The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is 1 of the leading causes of infant mortality. SMA is mostly caused by low levels of Survival Motor Neuron (SMN) protein due to deletion of or mutation in the SMN1 gene. Its nearly identical copy, SMN2, fails to compensate for the loss of SMN1 due to predominant skipping of exon 7. Correction of SMN2 exon 7 splicing by an antisense oligonucleotide (ASO), nusinersen (Spinraza™), that targets the intronic splicing silencer N1 (ISS-N1) became the first approved therapy for SMA. Restoration of SMN levels using gene therapy was the next. Very recently, an orally deliverable small molecule, risdiplam (Evrysdi™), became the third approved therapy for SMA. Here we discuss how these therapies are positioned to meet the needs of the broad phenotypic spectrum of SMA patients.

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Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

Journal of Experimental Neuroscience ◽

10.4137/jen.s33122 ◽

2016 ◽

Vol 10 ◽

pp. JEN.S33122 ◽

Cited By ~ 36

Author(s):

Saif Ahmad ◽

Kanchan Bhatia ◽

Annapoorna Kannan ◽

Laxman Gangwani

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Skeletal Muscle Atrophy ◽

Spinal Motor Neurons ◽

Low Levels ◽

Smn Protein

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA.

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Onasemnogene Abeparvovec-xioi: Gene Therapy for Spinal Muscular Atrophy

Annals of Pharmacotherapy ◽

10.1177/1060028020914274 ◽

2020 ◽

Vol 54 (10) ◽

pp. 1001-1009 ◽

Cited By ~ 7

Author(s):

Debra Stevens ◽

Melanie K. Claborn ◽

Brooke L. Gildon ◽

Tiffany L. Kessler ◽

Cheri Walker

Keyword(s):

Gene Therapy ◽

Spinal Muscular Atrophy ◽

English Language ◽

Liver Toxicity ◽

Muscular Atrophy ◽

Data Extraction ◽

Case Series ◽

Survival Motor Neuron ◽

Smn1 Gene ◽

Smn Protein

Objective: To review the efficacy and safety of onasemnogene abeparvovec-xioi (Zolgensma) in the treatment of spinal muscular atrophy (SMA). Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to December 2019) was completed using the terms onasemnogene, AVXS-101, and spinal muscular atrophy. Manufacturer prescribing information, article bibliographies, and data from ClinicalTrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on ClinicalTrials.gov were incorporated in the reviewed data. Data Synthesis: Onasemnogene is the first agent for SMA utilizing gene therapy to directly provide survival motor neuron 1 ( SMN1) gene to produce SMN protein. Four publications of 1 clinical trial, 1 comparison study of treatment effects, and 1 combination therapy case series have been published. Relevance to Patient Care and Clinical Practice: Onasemnogene is a one time dose approved by the Food and Drug Administration for SMA patients <2 years old who possess mutations in both copies of the SMN1 gene. Conclusion: Onasemnogene appears to be an efficacious therapy for younger pediatric patients with SMA type 1. Concerns include drug cost and potential liver toxicity. Long-term benefits and risks have not been determined.

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Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development

International Journal of Molecular Sciences ◽

10.3390/ijms22157896 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7896

Author(s):

Matthew E. R. Butchbach

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Smn1 Gene ◽

Spinal Motor Neurons ◽

Copy Numbers ◽

Smn Protein ◽

High Degree

Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1–SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.

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The influence of storage parameters on measurement of survival motor neuron (SMN) protein levels: Implications for pre-clinical studies and clinical trials for spinal muscular atrophy

Neuromuscular Disorders ◽

10.1016/j.nmd.2014.05.013 ◽

2014 ◽

Vol 24 (11) ◽

pp. 973-977 ◽

Cited By ~ 4

Author(s):

Gillian Hunter ◽

Sarah L. Roche ◽

Eilidh Somers ◽

Heidi R. Fuller ◽

Thomas H. Gillingwater

Keyword(s):

Clinical Trials ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Clinical Studies ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Protein Levels ◽

Smn Protein

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Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron

Molecular Biology of the Cell ◽

10.1091/mbc.e17-11-0627 ◽

2018 ◽

Vol 29 (2) ◽

pp. 96-110 ◽

Cited By ~ 15

Author(s):

Kelsey M. Gray ◽

Kevin A. Kaifer ◽

David Baillat ◽

Ying Wen ◽

Thomas R. Bonacci ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Protein Isoforms ◽

Survival Motor Neuron Protein ◽

Protein Levels ◽

Motor Neuron Protein ◽

Smn Protein ◽

Oligomerization Domain

SMN protein levels inversely correlate with the severity of spinal muscular atrophy. The SCFSlmbE3 ligase complex interacts with a degron embedded within the C-terminal self-oligomerization domain of SMN. The findings elucidate a model whereby accessibility of the SMN degron is regulated by self-multimerization.

