Advances in therapeutic development for spinal muscular atrophy

Future Medicinal Chemistry

Volumn 6, Issue 9, 2014, Pages 1081-1099

  Howell, Matthew D ^a   Singh, Natalia N ^a   Singh, Ravindra N ^a  

^a IOWA STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (1 AMINOETHYL) N (4 PYRIDYL)CYCLOHEXANECARBOXAMIDE; FASUDIL; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN; OLESOXIME; SMALL NUCLEAR RIBONUCLEOPROTEIN; SURVIVAL MOTOR NEURON PROTEIN 1; SURVIVAL MOTOR NEURON PROTEIN 2; TRICHOSTATIN A; VALPROIC ACID; VORINOSTAT; SMN1 PROTEIN, HUMAN; SMN2 PROTEIN, HUMAN;

ALTERNATIVE RNA SPLICING; ANTISENSE THERAPY; GENE CONVERSION; GENE DELETION; GENE MUTATION; GENE THERAPY; GENETIC REGULATION; GENETIC TRANSCRIPTION; HUMAN; MISSENSE MUTATION; NONHUMAN; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POINT MUTATION; PRIORITY JOURNAL; PROTEIN RNA BINDING; REVIEW; RNA DECAPPING; RNA SPLICING; SPINAL MUSCULAR ATROPHY; STRUCTURE ACTIVITY RELATION; TRANSCRIPTION REGULATION; GENETICS; METABOLISM; MUSCULAR ATROPHY, SPINAL;

HUMANS; MUSCULAR ATROPHY, SPINAL; SURVIVAL OF MOTOR NEURON 1 PROTEIN; SURVIVAL OF MOTOR NEURON 2 PROTEIN;

EID: 84905195828     PISSN: 17568919     EISSN: 17568927     Source Type: Journal    
DOI: 10.4155/fmc.14.63     Document Type: Review

References (150)

1. Prior TW. Spinal muscular atrophy diagnostics. J. Child Neurol. 22(8), 952-956 (2007).
2. Lefebvre S, Bürglen L, Reboullet S et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80(1), 155-165 (1995).
3. McAndrew PE, Parsons DW, Simard LR et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am. J. Hum. Genet. 60(6), 1411-1422 (1997).
4. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc. Natl Acad. Sci. USA 96(11), 6307-6311 (1999).
5. Kashima T, Rao N, Manley JL. An intronic element contributes to splicing repression in spinal muscular atrophy. Proc. Natl Acad. Sci. USA 104(9), 3426-3431 (2007).
6. Burnett BG, Muñoz E, Tandon A, Kwon DY, Sumner CJ, Fischbeck KH. Regulation of SMN protein stability. Mol. Cell. Biol. 29(5), 1107-1115 (2009).
7. Cho S, Dreyfuss G. A degron created by SMN2 exon 7 skipping is a principal contributor to spinal muscular atrophy severity. Genes Dev. 24(5), 438-442 (2010).
8. Singh NN, Seo J, Rahn SJ, Singh RN. A multi-exon-skipping detection assay reveals surprising diversity of splice isoforms of spinal muscular atrophy genes. PLoS ONE 7(11), e49595 (2012).
9. Sabra M, Texier P, El Maalouf J, Lomonte P. The Tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated lysine 79 of histone H3. J. Cell. Sci. 126(Pt 16), 3664-3677 (2013).
10. Nurputra DK, Lai PS, Harahap NIF et al. Spinal muscular atrophy: from gene discovery to clinical trials. Ann. Hum. Genet. 77(5), 435-463 (2013).
11. Yamamoto T, Sato H, Lai PS et al. Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers in some spinal muscular atrophy (SMA) patients. Brain Dev. doi:10.1016/j.braindev. 2013.11.009 (2013)
12. Lefebvre S, Burlet P, Liu Q et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat. Genet. 16(3), 265-269 (1997).
13. Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. 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. 70(2), 358-368 (2002).
14. Wirth B, Brichta L, Schrank B et al. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum. Genet. 119(4), 422-428 (2006).
15. Campbell L, Potter A, Ignatius J, Dubowitz V, Davies K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am. J. Hum. Genet. 61(1), 40-50 (1997).
