Spinal muscular atrophy: mechanisms and therapeutic strategies
Open accessAbstract
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and a leading genetic cause of infantile mortality. SMA is caused by mutation or deletion of Survival Motor Neuron-1 (SMN1). The clinical features of the disease are caused by specific degeneration of alpha-motor neurons in the spinal cord, leading to muscle weakness, atrophy and, in the majority of cases, premature death. A highly homologous copy gene (SMN2) is retained in almost all SMA patients but fails to generate adequate levels of SMN protein due to its defective splicing pattern. The severity of the SMA phenotype is inversely correlated with SMN2 copy number and the level of full-length SMN protein produced by SMN2 ( approximately 10-15% compared with SMN1). The natural history of SMA has been altered over the past several decades, primarily through supportive care measures, but an effective treatment does not presently exist. However, the common genetic etiology and recent progress in pre-clinical models suggest that SMA is well-suited for the development of therapeutic regimens. We summarize recent advances in translational research that hold promise for the progression towards clinical trials.
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Chen, J., & Weiss, W. A. (2014) · Oncogene · doi:10.1038/onc.2013.570 · Cited by 304 · see citing works
hnRNP A1: The Swiss Army Knife of Gene Expression
Jean-Philippe, J., Paz, S., & Caputi, M. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140918999 · Cited by 299 · see citing works
“motor neurons results in system-wide muscle atrophy [181].”
BackgroundA walk through tau therapeutic strategies
Jadhav, S., Ávila, J., Schöll, M., Kovács, G. G., Kövari, E., Škrabana, R., Evans, L., Kontseková, E., Malawska, B., de Silva, R., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0664-z · Cited by 286 · see citing works
Antisense oligonucleotides in therapy for neurodegenerative disorders
Evers, M. M., Toonen, L. J. A., & van Roon‐Mom, W. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.03.008 · Cited by 284 · see citing works
Spinal muscular atrophy: a motor neuron disorder or a multi‐organ disease?
Shababi, M., Lorson, C. L., & Rudnik‐Schöneborn, S. (2013) · Journal of Anatomy · doi:10.1111/joa.12083 · Cited by 263 · see citing works
“Recent reviews have focused upon these compounds and their modes-of-action (Lorson et al., 2010; Shababi et al. 2010b; Cherry & Androphy, 2012; Lewelt et al. 2012; Lorson & Lorson, 2012).”
BackgroundMutations in the tail domain of DYNC1H1 cause dominant spinal muscular atrophy
Harms, M. B., Ori-McKenney, K. M., Scoto, M., Tuck, E. P., Bell, S., Ma, D., Masi, S., Allred, P., Al-Lozi, M., Reilly, M. M., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e3182556c05 · Cited by 217 · see citing works
Kumar, V., Kundu, S., Singh, A., & Singh, S. (2022) · Current Neuropharmacology · doi:10.2174/1570159x19666210609160017 · Cited by 210 · see citing works
“Mutation in the SMN1 gene (survival motor neuron-1) causes fatal motor neuron and autosomal recessive disease by the duplication of SMN locus and SMN2 gene (SMN2), however, SMN1 is also coded by the SMN protein [48].”
BackgroundLing, K., Gibbs, R. M., Feng, Z., & Ko, C. P. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr453 · Cited by 201 · see citing works
Antisense-based therapy for the treatment of spinal muscular atrophy
Rigo, F., Hua, Y., Krainer, A. R., & Bennett, C. F. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201207087 · Cited by 172 · see citing works
Lutz, C. M., Kariya, S., Patruni, S., Osborne, M. A., Liu, D., Henderson, C. E., Li, D. K., Pellizzoni, L., Rojas, J. L. V., Valenzuela, D. M., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57291 · Cited by 168 · see citing works
Constructing and Deconstructing Stem Cell Models of Neurological Disease
Han, S. S. W., Williams, L. A., & Eggan, K. C. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.003 · Cited by 159 · see citing works
“While five nucleotides, none of which lead to an amino acid change, differentiate SMN2 from SMN1, SMN2 mRNA, through alternative splicing, results predominantly in transcripts lacking exon 7, thereby leading to a truncated, unstable protein (Lorson et al., 2010).”
