyenvalle, A., Vulin, A., Fougerousse, F., Leturcq, F., Kaplan, J.C., Garcia, L. and Danos, O. (2004) Rescue of dystrophic muscle through U7 snRNA-mediated exon skipping. Science, 306, 1796-1799.
45. Suter, D., Tomasini, R., Reber, U., Gorman, L., Kole, R. and Schumperli, D. (1999) Double-target antisense U7 snRNAs promote efficient skipping of an aberrant exon in three human beta-thalassemic mutations. Hum. Mol. Genet., 8, 2415-2423.
46. Gorman, L., Suter, D., Emerick, V., Schumperli, D. and Kole, R. (1998) Stable alteration of pre-mRNA splicing patterns by modified U7 small nuclear RNAs. Proc. Natl Acad. Sci. USA, 95, 4929-4934.
47. Coovert, D.D., Le, T.T., McAndrew, P.E., Strasswimmer, J., Crawford, T.O., Mendell, J.R., Coulson, S.E., Androphy, E.J., Prior, T.W. and Burghes, A.H. (1997) The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Genet., 6, 1205-1214.
48. Alter, J., Lou, F., Rabinowitz, A., Yin, H., Rosenfeld, J., Wilton, S.D., Partridge, T.A. and Lu, Q.L. (2006) Systemic delivery of morpholino oligonucleotide restores dystrophin expression bodywide and improves dystrophic pathology. Nat. Med., 12, 175-177.
49. Lu, Q.L., Rabinowitz, A., Chen, Y.C., Yokota, T., Yin, H., Alter, J., Jadoon, A., Bou-Gharios, G. and Partridge, T. (2005) Systemic delivery of antisense oligoribonucleotide restores dystrophin expression in body-wide skeletal muscles. Proc. Natl Acad. Sci. USA, 102, 198-203.
50. Smith, R.A., Miller, T.M., Yamanaka, K., Monia, B.P., Condon, T.P., Hung, G., Lobsiger, C.S., Ward, C.M., McAlonis-Downes, M., Wei, H. et al. (2006) Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest., 116, 2290-2296.
51. Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J. and Burghes, A.H. (2005) SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum. Mol. Genet., 14, 845-857.
52. Coady, T.H., Baughan, T.D., Shababi, M., Passini, M.A. and Lorson, C.L. (2008) Development of a single vector system that enhances trans splicing of SMN2 transcripts. PLoS ONE, 3, e3468.
53. Monani, U.R., Sendtner, M., Coovert, D.D., Parsons, D.W., Andreassi, C., Le, T.T., Jablonka, S., Schrank, B., Rossoll, W., Prior, T.W. et al. (2000) The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. Hum. Mol. Genet., 9, 333-339.
54. Ramchatesingh, J., Zahler, A.M., Neugebauer, K.M., Roth, M.B. and Cooper, T.A. (1995) A subset of SR proteins activates splicing of the cardiac troponin T alternative exon by direct interactions with an exonic enhancer. Mol. Cell. Biol., 15, 4898-4907.
55. Matsushita, T., Elliger, S., Elliger, C., Podsakoff, G., Villarreal, L., Kurtzman, G.J., Iwaki, Y. and Colosi, P. (1998) Adeno-associated virus vectors can be efficiently produced without helper virus. Gene Ther. 5, 938-945.
56. Aartsma-Rus, A., Bremmer-Bout, M., Janson, A.A., den Dunnen, J.T., van Ommen, G.J. and van Deutekom, J.C. (2002) Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy. Neuromuscul. Disord., 12 (Suppl. 1), S71-S77.
57. van Deutekom, J.C., Bremmer-Bout, M., Janson, A.A., Ginjaar, I.B., Baas, F., den Dunnen, J.T. and van Ommen, G.J. (2001) Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells. Hum. Mol. Genet., 10, 1547-1554.