16. Vitali T, Sossi V, Tiziano F et al. Detection of the survival motor neuron (SMN) genes by FISH: further evidence for a role for SMN2 in the modulation of disease severity in SMA patients. Hum. Mol. Genet. 8(13), 2525-2532 (1999).
17. Boyer JG, Ferrier A, Kothary R. More than a bystander: the contributions of intrinsic skeletal muscle defects in motor neuron diseases. Front Physiol. 4, 356 (2013).
18. Seo J, Howell MD, Singh NN, Singh RN. Spinal muscular atrophy: An update on therapeutic progress. Biochim. Biophys. Acta. 1832(12), 2180-2190 (2013).
19. Zhang R, So BR, Li P et al. Structure of a key intermediate of the SMN complex reveals Gemin2's crucial function in snRNP assembly. Cell 146(3), 384-395 (2011).
20. Piazzon N, Schlotter F, Lefebvre S et al. Implication of the SMN complex in the biogenesis and steady state level of the signal recognition particle. Nucleic Acids Res. 41(2), 1255-1272 (2013).
21. Takaku M, Tsujita T, Horikoshi N et al. Purification of the human SMN-GEMIN2 complex and assessment of its stimulation of RAD51-mediated DNA recombination reactions. Biochemistry 50(32), 6797-6805 (2011).
22. Fallini C, Zhang H, Su Y et al. The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J. Neurosci. 31(10), 3914-3925 (2011).
23. Sanchez G, Dury AY, Murray LM et al. A novel function for the survival motoneuron protein as a translational regulator. Hum. Mol. Genet. 22(4), 668-684 (2013).
24. Bussaglia E, Clermont O, Tizzano E et al. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat. Genet. 11(3), 335-337 (1995).
25. Brahe C, Clermont O, Zappata S, Tiziano F, Melki J, Neri G. Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I. Hum. Mol. Genet. 5(12), 1971-1976 (1996).
26. Parsons DW, McAndrew PE, Monani UR, Mendell JR, Burghes AH, Prior TW. An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. Hum. Mol. Genet. 5(11), 1727-1732 (1996).
27. Hahnen E, Schönling J, Rudnik-Schöneborn S, Raschke H, Zerres K, Wirth B. Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA). Hum. Mol. Genet. 6(5), 821-825 (1997).
28. Talbot K, Ponting CP, Theodosiou AM et al. Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein in RNA metabolism? Hum. Mol. Genet. 6(3), 497-500 (1997).
29. Parsons DW, McAndrew PE, Iannaccone ST, Mendell JR, Burghes AH, Prior TW. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number. Am. J. Hum. Genet. 63(6), 1712-1723 (1998).
30. Wang CH, Papendick BD, Bruinsma P, Day JK. Identification of a novel missense mutation of the SMN(T) gene in two siblings with spinal muscular atrophy. Neurogenetics 1(4), 273-276 (1998).
31. Bühler D, Raker V, Lührmann R, Fischer U. Essential role for the tudor domain of SMN in spliceosomal U snRNP assembly: implications for spinal muscular atrophy. Hum. Mol. Genet. 8(13), 2351-2357 (1999).
32. Wirth B, Herz M, Wetter A et al. Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am. J. Hum. Genet. 64(5), 1340-1356 (1999).
33. Rochette CF, Suhr LC, Ray PN et al. Molecular diagnosis of non-deletion SMA patients using quantitative PCR of SMN exon 7. Neurogenetics 1(2), 141-147 (1997).
34. Skordis LA, Dunckley MG, Burglen L et al. Characterisation of novel point mutations in the survival motor neuron gene SMN, in three patients with SMA. Hum. Genet. 108(4), 356-357 (2001).
35. Sossi V, Giuli A, Vitali T et al. Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype. Eur. J. Hum. Genet. 9(2), 113-120 (2001).
36. Tsai CH, Jong YJ, Hu CJ et al. Molecular analysis of SMN, NAIP and P44 genes of SMA patients and their families. J. Neurol. Sci. 190(1-2), 35-40 (2001).
37. Martín Y, Valero A, Del Castillo E, Pascual SI, Hernández-Chico C. Genetic study of SMA patients without homozygous SMN1 deletions: identification of compound heterozygotes and characterisation of novel intragenic SMN1 mutations. Hum. Genet. 110(3), 257-263 (2002).