Granulostasis: Protein Quality Control of RNP Granules
Alberti, S., Matějů, D., Mediani, L., & Carra, S. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00084 · Cited by 147 · see citing works
Spinal Muscular Atrophy: Manifestations and Management
Mesfin, A., Sponseller, P. D., & Leet, A. I. (2012) · Journal of the American Academy of Orthopaedic Surgeons · doi:10.5435/jaaos-20-06-393 · Cited by 146 · see citing works
“In humans, SMN2 is a gene nearly identical to SMN1 except that SMN2 produces a limited level of full-length survival motor neurons, resulting in decreased protein production.4,8 The structural difference between the two genes is that SMN2 has a nucleotide change from C to T in exon 7.8,10 Increased levels of SMN2 have…”
BackgroundInfluentialPharmaceutical therapies to recode nonsense mutations in inherited diseases
Lee, H.-L. R., & Dougherty, J. P. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.07.007 · Cited by 138 · see citing works
Cardiac pathology in spinal muscular atrophy: a systematic review
Wijngaarde, C. A., Blank, A. C., Stam, M., Wadman, R. I., van den Berg, L. H., & van der Pol, W. L. (2017) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-017-0613-5 · Cited by 111 · see citing works
Uversky, V. N. (2014) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2014.00006 · Cited by 107 · see citing works
“One of the causative agents of SMA, an autosomal recessive neurodegenerative disorder which is a leading genetic cause of infantile mortality, is deletion of a highly disordered protein, survival motor neuron-1 (SMN1) (Lorson et al., 2010).”
BackgroundInfluentialTargeting Nonsense Mutations in Diseases with Translational Read-Through-Inducing Drugs (TRIDs)
Nagel‐Wolfrum, K., Möller, F., Penner, I., Baasov, T., & Uwe Wolfrum, B. (2016) · BioDrugs · doi:10.1007/s40259-016-0157-6 · Cited by 101 · see citing works
“This reduces the expression of functional SMN proteins [65].”
BackgroundAn exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects
Fernandez-Alanis, E., Pinotti, M., Mas, A. D., Balestra, D., Cavallari, N., Rogalska, M. E., Bernardi, F., & Pagani, F. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds045 · Cited by 103 · see citing works
“Here, to study the effect of mutations on splicing and identify a correction strategy on an exon basis, we considered three genes relevant in human pathology, the coagulation F9, the Cystic Fibrosis Transmembrane Regulator (CFTR) and the SMN2 (Survival of Motoneuron 2), whose mutations are associated to coagulation fa…”
BackgroundInfluentialReversible molecular pathology of skeletal muscle in spinal muscular atrophy
Mutsaers, C. A., Wishart, T. M., Lamont, D. J., Rießland, M., Schreml, J., Comley, L. H., Murray, L. M., Parson, S. H., Lochmüller, H., Wirth, B., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr360 · Cited by 100 · see citing works
“The SMN2 gene, however, produces only 10% of full-length SMN protein due to a defective splicing pattern (4,5).”
BackgroundWirth, B., Garbes, L., & Rießland, M. (2013) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2013.03.003 · Cited by 96 · see citing works
TDP-43-Based Animal Models of Neurodegeneration: New Insights into ALS Pathology and Pathophysiology
Wegorzewska, I., & Baloh, R. H. (2010) · Neurodegenerative Diseases · doi:10.1159/000321547 · Cited by 93 · see citing works
“Gemini bodies are rich in SMN (survival motor neuron) protein, and are required for assembling snRNPs, critical components of the pre-mRNA splicing apparatus. Decreased levels of SMN protein lead to a childhood onset motor neuron disease called spinal muscular atrophy [”
BackgroundBekenstein, U., & Soreq, H. (2012) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2012.12.002 · Cited by 91 · see citing works
Expanding the action of duplex RNAs into the nucleus: redirecting alternative splicing
Liu, J., Hu, J., & Corey, D. R. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr780 · Cited by 86 · see citing works
“Spinal muscular atrophy (SMA) is an inherited neurodegenerative disorder caused by loss or mutation of the survival motor neuron 1 (SMN1) gene (28).”
Disruption of Axonal Transport in Motor Neuron Diseases
Ikenaka, K., Katsuno, M., Kawai, K., Ishigaki, S., Tanaka, F., & Sobue, G. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13011225 · Cited by 84 · see citing works
“by the mutation or deletion of the “survival motor neuron 1” gene (SMN1), which plays an important role in RNA metabolism [79].”
