scholarly journals Drug Discovery of Spinal Muscular Atrophy (SMA) in Computational Perspective: A Comprehensive Review

2021 ◽  
Vol 22 (16) ◽  
pp. 8962
Author(s):  
Li Chuin Chong ◽  
Gayatri Gandhi ◽  
Jian Ming Lee ◽  
Wendy Wai Yeng Yeo ◽  
Sy-Bing Choi
Keyword(s):  
Drug Discovery ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Drug Repurposing ◽  
Survival Motor Neuron ◽  
Biomedical Data ◽  
Loss Of Function ◽  
Therapeutic Development ◽  
Smn Protein ◽  
Approved Drugs

Spinal muscular atrophy (SMA), one of the leading inherited causes of child mortality, is a rare neuromuscular disease arising from loss-of-function mutations of the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein. When lacking the SMN protein in neurons, patients suffer from muscle weakness and atrophy, and in the severe cases, respiratory failure and death. Several therapeutic approaches show promise with human testing and three medications have been approved by the U.S. Food and Drug Administration (FDA) to date. Despite the shown promise of these approved therapies, there are some crucial limitations, one of the most important being the cost. The FDA-approved drugs are high-priced and are shortlisted among the most expensive treatments in the world. The price is still far beyond affordable and may serve as a burden for patients. The blooming of the biomedical data and advancement of computational approaches have opened new possibilities for SMA therapeutic development. This article highlights the present status of computationally aided approaches, including in silico drug repurposing, network driven drug discovery as well as artificial intelligence (AI)-assisted drug discovery, and discusses the future prospects.

scholarly journals Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

2016 ◽  
Vol 113 (39) ◽  
pp. 10962-10967 ◽  
Author(s):  
Suzan M. Hammond ◽  
Gareth Hazell ◽  
Fazel Shabanpoor ◽  
Amer F. Saleh ◽  
Melissa Bowerman ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
High Efficiency ◽  
Muscular Atrophy ◽  
Neuromuscular Diseases ◽  
Survival Motor Neuron ◽  
Loss Of Function ◽  
Term Survival ◽  
Peripheral Tissues ◽  
Order Of Magnitude ◽  
Smn Protein

The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.

scholarly journals Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

2016 ◽  
Vol 10 ◽  
pp. JEN.S33122 ◽  
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.

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

2018 ◽  
Vol 29 (2) ◽  
pp. 96-110 ◽  
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.

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

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.

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

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.

Treatment strategies for spinal muscular atrophy

2010 ◽  
Vol 1 (4) ◽  
Author(s):  
Heidi Fuller ◽  
Marija Barišić ◽  
Đurđica Šešo-Šimić ◽  
Tea Špeljko ◽  
Glenn Morris ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Treatment Strategies ◽  
Transcript Level ◽  
Survival Motor Neuron ◽  
Current Status ◽  
Protein Levels ◽  
Smn2 Gene ◽  
Smn Protein ◽  
Cell And Gene Therapy

AbstractProgress in understanding the genetic basis and pathophysiology of spinal muscular atrophy (SMA), along with continuous efforts in finding a way to increase survival motor neuron (SMN) protein levels have resulted in several strategies that have been proposed as potential directions for efficient drug development. Here we provide an overview on the current status of the following approaches: 1) activation of SMN2 gene and increasing full length SMN2 transcript level, 2) modulating SMN2 splicing, 3) stabilizing SMN mRNA and SMN protein, 4) development of neurotrophic, neuroprotective and anabolic compounds and 5) stem cell and gene therapy. The new preclinical advances warrant a cautious optimism for emergence of an effective treatment in the very near future.

scholarly journals Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy

2019 ◽  
Author(s):  
Katharina E. Meijboom ◽  
Viola Volpato ◽  
Jimena Monzón-Sandoval ◽  
Joseph M. Hoolachan ◽  
Suzan M. Hammond ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Muscle Pathology ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Disease Phenotypes ◽  
Parallel Data ◽  
Smn Protein

ABSTRACTSpinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.

scholarly journals Utilizing gene therapy methods to probe the genetic requirements to prevent spinal muscular atrophy.

2016 ◽  
Author(s):  
◽  
Madeline R. Miller
Keyword(s):  
Neuromuscular Junction ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Survival Motor Neuron ◽  
Downstream Effects ◽  
Smn Protein ◽  
Progressive Weakness

Spinal Muscular Atrophy is clinically recognized as a progressive weakness within the trunk and proximal limbs that will lead to breathing failure and death within infants. As a neurodegenerative genetic disease, SMA is caused by loss of motor neurons, which in turn is caused by low levels of the Survival Motor Neuron (SMN) protein. The mechanism by which a ubiquitously expressed protein such as SMN is able to cause the specific death of motor neurons is highly debated and of great interest. Work presented here focuses on understanding the biological requirements of SMN and its downstream effects on the neuromuscular junction. To this end we utilize viral based gene delivery as a powerful tool to assess the effects of genes of interest in vivo. Our findings contribute to the conversation regarding whether SMA is truly a "motor neuron" disease, suggesting that astrocytes play a meaningful role in staving off SMA. Further, we investigate the domains within SMN needed to maintain its function in a mammalian system. We take a novel and challenging approach to identify a minimal domain capable of maintaining function. Finally, we demonstrate the practical use of morophological analysis of the neuromuscular junction as a means to characterize SMA pathology.

Sign in / Sign up

Export Citation Format

Share Document