38. Cuscó I, López E, Soler-Botija C, Jesús Barceló M, Baiget M, Tizzano EF. A genetic and phenotypic analysis in Spanish spinal muscular atrophy patients with c.399-402del AGAG, the most frequently found subtle mutation in the SMN1 gene. Hum. Mutat. 22(2), 136-143 (2003).
39. Clermont O, Burlet P, Benit P et al. Molecular analysis of SMA patients without homozygous SMN1 deletions using a new strategy for identification of SMN1 subtle mutations. Hum. Mutat. 24(5), 417-427 (2004).
40. Cuscó I, Barceló MJ, Del Río E, Baiget M, Tizzano EF. Detection of novel mutations in the SMN Tudor domain in type I SMA patients. Neurology 63(1), 146-149 (2004).
41. Sun Y, Grimmler M, Schwarzer V, Schoenen F, Fischer U, Wirth B. Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy. Hum. Mutat. 25(1), 64-71 (2005).
42. Moutou C, Machev N, Gardes N, Viville S. Case report: birth after preimplantation genetic diagnosis of a subtle mutation in SMN1 gene. Prenat. Diagn. 26(11), 1037-1041 (2006).
43. Kotani T, Sutomo R, Sasongko TH et al. A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins. J. Neurol. 254(5), 624-630 (2007).
44. Zapletalová E, Hedvicáková P, Kozák L et al. Analysis of point mutations in the SMN1 gene in SMA patients bearing a single SMN1 copy. Neuromuscul. Disord. 17(6), 476-481 (2007).
45. Brichta L, Garbes L, Jedrzejowska M et al. Nonsense-mediated messenger RNA decay of survival motor neuron 1 causes spinal muscular atrophy. Hum. Genet. 123(2), 141-153 (2008).
46. Eggermann T, Eggermann K, Elbracht M, Zerres K, Rudnik-Schöneborn S. A new splice site mutation in the SMN1 gene causes discrepant results in SMN1 deletion screening approaches. Neuromuscul. Disord. 18(2), 146-149 (2008).
47. Alías L, Bernal S, Fuentes-Prior P et al. Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Hum. Genet. 125(1), 29-39 (2009).
48. Prior TW, Krainer AR, Hua Y et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am. J. Hum. Genet. 85(3), 408-413 (2009).
49. Bernal S, Alías L, Barceló MJ et al. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J. Med. Genet. 47(9), 640-642 (2010).
50. Sheng-Yuan Z, Xiong F, Chen Y-J et al. Molecular characterization of SMN copy number derived from carrier screening and from core families with SMA in a Chinese population. Eur. J. Hum. Genet. 18(9), 978-984 (2010).
51. Vezain M, Saugier-Veber P, Goina E et al. A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy. Hum. Mutat. 31(1), E1110-E1125 (2010).
52. Nölle A, Zeug A, Van Bergeijk J et al. The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profilin. Hum. Mol. Genet. 20(24), 4865-4878 (2011).
53. Yu-Jin Q, Juan D, Er-zhen L et al. Subtle mutations in the SMN1 gene in Chinese patients with SMA: p.Arg288Met mutation causing SMN1 transcript exclusion of exon7. BMC Med. Genet. 13, 86 (2012).
54. Kirwin SM, Vinette KMB, Gonzalez IL, Abdulwahed HA, Al-Sannaa N, Funanage VL. A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA. Mol. Genet. Genomic Med. 1(2), 113-117 (2013).
55. Ganji H, Nouri N, Salehi M et al. Detection of intragenic SMN1 mutations in spinal muscular atrophy patients with a single copy of SMN1. J. Child Neurol. doi:10.1177/0883073814521297 (2014)
56. Mattis VB, Fosso MY, Chang C-W, Lorson CL. Subcutaneous administration of TC007 reduces disease severity in an animal model of SMA. BMC Neurosci. 10, 142 (2009).
57. Finkel RS, Flanigan KM, Wong B et al. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLoS ONE 8(12), e81302 (2013).
58. Mohseni J, Zabidi-Hussin ZAMH, Sasongko TH. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy. Genet. Mol. Biol. 36(3), 299-307 (2013).
59. Bowerman M, Beauvais A, Anderson CL, Kothary R. Rho-kinase inactivation prolongs survival of an intermediate SMA mouse model. Hum. Mol. Genet. 19(8), 1468-1478 (2010).