BackgroundNewborn screening for spinal muscular atrophy: Anticipating an imminent need
Phan, H. C., Taylor, J. L., Hannon, H., & Howell, R. R. (2015) · Seminars in Perinatology · doi:10.1053/j.semperi.2015.03.006 · Cited by 81 · see citing works
Kissel, J. T., Elsheikh, B., King, W. M., Freimer, M. L., Scott, C., Kolb, S. J., Reyna, S. P., Crawford, T. O., Simard, L. R., Krosschell, K. J., et al. (2013) · Muscle & Nerve · doi:10.1002/mus.23904 · Cited by 79 · see citing works
Severe SMA mice show organ impairment that cannot be rescued by therapy with the HDACi JNJ-26481585
Schreml, J., Rießland, M., Paterno, M., Garbes, L., Roßbach, K., Ackermann, B., Kramer, J. S., Somers, E., Parson, S. H., Heller, R., et al. (2012) · European Journal of Human Genetics · doi:10.1038/ejhg.2012.222 · Cited by 78 · see citing works
TIA1 Prevents Skipping of a Critical Exon Associated with Spinal Muscular Atrophy
Singh, N. N., Seo, J., Ottesen, E. W., Shishimorova, M., Bhattacharya, D., & Singh, R. N. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00945-10 · Cited by 78 · see citing works
“Spinal muscular atrophy (SMA), the second most common autosomal recessive disorder, is caused by deletions or mutations of the Survival Motor Neuron 1 (SMN1) gene (36).”
BackgroundPraveen, K., Wen, Y., & Matera, A. G. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.05.014 · Cited by 76 · see citing works
“Humans have two paralogs of SMN, named SMN1 and SMN2, both of which contribute to total cellular levels of SMN protein.”
InfluentialComplex neuroprotective and neurotoxic effects of histone deacetylases
Thomas, E. A., & D’Mello, S. R. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14309 · Cited by 75 · see citing works
Antisense Therapy in Neurology
Lee, J. K., & Yokota, T. (2013) · Journal of Personalized Medicine · doi:10.3390/jpm3030144 · Cited by 74 · see citing works
“Consequently, upregulation of SMN by modification of SMN2 exon 7 splicing is a promising therapeutic approach (Figure 5), an approach that has already demonstrated favourable results in animal models [69,140–143].”
ResultBone and Spinal Muscular Atrophy
Vai, S., Bianchi, M. L., Moroni, I., Mastella, C., Broggi, F., Morandi, L. O., Arnoldi, M. T., Bussolino, C., & Baranello, G. (2015) · Bone · doi:10.1016/j.bone.2015.05.039 · Cited by 74 · see citing works
“The disease is due to defects in the Survival Motor Neuron 1 (SMN1) gene in chromosome 5, with deficiency in the SMN protein, critical to the health and survival of the motor neurons [1–3].”
BackgroundSMN in spinal muscular atrophy and snRNP biogenesis
Coady, T. H., & Lorson, C. L. (2011) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.76 · Cited by 74 · see citing works
Stem Cell Technology for the Study and Treatment of Motor Neuron Diseases
Lunn, J. S., Sakowski, S. A., Federici, T., Glass, J. D., Boulis, N. M., & Feldman, E. L. (2011) · Regenerative Medicine · doi:10.2217/rme.11.6 · Cited by 72 · see citing works
Genetic therapy for the nervous system
Bowers, W. J., Breakefield, X. O., & Sena‐Esteves, M. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr110 · Cited by 70 · see citing works
Stem Cell Transplantation for Motor Neuron Disease: Current Approaches and Future Perspectives
Gowing, G., & Svendsen, C. N. (2011) · Neurotherapeutics · doi:10.1007/s13311-011-0068-7 · Cited by 70 · see citing works
“Affecting 1 in 6000 to 10,000 live births, the autosomal recessive disorder SMA is the most common genetic cause of infantile death [28, 29].”
