Cited by 209Neurogenetic and Muscular Disorders ResearchAmyotrophic Lateral Sclerosis ResearchHereditary Neurological Disorders

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Spinal muscular atrophy: mechanisms and therapeutic strategies

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Lorson, C. L., Rindt, H., Shababi, M.·2010·Human Molecular Genetics

DOI 10.1093/hmg/ddq147PMC PMC2875050

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Abstract

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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Background
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“This number varies from 0 to 8 in the normal population (Butchbach, 2016; Kolb & Kissel, 2015) where the presence of three or more copies of SMN2 is associated with a milder phenotype (Mailman et al., 2002).”
Background
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Background
Spinal Muscular Atrophy
Chen, H. (2015) · Springer eBooks · doi:10.1007/978-1-4614-6430-3_221-2 · Cited by 16
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“SMA is associated with mutations in SMN1 .”
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“Because of its unique anatomy and physiological properties, researchers were unable to study SMA extensively [65].”
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Kunkanjanawan, T., Noisa, P., & Parnpai, R. (2011) · BioMed Research International · doi:10.1155/2011/350131 · Cited by 14
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Background
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Background
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Background
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“a SMA therapeutic target [9, 10] with efforts directed”
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Background
Investigation of a recombinant SMN protein delivery system to treat spinal muscular atrophy
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BackgroundMethod
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“Background Spinal muscular atrophy is estimated to affect 1 in 11,000 live births and is one of the leading causes of infantile mortality [1, 2].”
Background
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“[7] approximately 8% of the population lack the SMN2 gene but have a copy of the SMN1 gene [9].”
BackgroundInfluential
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“Therapeutic strategies aim to increase SMN protein levels to reduce the severity of the disease [7,8].”
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“Deﬁciency of the SMN protein and consequently loss of a -motor neurons in the spinal cord can lead to progressive proximal muscle weakness and paralysis [7,8].”
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Shushing down the epigenetic landscape towards stem cell differentiation
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“In the childhood disease SMA, motor neurons degenerate (Lorson et al., 2010).”
Background
Ameliorating Huntington's Disease by Targeting Huntingtin mRNA
Melvin, M., Vlamings, R., Temel, Y., & van Roon‐Mom, W. (2012) · InTech eBooks · doi:10.5772/30283
“The majority of SMN2 transcripts are therefore lacking exon 7, which results in a truncated protein and lower expression of a functional SMN protein (Lorson et al., 2010).”
Background
Recent Advances in Understanding of Alternative Splicing in Neuronal Pathogenesis
Chen, H.-H., Lin, J.-C., & Tar, W.-Y. (2011) · InTech eBooks · doi:10.5772/22477
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Role of p38 and STAT5 Kinase Pathways in the Regulation of Survival of Motor Neuron Gene Expression for Development of Novel Spinal Muscular Atrophy Therapeutics
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Study of Protein Production, Folding, Crystallization and Structure: Survival of Motor Neuron Protein and Fenna-Matthews-Olson Protein
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Gene Therapy in Spinal Muscular Atrophy (SMA) Models Using Intracerebroventricular Injection into Neonatal Mice
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Defining the anti-apoptotic function of the survival of motor neuron (SMN) protein and assessment of a novel therapy for the treatment of spinal muscular atrophy (SMA)
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ANTISENSE OLIGONUCLEOTIDE MEDIATED THERAPY OF SPINAL
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Functional analysis of Nopp140 and P5CDh1 in Drosophila melanogaster
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“…the survival of motor neuron (SMN) protein is required for Nopp140 localization within CBs. SMA is a neuronal degenerative disease marked by low levels of the SMN (for review, see Lorson et al., 2010); SMN is required for snRNP biogenesis both in the 22 cytoplasm and in CBs (Carvalho et al., 1999).”
Background