60. Bowerman M, Murray LM, Boyer JG, Anderson CL, Kothary R. Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy. BMC Med. 10, 24 (2012).
61. Zhang Z, Kelemen O, Van Santen MA et al. Synthesis and characterization of pseudocantharidins, novel phosphatase modulators that promote the inclusion of exon 7 into the SMN (survival of motoneuron) pre-mRNA. J. Biol. Chem. 286(12), 10126-10136 (2011).
62. ClinicalTrials.gov: NCT01302600. www.clinicaltrials.gov/ct2/show/ NCT01302600
63. Battle DJ, Kasim M, Yong J et al. The SMN complex: an assembly machine for RNPs. Cold Spring Harb. Symp. Quant. Biol. 71, 313-320 (2006).
64. Kolb SJ, Battle DJ, Dreyfuss G. Molecular functions of the SMN complex. J. Child Neurol. 22(8), 990-994 (2007).
65. Strasswimmer J, Lorson CL, Breiding DE et al. Identification of survival motor neuron as a transcriptional activator-binding protein. Hum. Mol. Genet. 8(7), 1219-1226 (1999).
66. Campbell L, Hunter KM, Mohaghegh P, Tinsley JM, Brasch MA, Davies KE. Direct interaction of Smn with dp103, a putative RNA helicase: a role for Smn in transcription regulation? Hum. Mol. Genet. 9(7), 1093-1100 (2000).
67. Bowerman M, Shafey D, Kothary R. Smn depletion alters profilin II expression and leads to upregulation of the RhoA/ROCK pathway and defects in neuronal integrity. J. Mol. Neurosci. 32(2), 120-131 (2007).
68. Zou T, Yang X, Pan D, Huang J, Sahin M, Zhou J. SMN deficiency reduces cellular ability to form stress granules, sensitizing cells to stress. Cell. Mol. Neurobiol. 31(4), 541-550 (2011).
69. Rossoll W, Kröning A-K, Ohndorf U-M, Steegborn C, Jablonka S, Sendtner M. Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons? Hum. Mol. Genet. 11(1), 93-105 (2002).
70. Peter CJ, Evans M, Thayanithy V et al. The COPI vesicle complex binds and moves with survival motor neuron within axons. Hum. Mol. Genet. 20(9), 1701-1711 (2011).
71. Akten B, Kye MJ, Hao LT et al. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc. Natl Acad. Sci. USA 108(25), 10337-10342 (2011).
72. Fallini C, Bassell GJ, Rossoll W. Spinal muscular atrophy: the role of SMN in axonal mRNA regulation. Brain Res. 1462, 81-92 (2012).
73. Grimmler M, Bauer L, Nousiainen M, Körner R, Meister G, Fischer U. Phosphorylation regulates the activity of the SMN complex during assembly of spliceosomal U snRNPs. EMBO Rep. 6(1), 70-76 (2005).
74. Renvoisé B, Quérol G, Verrier ER, Burlet P, Lefebvre S. A role for protein phosphatase PP1? in SMN complex formation and subnuclear localization to Cajal bodies. J. Cell. Sci. 125(Pt 12), 2862-2874 (2012).
75. Wu C-Y, Curtis A, Choi YS et al. Identification of the phosphorylation sites in the survival motor neuron protein by protein kinase A. Biochim. Biophys. Acta. 1814(9), 1134-1139 (2011).
76. Makhortova NR, Hayhurst M, Cerqueira A et al. A screen for regulators of survival of motor neuron protein levels. Nat. Chem. Biol. 7(8), 544-552 (2011).
77. Setola V, Terao M, Locatelli D, Bassanini S, Garattini E, Battaglia G. Axonal-SMN (a-SMN), a protein isoform of the survival motor neuron gene, is specifically involved in axonogenesis. Proc. Natl Acad. Sci. USA 104(6), 1959-1964 (2007).
78. Gunadi, , Sasongko TH, Yusoff S et al. Hypomutability at the polyadenine tract in SMN intron 3 shows the invariability of the a-SMN protein structure. Ann. Hum. Genet. 72(Pt 2), 288-291 (2008).
79. Locatelli D, Terao M, Fratelli M et al. Human axonal survival of motor neuron (a-SMN) protein stimulates axon growth, cell motility, C-C motif ligand 2 (CCL2), and insulin-like growth factor-1 (IGF1) production. J. Biol. Chem. 287(31), 25782-25794 (2012).