Human induced pluripotent stem cells and neurodegenerative disease: prospects for novel therapies
Jung, Y.-W., Hysolli, E., Kim, K.-Y., Tanaka, Y., & Park, I.-H. (2012) · Current Opinion in Neurology · doi:10.1097/wco.0b013e3283518226 · Cited by 66 · see citing works
Nuclear Pre-snRNA Export Is an Essential Quality Assurance Mechanism for Functional Spliceosomes
Becker, D., Hirsch, A. G., Bender, L., Lingner, T., Salinas, G., & Krebber, H. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.031 · Cited by 65 · see citing works
McGovern, V. L., Iyer, C. C., Arnold, W. D., Gombash, S. E., Zaworski, P. G., Blatnik, A. J., Foust, K. D., & Burghes, A. H. M. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv283 · Cited by 67 · see citing works
“(90) reported that expression of high levels of SMN in astrocytes benefited SMA mice.”
BackgroundOsman, E. Y., Yen, P., & Lorson, C. L. (2011) · Molecular Therapy · doi:10.1038/mt.2011.232 · Cited by 66 · see citing works
Characterization of the RNA recognition mode of hnRNP G extends its role in SMN2 splicing regulation
Moursy, A., Allain, F. H. ‐., & Cléry, A. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku244 · Cited by 65 · see citing works
“Spinal Muscular Atrophy (SMA) is an inherited disease characterized by degeneration of the spinal cord -motor neurons, which results in a system-wide muscle wasting (1).”
BackgroundNizzardo, M., Nardini, M., Ronchi, D., Salani, S., Donadoni, C., Fortunato, F., Colciago, G., Falcone, M., Simone, C., Riboldi, G., et al. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.01.017 · Cited by 64 · see citing works
Argonaute and the Nuclear RNAs: New Pathways for RNA-Mediated Control of Gene Expression
Gagnon, K. T., & Corey, D. R. (2012) · Nucleic Acid Therapeutics · doi:10.1089/nat.2011.0330 · Cited by 64 · see citing works
“The symptoms of spinal muscular atrophy and Duchenne’s muscular dystrophy might be alleviated if splicing of the respective genes, SMN2 and dystrophin , can be redirected (Lorson et al., 2010; Lu et al., 2010).”
SMN1 gene duplications are associated with sporadic ALS
Blauw, H. M., Barnes, C. P., van Vught, P. W. J., van Rheenen, W., Verheul, M., Cuppen, E. P. J. G., Veldink, J. H., & van den Berg, L. H. (2012) · Neurology · doi:10.1212/wnl.0b013e318249f697 · Cited by 60 · see citing works
Increasing Agrin Function Antagonizes Muscle Atrophy and Motor Impairment in Spinal Muscular Atrophy
Boido, M., Amicis, E. D., Valsecchi, V., Trevisan, M., Ala, U., Rüegg, M. A., Hettwer, S., & Vercelli, A. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00017 · Cited by 60 · see citing works
“SMA And NMJ Alterations SMA is characterized by MN degeneration, due to deletion or mutation of the telomeric SMN1 gene and to the insufficient efficiency of SMN2 gene: this determines in the affected patients muscular atrophy, paralysis and reduced lifespan, according to the disease severity (Lorson et al., 2010).”
BackgroundInfluentialCorti, S. P., Faravelli, I., Cardano, M., & Conti, L. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1037737 · Cited by 59 · see citing works
“The clinical phenotype is featured by progressive symmetric muscular paralysis and children usually present hypotonic and atrophic limbs [78].”
BackgroundImprovement of SMN2 Pre-mRNA Processing Mediated by Exon-Specific U1 Small Nuclear RNA
Mas, A. D., Rogalska, M. E., Bussani, E., & Pagani, F. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.12.009 · Cited by 56 · see citing works
“The small amount of full-length (FL) protein produced by SMN2 is therefore essential for survival, and the number of copies of SMN2 inversely correlate with the severity of the pathology.(17) Although SMA is not a splicing disease per se, SMN2 is an optimum candidate for a splicing therapy, because all SMA-affected in…”
BackgroundPastor, D., Viso-León, M. C., Jones, J., Jaramillo-Merchán, J., Toledo‐Aral, J. J., Moraleda, J. M., & Martı́nez, S. (2011) · Stem Cell Reviews and Reports · doi:10.1007/s12015-011-9295-x · Cited by 56 · see citing works
“Many authors have studied the use of stem cells to treat SMA [7] or ALS [8], by transplanting bone marrow-derived stem cells in transgenic animal models, in order to try to”
Alternative splicing in spinal muscular atrophy underscores the role of an intron definition model
Singh, N. N., & Singh, R. N. (2011) · RNA Biology · doi:10.4161/rna.8.4.16224 · Cited by 55 · see citing works
“SMN2, a nearly identical copy of SMN1, fails to prevent SMA due to a critical C-to-T mutation at the 6 position (C6U mutation in RNA) of exon 7.(5-7) C6U mutation leads to a predominant exon 7 skipping from SMN2, producing mostly truncated protein SMNΔ7, which is unstable.”