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Spinal Muscular Atrophy Type B Awareness and Symptoms Prediction Using 3D Segmentation Process in MRI Images

International Journal of Scientific Research in Computer Science Engineering and Information Technology ◽

10.32628/cseit195142 ◽

2019 ◽

pp. 312-318

Author(s):

V. Manochithra ◽

G. Sumithra

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Muscular Atrophy ◽

Homozygous Deletion ◽

Survival Motor Neuron ◽

Molecular Testing ◽

Prevention Measures ◽

Neuron Loss ◽

Motor Neuron Loss ◽

Smn Protein

Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials. This proposed model investigates the symptoms and scans readings from the initial MRI scan images of babies with mutation progress and SMN proteins formation benchmark values for this particular disorder SMA and further this segmented parameters are acquitted into the K-means clustering technique that predict the report with the disorder symptoms with MSE (mean square error) values that helps the babies in future to take prevention measures to overcome this problem.

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Small-molecule flunarizine increases SMN protein in nuclear Cajal bodies and motor function in a mouse model of spinal muscular atrophy

Scientific Reports ◽

10.1038/s41598-018-20219-1 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 2

Author(s):

Delphine Sapaly ◽

Matthieu Dos Santos ◽

Perrine Delers ◽

Olivier Biondi ◽

Gwendoline Quérol ◽

...

Keyword(s):

Mouse Model ◽

Spinal Muscular Atrophy ◽

Motor Function ◽

Small Molecule ◽

Muscular Atrophy ◽

Cajal Bodies ◽

Smn Protein

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N.P.2 04 Patients with spinal muscular atrophy (SMA) and healthy siblings sharing homozygous deletions of the SMN1 gene reveal an identical number of SMN2 gene copies but different SMN protein levels

Neuromuscular Disorders ◽

10.1016/j.nmd.2006.05.042 ◽

2006 ◽

Vol 16 (9-10) ◽

pp. 652

Author(s):

H.H. Lemmink ◽

Y.J. Vos ◽

I. Plaza de Menacho ◽

J. Dijkhuis ◽

N.V.A.M. Knoers ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Muscular Atrophy ◽

Smn1 Gene ◽

Protein Levels ◽

Gene Copies ◽

Smn2 Gene ◽

Healthy Siblings ◽

Identical Number ◽

Smn Protein ◽

Homozygous Deletions

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Circulating microRNAs as potential biomarkers and therapeutic targets in spinal muscular atrophy

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756286420979954 ◽

2020 ◽

Vol 13 ◽

pp. 175628642097995

Author(s):

Tai-Heng Chen

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Molecular Mechanisms ◽

Muscular Atrophy ◽

Therapeutic Targets ◽

Homozygous Deletion ◽

Survival Motor Neuron ◽

Novel Mirna ◽

Potential Applications ◽

Smn Protein

Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterized by the selective loss of particular groups of motor neurons (MNs) in the anterior horn of the spinal cord with progressive muscle wasting. SMA is caused by a deficiency of the survival motor neuron (SMN) protein due to a homozygous deletion or mutation of the SMN1 gene. However, the molecular mechanisms whereby the SMN complex regulates MN functions are not fully elucidated. Emerging studies on SMA pathogenesis have turned the attention of researchers to RNA metabolism, given that increasingly identified SMN-associated modifiers are involved in both coding and non-coding RNA (ncRNA) processing. Among various ncRNAs, microRNAs (miRNAs) are the most studied in terms of regulation of posttranscriptional gene expression. Recently, the discovery that miRNAs are critical to MN function and survival led to the study of dysregulated miRNAs in SMA pathogenesis. Circulating miRNAs have drawn attention as a readily available biomarker due to their property of being clinically detectable in numerous human biofluids through non-invasive approaches. As there are recent promising findings from novel miRNA-based medicines, this article presents an extensive review of the most up-to-date studies connecting specific miRNAs to SMA pathogenesis and the potential applications of miRNAs as biomarkers and therapeutic targets for SMA.

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