80. Le TT, McGovern VL, Alwine IE et al. Temporal requirement for high SMN expression in SMA mice. Hum. Mol. Genet. 20(18), 3578-3591 (2011).
81. Lutz CM, Kariya S, Patruni S et al. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J. Clin. Invest. 121(8), 3029-3041 (2011).
82. Hao LT, Duy PQ, Jontes JD, Wolman M, Granato M, Beattie CE. Temporal requirement for SMN in motoneuron development. Hum. Mol. Genet. 22(13), 2612-2625 (2013).
83. Kariya S, Obis T, Garone C et al. Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation. J. Clin. Invest. 124(2), 785-800 (2014).
84. Shababi M, Lorson CL, Rudnik-Schöneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J. Anat. 224(1), 15-28 (2014).
85. Cartegni L, Krainer AR. Disruption of an SF2/ASF-dependent exonic splicing enhancer in SMN2 causes spinal muscular atrophy in the absence of SMN1. Nat. Genet. 30(4), 377-384 (2002).
86. Kashima T, Manley JL. A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy. Nat. Genet. 34(4), 460-463 (2003).
87. Singh NN, Androphy EJ, Singh RN. An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy. Biochem. Biophys. Res. Commun. 315(2), 381-388 (2004).
88. Singh NN, Singh RN. Alternative splicing in spinal muscular atrophy underscores the role of an intron definition model. RNA Biol. 8(4), 600-606 (2011).
89. Singh NN, Androphy EJ, Singh RN. In vivo selection reveals combinatorial controls that define a critical exon in the spinal muscular atrophy genes. RNA 10(8), 1291-1305 (2004).
90. Singh NN, Seo J, Ottesen EW, Shishimorova M, Bhattacharya D, Singh RN. TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy. Mol. Cell. Biol. 31(5), 935-954 (2011).
91. Singh NN, Singh RN, Androphy EJ. Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Res. 35(2), 371-389 (2007).
92. Singh NN, Lawler MN, Ottesen EW, Upreti D, Kaczynski JR, Singh RN. An intronic structure enabled by a long-distance interaction serves as a novel target for splicing correction in spinal muscular atrophy. Nucleic Acids Res. 41(17), 8144-8165 (2013).
93. Hua Y, Vickers TA, Baker BF, Bennett CF, Krainer AR. Enhancement of SMN2 exon 7 inclusion by antisense oligonucleotides targeting the exon. PLoS Biol. 5(4), e73 (2007).
94. Singh NK, Singh NN, Androphy EJ, Singh RN. 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(4), 1333-1346 (2006).
95. Singh NN, Shishimorova M, Cao LC, Gangwani L, Singh RN. A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy. RNA Biol. 6(3), 341-350 (2009).
96. Hua Y, Vickers TA, Okunola HL, Bennett CF, Krainer AR. Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. Am. J. Hum. Genet. 82(4), 834-848 (2008).
97. Singh NN, Hollinger K, Bhattacharya D, Singh RN. An antisense microwalk reveals critical role of an intronic position linked to a unique long-distance interaction in pre-mRNA splicing. RNA 16(6), 1167-1181 (2010).
98. Klar J, Sobol M, Melberg A et al. Welander distal myopathy caused by an ancient founder mutation in TIA1 associated with perturbed splicing. Hum. Mutat. 34(4), 572-577 (2013).
99. Keil J, Seo J, Howell MD, Hsu W, Singh RN, DiDonato CJ. A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy. Mol. Ther. Nucleic Acids. (2014) In Press).
100. Lee RG, Crosby J, Baker BF, Graham MJ, Crooke RM. Antisense technology: an emerging platform for cardiovascular disease therapeutics. J. Cardiovasc. Transl. Res. 6(6), 969-980 (2013).
101. Roberts TC, Wood MJA. Therapeutic targeting of non-coding RNAs. Essays Biochem. 54, 127-145 (2013).
102. Sivanesan S, Howell MD, DiDonato CJ, Singh RN. Antisense oligonucleotide mediated therapy of spinal muscular atrophy. Translat. Neurosci. 4(1), 1-7 (2013).
103. Porensky PN, Burghes AHM. Antisense oligonucleotides for the treatment of spinal muscular atrophy. Hum. Gene Ther. 24(5), 489-498 (2013).