BackgroundBranchu, J., Biondi, O., Chali, F., Collin, T., Leroy, F., Mamchaoui, K., Makoukji, J., Pariset, C. C., Lopes, P., Massaad, C., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2728-12.2013 · Cited by 55 · see citing works
“…identified SMN2 gene-inducing molecules (Chang et al., 2001; Avila et al., 2007; Thurmond et al., 2008; Tsai et al., 2008; Butchbach et al., 2010; Lorson et al., 2010), but so far, most of these agents yielded inconclusive results in clinical trials (Mercuri et al., 2007; Swoboda et al., 2009,…”
ResultQuality control of assembly-defective U1 snRNAs by decapping and 5′-to-3′ exonucleolytic digestion
Shukla, S., & Parker, R. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1412614111 · Cited by 55 · see citing works
“For example, spinal muscular atrophy (SMA) is a neurodegenerative disease caused by low levels of the survival motor neuron (SMN) protein due to mutations in the principal SMN-coding gene SMN1 (6, 7).”
BackgroundFarooq, F., Abadía‐Molina, F., MacKenzie, D., Hadwen, J., Shamim, F., O’Reilly, S., Holčı́k, M., & MacKenzie, A. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt191 · Cited by 55 · see citing works
“Increasing SMN levels through the SMN2 gene can partially rescue the disease phenotype (21).”
BackgroundThe Silent Sway of Splicing by Synonymous Substitutions
Mueller, W. F., Larsen, L. S. Z., Garibaldi, A., Hatfield, G. W., & Hertel, K. J. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.684035 · Cited by 55 · see citing works
“green, whereas those that decrease inclusion are shown in red (22, 30).”
BackgroundBohačiaková, D., Hruška-Plocháň, M., Bjarkam, C. R., Sørensen, J. C. H., Cunningham, M. G., Weingarten, D., Ciacci, J. D., Juhás, Š., Juhásová, J., Motlík, J., et al. (2014) · The Journal of Comparative Neurology · doi:10.1002/cne.23575 · Cited by 54 · see citing works
“Recently, the first step in development of a porcine animal model for SMA has been undertaken and heterozygous SMN1 knockout pigs were generated (Lorson et al., 2011).”
BackgroundDisruption of the Survival Motor Neuron (SMN) gene in pigs using ssDNA
Lorson, M. A., Spate, L. D., Samuel, M., Murphy, C. N., Lorson, C. L., Prather, R. S., & Wells, K. D. (2011) · Transgenic Research · doi:10.1007/s11248-011-9496-8 · Cited by 54 · see citing works
“(4) Advancements in drug development, gene therapy and SMN2 modulation are progressing toward clinical application (Lorson et al. 2010; MacKenzie 2010; Stavarachi et al. 2010).”
Tapia, O., Bengoechea, R., Palanca, A., Arteaga, R., Val‐Bernal, J. F., Tizzano, E. F., Berciano, M. T., & Lafarga, M. (2012) · Histochemistry and Cell Biology · doi:10.1007/s00418-012-0921-8 · Cited by 51 · see citing works
“2011), and in the axonal transport of certain mRNAs (Cauchi 2010; Lorson et al. 2010).”
Garcia, E. L., Lu, Z., Meers, M. P., Praveen, K., & Matera, A. G. (2013) · RNA · doi:10.1261/rna.038919.113 · Cited by 46 · see citing works
“Although the severity of SMA clearly depends on SMN protein levels (Lorson et al. 2010), the etiologic connection between loss of SMN expression and disease pathology remains unknown.”
