Spinal Muscular Atrophy and Common Therapeutic Advances

Qomi, Saeed Bozorg; Asghari, Amir; Salmaninejad, Arash; Mojarrad, Majid

doi:10.1080/15513815.2018.1520374

Cited by 5 publications

(2 citation statements)

References 93 publications

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“…The incidence of SMA, which is an autosomal recessive disease, is 1/10,000 in the world. The SMN protein acts as a molecular chaperone in the formation of the splicosome complex, which catalyzes the splicing of pre-mRNA, enabling mRNAs and non-coding RNAs to mature (Bozorg Qomi et al, 2019). The factor that causes SMA disease is the loss of the ability to produce a full-length functional SMN protein as a result of various mutations and deletions in both alleles of the Survival Motor Neuron 1 ( SMN1 ) gene.…”

Section: Introductionmentioning

confidence: 99%

Exon7 Targeted CRISPR-Prime Editing Approaches for SMN2 Gene Editing in Spinal Muscular Atrophy (SMA) Disease Can Increase In Vitro SMN Expression

Odabas

Bal

Yelgen

et al. 2022

Preprint

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Spinal Muscular Atrophy (SMA) is a fatal neuromuscular disease characterized by motor neuron loss and advanced muscle weakness, which occurs in functional SMN (Survival Motor Neuron) protein deficiency with SMN1 gene-induced deletions and mutations. The incidence of SMA, which is an autosomal recessive disease, is 1/10,000 in the world. The SMN protein acts as a molecular chaperone in the formation of the spliceosome complex, which catalyzes the splicing of pre-mRNA, enabling mRNAs and non-coding RNAs to mature. Since the current SMN1-encoding Adeno-associated virus (AAV) or SMN2 gene targeting antisense oligonucleotide-based strategies cannot provide long-term stable SMN expression in neuron cells, more effective methods need to be developed. CRISPR technology, which adds a new dimension to genetic engineering and gene therapies, makes it possible to treat many genetic diseases. In terms of SMA, some previous studies in the literature prove that it is possible to treat SMA with the CRISPR strategy. Homology Directed Repair (HDR)-based CRISPR technology, which results in a high rate of in-del (insertion-deletion) mutations rather than editing, was shown unsuitable for therapeutic applications. CRISPR-Prime editing (PE) technology is a new generation of gene editing approach that precisely provides various genomic modifications without the need for double-strand breakage or donor DNA sequences. CRISPR-Prime Editing method has also been used in rare diseases such as sickle cell anemia and Tay-Sachs, and their efficiency in editing various pathogenic mutations has been demonstrated. However, CRISPR Prime Editing-mediated gene editing for Spinal Muscular Atrophy (SMA) have not yet been investigated. The c.840 T-C transition and c.859 G-C transformations in the SMN2 gene and the correction of these point mutations with a single pegRNA at the same time were investigated for the first time in this study. Here, we showed that CRISPR-PE systems could increase SMN2 gene activity and SMN protein expression by ensuring exon 7 participation by editing c.840 T-C transition and c.859 G-C transformations. The fact that Prime Editing method showed the efficacy and stability of modifications in SMN2 genes that were investigated in SMN-low Jurkat cells as a proof-of-concept. This study enabled the next step with the CRISPR-Prime Editing approach to be tested ex vivo in primary cell lines from SMA patients and SMN-low neuronal cells.

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Section: Introductionmentioning

confidence: 99%

Exon7 Targeted CRISPR-Prime Editing Approaches for SMN2 Gene Editing in Spinal Muscular Atrophy (SMA) Disease Can Increase In Vitro SMN Expression

Odabas

Bal

Yelgen

et al. 2022

Preprint

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“…For patients presenting SMA (most common reason of inherited infant mortality), the gene therapy seems to be the most effective strategy [18].…”

Section: Introductionmentioning

confidence: 99%

Introduction to Novel Motor Neuron Disease

Sibat¹,

Valdés²

2020

Novel Aspects on Motor Neuron Disease

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Motor neuron disease (MND) is a progressive and fatal neuromuscular disease; the most common and severe form of MND presentation is amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease. The majority of ALS patients die within 2-5 years of receiving a diagnosis. Familial ALS is a hereditary form of the disease and accounts for 5-10% of cases, whereas the remaining cases have no clearly defined etiology. ALS affects persons of all ethnicities and races; currently, no curative treatment for ALS is available worldwide. ALS is also the major adult-onset MND and is clinically, pathologically, and genetically associated with fronto-temporal dementia in some cases, which is the second cause of dementia in elderly people. However, MND does not affect sphincter, sexual function, or eye movements. MND is the most common degenerative disorder affecting the upper and lower motor neurons at the same time. Most of the patients presenting MND in our series complained of muscle weakness, muscle wasting, fasciculation, and spasticity plus lower cranial nerve disturbances. According to our bibliographic studies, apart from nusinersen, it seems to be that riluzole and edaravone also improve motor neuron function by acting on SK channels.

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Systematic review and meta-analysis determining the benefits of in vivo genetic therapy in spinal muscular atrophy rodent models

et al. 2021

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Spinal muscular atrophy (SMA) is a severe childhood neuromuscular disease for which two genetic therapies, Nusinersen (Spinraza, an antisense oligonucleotide), and AVXS-101 (Zolgensma, an adeno-associated viral vector of serotype 9 AAV9), have recently been approved. We investigated the pre-clinical development of SMA genetic therapies in rodent models and whether this can predict clinical efficacy. We have performed a systematic review of relevant publications and extracted median survival and details of experimental design. A random effects meta-analysis was used to estimate and compare efficacy. We stratified by experimental design (type of genetic therapy, mouse model, route and time of administration) and sought any evidence of publication bias. 51 publications were identified containing 155 individual comparisons, comprising 2573 animals in total. Genetic therapies prolonged survival in SMA mouse models by 3.23-fold (95% CI 2.75–3.79) compared to controls. Study design characteristics accounted for significant heterogeneity between studies and greatly affected observed median survival ratios. Some evidence of publication bias was found. These data are consistent with the extended average lifespan of Spinraza- and Zolgensma-treated children in the clinic. Together, these results support that SMA has been particularly amenable to genetic therapy approaches and highlight SMA as a trailblazer for therapeutic development.

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Spinal Muscular Atrophy and Common Therapeutic Advances

Cited by 5 publications

References 93 publications

Exon7 Targeted CRISPR-Prime Editing Approaches for SMN2 Gene Editing in Spinal Muscular Atrophy (SMA) Disease Can Increase In Vitro SMN Expression

Exon7 Targeted CRISPR-Prime Editing Approaches for SMN2 Gene Editing in Spinal Muscular Atrophy (SMA) Disease Can Increase In Vitro SMN Expression

Introduction to Novel Motor Neuron Disease

Systematic review and meta-analysis determining the benefits of in vivo genetic therapy in spinal muscular atrophy rodent models

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