104. Buratti E, Baralle M, Baralle FE. Defective splicing, disease and therapy: searching for master checkpoints in exon definition. Nucleic Acids Res. 34(12), 3494-3510 (2006).
105. Hua Y, Sahashi K, Rigo F et al. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature 478(7367),123-126 (2011).
106. Porensky PN, Mitrpant C, McGovern VL et al. A single administration of morpholino antisense oligomer rescues spinal muscular atrophy in mouse. Hum. Mol. Genet. 21(7), 1625-1638 (2012).
107. Zhou H, Janghra N, Mitrpant C et al. A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice. Hum. Gene Ther. 24(3), 331-342 (2013).
108. Mitrpant C, Porensky P, Zhou H et al. Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: towards a treatment for spinal muscular atrophy. PLoS ONE 8(4), e62114 (2013).
109. Clinical Trials.gov: NCT01839656. www.clinicaltrials.gov/show/NCT01839656
110. ClinicalTrials.gov: NCT01494701. www.clinicaltrials.gov/ct2/show/ NCT01494701
111. Friedman Y, Balaga O, Linial M. Working together: combinatorial regulation by microRNAs. Adv. Exp. Med. Biol. 774, 317-337 (2013).
112. Brosseau J-P, Lucier J-F, Lamarche A-A et al. Redirecting splicing with bifunctional oligonucleotides. Nucl. Acids Res. 42(6), e40-e40 (2014).
113. Obad S, Dos Santos CO, Petri A et al. Silencing of microRNA families by seed-targeting tiny LNAs. Nat. Genet. 43(4), 371-378 (2011).
114. Echaniz-Laguna A, Miniou P, Bartholdi D, Melki J. The promoters of the survival motor neuron gene (SMN) and its copy (SMNc) share common regulatory elements. Am. J. Hum. Genet. 64(5), 1365-1370 (1999).
115. Monani UR, Lorson CL, Parsons DW et al. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum. Mol. Genet. 8(7), 1177-1183 (1999).
116. Germain-Desprez D, Brun T, Rochette C, Semionov A, Rouget R, Simard LR. The SMN genes are subject to transcriptional regulation during cellular differentiation. Gene 279(2), 109-117 (2001).
117. Boda B, Mas C, Giudicelli C et al. Survival motor neuron SMN1 and SMN2 gene promoters: identical sequences and differential expression in neurons and non-neuronal cells. Eur. J. Hum. Genet. 12(9), 729-737 (2004).
118. Branchu J, Biondi O, Chali F et al. Shift from extracellular signal-regulated kinase to AKT/cAMP response element-binding protein pathway increases survival-motor-neuron expression in spinal-muscular-atrophy-like mice and patient cells. J. Neurosci. 33(10), 4280-4294 (2013).
119. Farooq F, Molina FA, Hadwen J et al. Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway. J. Clin. Invest. 121(8), 3042-3050 (2011).
120. Biondi O, Branchu J, Sanchez G et al. In vivo NMDA receptor activation accelerates motor unit maturation, protects spinal motor neurons, and enhances SMN2 gene expression in severe spinal muscular atrophy mice. J. Neurosci. 30(34), 11288-11299 (2010).
121. Kolb EA, Gorlick R, Houghton PJ et al. Initial testing (stage 1) of AZD6244 (ARRY-142886) by the Pediatric Preclinical Testing Program. Pediatr. Blood Cancer 55(4), 668-677 (2010).
122. Majumder S, Varadharaj S, Ghoshal K, Monani U, Burghes AHM, Jacob ST. Identification of a novel cyclic AMP-response element (CRE-II) and the role of CREB-1 in the cAMP-induced expression of the survival motor neuron (SMN) gene. J. Biol. Chem. 279(15), 14803-14811 (2004).
123. Besnard A, Galan-Rodriguez B, Vanhoutte P, Caboche J. Elk-1 a transcription factor with multiple facets in the brain. Front Neurosci. 5, 35 (2011).
124. Zhou Z, Qiu J, Liu W et al. The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol. Cell. 47(3), 422-433 (2012).
125. Swoboda KJ, Scott CB, Reyna SP et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS ONE 4(5), e5268 (2009).
126. Swoboda KJ, Scott CB, Crawford TO et al. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS ONE 5(8), e12140 (2010).