BackgroundAntisense oligonucleotide mediated therapy of spinal muscular atrophy
Sivanesan, S., Howell, M. D., DiDonato, C. J., & Singh, R. N. (2013) · Translational Neuroscience · doi:10.2478/s13380-013-0109-2 · Cited by 46 · see citing works
Splicing mutations in inherited retinal diseases
Weisschuh, N., Buena‐Atienza, E., & Wissinger, B. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100874 · Cited by 44 · see citing works
Alternative splicing interference by xenobiotics
Zaharieva, E. E., Chipman, J. K., & Soller, M. (2012) · Toxicology · doi:10.1016/j.tox.2012.01.014 · Cited by 43 · see citing works
Antisense oligonucleotides and spinal muscular atrophy: skipping along: Figure 1.Preprint
Burghes, A. H. M., & McGovern, V. L. (2010) · Genes & Development · doi:10.1101/gad.1961710 · Cited by 41 · see citing works
Pelletier, S. W., Gingras, S., Howell, S. R., Vogel, P., & Ihle, J. N. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1787-12.2012 · Cited by 39 · see citing works
“TDP-43 is a ubiquitously expressed DNA/RNAbinding protein involved in RNA metabolism (Buratti and Baralle, 2001; Mercado et al., 2005; Chen-Plotkin et al., 2010).”
BackgroundMutsaers, C. A., Lamont, D. J., Hunter, G., Wishart, T. M., & Gillingwater, T. H. (2013) · Genome Medicine · doi:10.1186/gm498 · Cited by 38 · see citing works
“Background The autosomal recessive disease spinal muscular atrophy (SMA) is caused by deficient expression of full-length survival motor neuron (SMN) protein resulting from disruption to the survival motor neuron 1 (SMN1) gene [1-3].”
BackgroundJędrzejowska, M., Goś, M., Zimowski, J. G., Kostera‐Pruszczyk, A., Ryniewicz, B., & Hausmanowa-Petrusewicz, I. (2014) · Neuromuscular Disorders · doi:10.1016/j.nmd.2014.04.003 · Cited by 37 · see citing works
Schellino, R., Boido, M., Borsello, T., & Vercelli, A. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00308 · Cited by 34 · see citing works
Liu, S., Kang, W.-J., Abrimian, A., Xu, J., Cartegni, L., Majumdar, S., Hesketh, P. J., Bekker, A., & Pan, Y. (2021) · Biomolecules · doi:10.3390/biom11101525 · Cited by 34 · see citing works
“Aberrant alternative splicing has been associated with a number of human diseases [41,42], such as amyotrophic lateral sclerosis [43,44], paraneoplastic neurological disorders [38,45], myotonic dystrophy [46], spinal muscular atrophy [47,48], and cancer [27,49–52].”
BackgroundPluripotent stem cell-based models of spinal muscular atrophy.
Frattini, E., Ruggieri, M., Salani, S., Faravelli, I., Zanetta, C., Nizzardo, M., Simone, C., Magri, F., & Corti, S. (2015) · Molecular and cellular neurosciences · doi:10.1016/j.mcn.2014.12.005 · Cited by 31 · see citing works
“, 2010), SMA represents the first genetic cause of mortality in infants (Lorson et al., 2010; Lunn and Wang, 2008) and the second most common autosomal recessive disease in Caucasians after cystic fibrosis (Wirth, 2000).”
BackgroundModulation of RNA Splicing by Oligonucleotides: Mechanisms of Action and Therapeutic Implications
Sergeeva, O. V., Shcherbinina, E. Y., Shomron, N., & Zatsepin, T. S. (2022) · Nucleic Acid Therapeutics · doi:10.1089/nat.2021.0067 · Cited by 34 · see citing works
“It has been previously shown that there are many alternative splice signals within and flanking an exon or an intron [66], so each splicing event should be thoroughly studied to uncover optimal silencer and enhancer sequences.”
Powis, R. A., Mutsaers, C. A., Wishart, T. M., Hunter, G., Wirth, B., & Gillingwater, T. H. (2014) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12168 · Cited by 32 · see citing works
“However, at present no effective treatments are available (15).”