58. Mann, C.J., Honeyman, K., Cheng, A.J., Ly, T., Lloyd, F., Fletcher, S., Morgan, J.E., Partridge, T.A. and Wilton, S.D. (2001) Antisense-induced exon skipping and synthesis of dystrophin in the mdx mouse. Proc. Natl Acad. Sci. USA, 98, 42-47.
59. Aartsma-Rus, A., Janson, A.A., Kaman, W.E., Bremmer-Bout, M., van Ommen, G.J., den Dunnen, J.T. and van Deutekom, J.C. (2004) Antisense-induced multiexon skipping for Duchenne muscular dystrophy makes more sense. Am. J. Hum. Genet., 74, 83-92.
60. Holzbaur, E.L., Howland, D.S., Weber, N., Wallace, K., She, Y., Kwak, S., Tchistiakova, L.A., Murphy, E., Hinson, J., Karim, R. et al. (2006) Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis. Neurobiol. Dis., 23, 697-707.
61. van Deutekom, J.C., Janson, A.A., Ginjaar, I.B., Frankhuizen, W.S., Aartsma-Rus, A., Bremmer-Bout, M., den Dunnen, J.T., Koop, K., van der Kooi, A.J., Goemans, N.M. et al. (2007) Local dystrophin restoration with antisense oligonucleotide PRO051. N. Engl. J. Med. 357, 2677-2686.
62. Passini, M.A., Macauley, S.L., Huff, M.R., Taksir, T.V., Bu, J., Wu, I.H., Piepenhagen, P.A., Dodge, J.C., Shihabuddin, L.S., O'Riordan, C.R. et al. (2005) AAV vector-mediated correction of brain pathology in a mouse model of Niemann-Pick A disease. Mol. Ther., 11, 754-762.
63. Passini, M.A., Bu, J., Fidler, J.A., Ziegler, R.J., Foley, J.W., Dodge, J.C., Yang, W.W., Clarke, J., Taksir, T.V., Griffiths, D.A. et al. (2007) Combination brain and systemic injections of AAV provide maximal functional and survival benefits in the Niemann-Pick mouse. Proc. Natl Acad. Sci. USA, 104, 9505-9510.
64. Passini, M.A., Watson, D.J., Vite, C.H., Landsburg, D.J., Feigenbaum, A.L. and Wolfe, J.H. (2003) Intraventricular brain injection of adeno-associated virus type 1 (AAV1) in neonatal mice results in complementary patterns of neuronal transduction to AAV2 and total long-term correction of storage lesions in the brains of beta-glucuronidase-deficient mice. J. Virol., 77, 7034-7040.
65. Smith, R.A., Miller, T.M., Yamanaka, K., Monia, B.P., Condon, T.P., Hung, G., Lobsiger, C.S., Ward, C.M., Mcalonis-Downes, M., Wei, H. et al. (2006) Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest., 116, 2290-2296.
66. Azzouz, M., Le, T., Ralph, G.S., Walmsley, L., Monani, U.R., Lee, D.C., Wilkes, F., Mitrophanous, K.A., Kingsman, S.M., Burghes, A.H. and Mazarakis, N.D. (2004) Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J. Clin. Invest., 114, 1726-1731.
67. Passini, M.A. and Wolfe, J.H. (2001) Widespread gene delivery and structure-specific patterns of expression in the brain after intraventricular injections of neonatal mice with an adeno-associated virus vector. J. Virol., 75, 12382-12392.
68. Briese,M., Esmaeili, B. and Sattelle, D.B. (2005) Is spinal muscular atrophy the result of defects in motor neuron processes? Bioessays 27, 946-957.
69. Rajendra, T.K., Gonsalvez, G.B., Walker, M.P., Shpargel, K.B., Salz, H.K. and Matera, A.G. (2007) A Drosophila melanogaster model of spinal muscular atrophy reveals a function for SMN in striated muscle. J. Cell. Biol., 176, 831-841.