127. Chen T-H, Chang J-G, Yang Y-H et al. Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy. Neurology 75(24), 2190-2197 (2010).
128. Kissel JT, Scott CB, Reyna SP et al. SMA carnival trial part II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS ONE6(7), e21296 (2011).
129. Darbar IA, Plaggert PG, Resende MBD, Zanoteli E, Reed UC. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid. BMC Neurol. 11, 36 (2011).
130. Liu H, Rodgers ND, Jiao X, Kiledjian M. The scavenger mRNA decapping enzyme DcpS is a member of the HIT family of pyrophosphatases. EMBO J. 21(17), 4699-4708 (2002).
131. Jarecki J, Chen X, Bernardino A et al. Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy. Hum. Mol. Genet. 14(14), 2003-2018 (2005).
132. Van Meerbeke JP, Gibbs RM, Plasterer HL et al. The DcpS inhibitor RG3039 improves motor function in SMA mice. Hum. Mol. Genet. 22(20), 4074-4083 (2013).
133. Gogliotti RG, Cardona H, Singh J et al. The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models. Hum. Mol. Genet. 22(20), 4084-4101 (2013).
134. Azzouz M, Le T, Ralph GS et al. Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy. J. Clin. Invest. 114(12), 1726-1731 (2004).
135. Dayton RD, Wang DB, Klein RL. The advent of AAV9 expands applications for brain and spinal cord gene delivery. Expert Opin. Biol. Ther. 12(6), 757-766 (2012).
136. Mendell JR, Rodino-Klapac L, Sahenk Z et al. Gene therapy for muscular dystrophy: lessons learned and path forward. Neurosci. Lett. 527(2), 90-99 (2012).
137. Passini MA, Bu J, Roskelley EM et al. CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy. J. Clin. Invest. 120(4), 1253-1264 (2010).
138. Foust KD, Wang X, McGovern VL et al. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat. Biotechnol. 28(3), 271-274 (2010).
139. Bevan AK, Hutchinson KR, Foust KD et al. Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery. Hum. Mol. Genet. 19(20), 3895-3905 (2010).
140. Shababi M, Habibi J, Ma L, Glascock JJ, Sowers JR, Lorson CL. Partial restoration of cardio-vascular defects in a rescued severe model of spinal muscular atrophy. J. Mol. Cell. Cardiol. 52(5), 1074-1082 (2012).
141. Dominguez E, Marais T, Chatauret N et al. Intravenous scAAV9 delivery of a codon-optimized SMN1 sequence rescues SMA mice. Hum. Mol. Genet. 20(4), 681-693 (2011).
142. Valori CF, Ning K, Wyles M et al. Systemic delivery of scAAV9 expressing SMN prolongs survival in a model of spinal muscular atrophy. Sci. Transl. Med. 2(35), 35-42 (2010).
143. Glascock JJ, Shababi M, Wetz MJ, Krogman MM, Lorson CL. Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of spinal muscular atrophy. Biochem. Biophys. Res. Commun. 417(1), 376-381 (2012).
144. Benkhelifa-Ziyyat S, Besse A, Roda M et al. Intramuscular scAAV9-SMN injection mediates widespread gene delivery to the spinal cord and decreases disease severity in SMA mice. Mol. Ther. 21(2), 282-290 (2013).
145. Families of SMA. US FDA approval to Nationwide Children's Hosptial for Phase I clinical trial of systemic AAV9-delivered SMN gene for spinal muscular atrophy.www.fsma.org/LatestNews/index.cfm?ID=8172&TYPE=1150 Future
146. Oprea GE, Kröber S, McWhorter ML et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 320(5875), 524-527 (2008).
147. Amara A, Adala L, Ben Charfeddine I et al. Correlation of SMN2, NAIP, p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients. Eur. J. Paediatr. Neurol. 16(2), 167-174 (2012).
148. Zhang Z, Pinto AM, Wan L et al. Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy. Proc. Natl Acad. Sci. USA 110(48), 19348-19353 (2013).
149. Ahmad S, Wang Y, Shaik GM, Burghes AH, Gangwani L. The zinc finger protein ZPR1 is a potential modifier of spinal muscular atrophy. Hum. Mol. Genet. 21(12), 2745-2758 (2012).
150. Perrin S. Preclinical research: Make mouse studies work. Nature 507(7493),423-425 (2014).