Recognition of single-stranded nucleic acids by small-molecule splicing modulators
Tang, Z., Akhter, S., Ramprasad, A., Wang, X., Reibarkh, M., Wang, J., Aryal, S., Thota, S. S., Zhao, J., Douglas, J. T., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab602 · Cited by 32 · see citing works
“A promising therapeutic strategy is to restore proper splicing of the SMN2 exon 7 to compensate for the loss of the SMN1 gene in SMA patients (2).”
BackgroundTargeting RNA-Splicing for SMA Treatment
Zhou, J., Zheng, X., & Shen, H. (2012) · Molecules and Cells · doi:10.1007/s10059-012-0005-6 · Cited by 29 · see citing works
Renvoisé, B., Quérol, G., Verrier, E. R., Burlet, P., & Lefebvre, S. (2012) · Journal of Cell Science · doi:10.1242/jcs.096255 · Cited by 28 · see citing works
“A plausible strategy for the development of therapeutics for SMA is to increase SMN protein levels (Lorson et al., 2010).”
BackgroundProspects for the gene therapy of spinal muscular atrophy
Passini, M. A., & Cheng, S. H. (2011) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2011.01.002 · Cited by 27 · see citing works
Jaiswal, M. K. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.206635 · Cited by 27 · see citing works
“SMA is characterized by extreme heterogeneity and is the leading genetic cause of infantile mortality in children (Lorson et al., 2010; Prior et al., 2010).”
BackgroundInduced Pluripotent Stem Cells to Model and Treat Neurogenetic Disorders
Wang, H., & Doering, L. C. (2012) · Neural Plasticity · doi:10.1155/2012/346053 · Cited by 26 · see citing works
“[93] C.”
SMN deficiency attenuates migration of U87MG astroglioma cells through the activation of RhoA
Caraballo-Miralles, V., Cardona-Rossinyol, A., Garcerá, A., Villalonga, P., Soler, R. M., Olmos, G., & Lladó, J. (2011) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2011.12.003 · Cited by 26 · see citing works
Gray, K. M., Kaifer, K. A., Baillat, D., Wen, Y., Bonacci, T., Ebert, A. D., Raimer, A. C., Spring, A. M., ten Have, S., Glascock, J., et al. (2017) · Molecular Biology of the Cell · doi:10.1091/mbc.e17-11-0627 · Cited by 26 · see citing works
“Although the amount of full-length protein produced by SMN2 is not enough to compensate for loss of SMN1, SMN2 is sufficient to rescue embryonic lethality (Monani et al., 2000).”
BackgroundInfluentialEffects of Arm Cycling Exercise in Spinal Muscular Atrophy Type II Patients: A Pilot Study
Bora, G., Subaşı-Yıldız, Ş., Kaymaz, A. Y., Bulut, N., Alemdaroğlu-Gürbüz, İ., Tunca-Yılmaz, Ö., Topaloğlu, H., Karaduman, A. A., & Erdem‐Yurter, H. (2018) · Journal of Child Neurology · doi:10.1177/0883073817750500 · Cited by 26 · see citing works
Ruiz, R., & Tabares, L. (2013) · Journal of Anatomy · doi:10.1111/joa.12038 · Cited by 25 · see citing works
“…SMN reaches a certain minimal threshold, as the requirement for this is higher during the embryonic and early postnatal period than in the adulthood, as demonstrated in the different therapeutic assays in SMA animal models (Lorson et al. 2010; Sendtner, 2010; Hua et al. 2011; Porensky et al. 2012).”
BackgroundManagement of Spinal Muscular Atrophy in the Adult Population
Rad, N., Cai, H., & Weiss, M. D. (2022) · Muscle & Nerve · doi:10.1002/mus.27519 · Cited by 25 · see citing works
The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis
Boyer, J. G., Bowerman, M., & Kothary, R. (2010) · Future Neurology · doi:10.2217/fnl.10.57 · Cited by 25 · see citing works
“Future perspective Currently the SMA field is aggressively assess‐ ing the therapeutic value of several approaches, namely gene therapy and the administration of compounds that increase full‐length SMN expression from the SMN2 gene [156].”
Cherry, J. J., Evans, M. C., Ni, J., Cuny, G. D., Glicksman, M. A., & Androphy, E. J. (2012) · SLAS DISCOVERY · doi:10.1177/1087057111431605 · Cited by 25 · see citing works
“All SMA patients retain at least one SMN2 gene, and disease severity inversely correlates with SMN2 copy number.(29) Because the SMN2 gene has the potential to express functional fulllength SMN protein, it is an attractive therapeutic target for the treatment for SMA.”