Vorteil durch frühen Therapiebeginn bei proximaler spinaler Muskelatrophie
Kölbel, H., Gangfuß, A., Rupprich, K., Andres, B., Marina, A. D., & Schara, U. (2018) · InFo Neurologie + Psychiatrie · doi:10.1007/s15005-018-2371-x
Spinal muscular atrophy counteracted by Agrin biological NT-1654
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“SMA1 is only affected while SMN2 gene is not affected by the disease [3].”
Background
Optimisation of lentiviral vectors for gene therapy of spinal muscular atrophy
Nafchi, N. A. M. (2017)
Spinal muscular atrophy: a perspective outlook
Шаймурзин, М. Р., & Луцкий, И. С. (2020) · Кубанский научный медицинский вестник · doi:10.25207/1608-6228-2020-27-6-80-93
Joint-Development Of Mobility Assistive Devices For Patients With Special Treatment
Wicaksono, D. H. B., Jeremy, M., & Kidarsa, L. A. (2020) · Prosiding Konferensi Nasional Pengabdian Kepada Masyarakat dan Corporate Social Responsibility (PKM-CSR) · doi:10.37695/pkmcsr.v3i0.898
Characterization of the stepwise maturation of the telomerase RNA TLC1 and assembly of the telomerase in Saccharomyces cerevisiae
Hirsch, A. G. (2021) · doi:10.53846/goediss-8918
Spinal motor atrophy in a floppy infant: a case report
Bainade, K., Kotrashetti, V. A., Sonawane, V. B., & Agarwal, R. (2022) · International Journal of Contemporary Pediatrics · doi:10.18203/2349-3291.ijcp20221080
A rare case of spinal muscular atrophy: prenatal type 0
TABAKOVA, N. G., Yordanova, D., & Tzvetkova, S. (2021) · Varna Medical Forum · doi:10.14748/vmf.v0i0.7843
The molecular mechanisms underlying sketetal and cardiac muscle remodeling in the hibernating thirteen-lined ground squirrel
Zhang, Y. (2016) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2016-11596
Spinal Muscular Atrophy
Chen, H. (2017) · Springer eBooks · doi:10.1007/978-1-4939-2401-1_221
Motor neuron disorders
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Trastornos de las neuronas motoras: causas, síntomas, factores de riesgo, diagnósticos y tratamientos
Fierro, Á. D. J. L., Aparicio, S. Y. L., Morgado‐Valle, C., Beltrán‐Parrazal, L., García, L. I., Hernández‐Aguilar, M. E., Manzo, J. G., & Pérez-Estudillo, C. A. (2022) · eNeurobiología · doi:10.25009/eb.v13i31.2599
A Family-based Association Test of the VDR Gene in Proximal Spinal Muscular Atrophy
Alexiu-Toma, O. A., Toma, M., Stavarachi, M., Danciu, A. V., Cimponeriu, D., Constantin, C., Nica, R. I., Butoianu, N., Nica, S., & Stoica, I. (2023) · Romanian Journal of Military Medicine · doi:10.55453/rjmm.2023.126.4.9
Observational analysis of the immunogenicity and safety of various types of spinal muscular atrophy vaccines
Sun, G., Wang, G., & Zhong, H. (2024) · Inflammopharmacology · doi:10.1007/s10787-023-01395-7
“SMA is caused by mutation or deletion of survival motor neuron-1 ( SMN1 ) and the susceptible population for this disease mainly comprises children under the age of five (Lorson et al. 2010).”
Recent Development in in vivo Clinical Gene Therapy Platforms
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Impact of liver specific survival motor neuron (SMN) depletion on peripheral and central nervous system tissue pathologyPreprint
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Stem cell therapy in neurodegenerative disorders
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Impact of liver-specific survival motor neuron (SMN) depletion on central nervous system and peripheral tissue pathologyPreprint
de Almeida, M. M. A., Repentigny, Y. D., Gagnon, S., Sutton, E. R., & Kothary, R. (2025) · eLife · doi:10.7554/elife.99141.2
Additional file 10 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986458
Additional file 11 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986461
Additional file 9 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986491
Additional file 2 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986470
Additional file 4 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986476
Additional file 6 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986482
Additional file 7 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986485
Additional file 8 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986488
Additional file 12 of Transgenic and knockout analyses of Masculinizer and doublesex illuminated the unique functions of doublesex in germ cell sexual development of the silkworm, Bombyx mori
Yuzawa, T., Matsuoka, M., Sumitani, M., Aoki, F., Sezutsu, H., & Suzuki, M. G. (2020) · Figshare · doi:10.6084/m9.figshare.12986464

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
DOI: 10.1093/hmg/ddq147
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 (clinical) › Neurogenetic and Muscular Disorders Research
Health Sciences › Medicine › Clinical 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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Spinal muscular atrophy: mechanisms and therapeutic strategies

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