BackgroundGama‐Carvalho, M., García‐Vaquero, M. L., Pinto, F. R., Besse, F., Weis, J., Voigt, A., Schulz, J. B., & Rivas, J. D. L. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13945 · Cited by 23 · see citing works
Optimization of SMN Trans-Splicing Through the Analysis of SMN Introns
Shababi, M., & Lorson, C. L. (2011) · Journal of Molecular Neuroscience · doi:10.1007/s12031-011-9614-3 · Cited by 23 · see citing works
“SMN2 exon 7 is a highly regulated exon and a number of enhancers and silencers are present that coordinate inclusion and exclusion ( Lorson et al. 2010 ).”
BackgroundPPP4R2 regulates neuronal cell differentiation and survival, functionally cooperating with SMN
Bosio, Y., Berto, G. E., Camera, P., Bianchi, F., Ambrogio, C., Claus, P., & Cunto, F. D. (2012) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2012.03.002 · Cited by 23 · see citing works
Muscle contractility in spinobulbar muscular atrophy
Dahlqvist, J. R., Oestergaard, S. T., Poulsen, N. S., Knak, K., Thomsen, C. E., & Vissing, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-41240-y · Cited by 22 · see citing works
Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets
Tsai, L. (2012) · Neural Plasticity · doi:10.1155/2012/456478 · Cited by 22 · see citing works
“The mode-of-action for a potential SMA therapy using small molecules mainly includes restoration of the SMN2 splicing pattern, activating the SMN2 promoter, and extending the half-life of SMN mRNA or protein [10].”
BackgroundA future perspective on neurodegenerative diseases: nasopharyngeal and gut microbiota
Khan, F., & Oloketuyi, S. F. (2016) · Journal of Applied Microbiology · doi:10.1111/jam.13327 · Cited by 22 · see citing works
“atrophy Mutation or deletion of survival neuron gene (SMN1) (Lorson et al. 2010; Zanetta et al. 2013)”
BackgroundTranscriptional and Splicing Regulation of Spinal Muscular Atrophy Genes
Singh, N. N., Howell, M. D., & Singh, R. N. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803685-3.00005-7 · Cited by 21 · see citing works
Aging—RNA in development and disease
Cookson, M. (2011) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.109 · Cited by 20 · see citing works
Rudnik‐Schöneborn, S., & Zerres, K. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-383834-6.00137-3 · Cited by 20 · see citing works
Bora, G., & Erdem‐Yurter, H. (2014) · BioMed Research International · doi:10.1155/2014/709108 · Cited by 19 · see citing works
Stem cell-derived neurotrophic support for the neuromuscular junction in spinal muscular atrophy
Wyatt, T. J., & Keirstead, H. (2010) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2010.529895 · Cited by 22 · see citing works
“Increased lifespan is shown following administration of SAHA, an HDAC inhibitor that acts more broadly than the more local action of TSA at transcription start sites [4,72].”
BackgroundMethodInfluential
- Authors
- Lorson, C. L., Rindt, H., & Shababi, M.
- Affiliations
- University of Missouri (US)
- Corresponding author
- Lorson, C. L.
- ORCID
- Lorson, C. L.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-04-13
- Volume
- 19
- Issue
- R1
- Pages
- R111-R118
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC2875050
- OpenAlex
- W2105989886
- Cited by
- 209
- References
- 86
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 7 · 2023: 6 · 2022: 12 · 2021: 8 · 2020: 16 · 2019: 5 · 2018: 8 · 2017: 11 · 2016: 4 · 2015: 14 · 2014: 18 · 2013: 21 · 2012: 29
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01 NS41584, R01NS041584)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD054413)
- Topics
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- spinal muscular atrophy, SMN1, SMN2, survival motor neuron protein, SMN2 splicing, SMN2 copy number, disease severity, treatment options, preclinical models, neurodegeneration
- MeSH terms
- Gene Expression Regulation, Humans, Muscular Atrophy, Spinal, Phenotype, RNA Splicing, Drug Design, Stem Cell Transplantation, Survival of Motor Neuron 1 Protein, Survival of Motor Neuron 2 Protein
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