Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy
Abstract
:1. Introduction
2. Spinal Muscular Atrophy (SMA)
3. Mechanisms of SMN2 Splicing Regulation Targeted by Therapeutics
4. Antisense Oligonucleotides
5. Small Molecules
6. Future Prospects
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Aim of the Study | Mechanism of Action | Results | References | |
---|---|---|---|---|
1 | Therapeutic effect of short ASO on two mouse models of SMA: healthy, adult Smn heterozygous mice containing human SMN2 and 5058-Hemi SMA mice | Blocking GCRS | Restoring the correct splicing of exon 7 and consequently the production of full-length SMN. Proving efficacy of short ASOs in pathology and expanding the range of ASO-based substances for use in SMA therapy | Keil et al. [64] 2014 |
2 | Variable mechanisms regulating splicing of exon 7 in SMA-patient-derived GM03813 cell line | Targeting ISS-N1 Targeting ISS-N2 | Increasing SMN level by stimulating exon 7 inclusion by sequestration of ISS-N1 Increasing SMN and Gemin2 levels with disruption of the 3′ strands of ISTL1 and ISTL2 caused with ISS-N2 blocking Long distance interactions between intron sequences are crucial in understanding the mechanism of disrupted SMA splicing. | Singh et al. [85] 2015 |
3 | Improvement of ASO targeting Element 1 in SMNΔ7 mouse model | Binding potential intronic splicing silencer—E1 in upstream of exon 7 SMN2 | SMN2 splicing modification to produce full-length SMN One of the compounds being tested, E1MOv11, has the potential to become a stand-alone ASO in the clinic, but it is critical to develop combination therapy with drugs that act on other SMA pathomechanisms. | Osman et al. [69] 2016 |
4 | Evaluation of the tolerability, safety, pharmacokinetics, and clinical efficacy of nusinersen in cohort of 28 children with type 2 and type 3 SMA aged 2–14 years | Targeting ISS-N1 | Initiating exon 7 inclusion resulting in full-length SMN expression No safety issues found with 9 mg nusinersen dose, supporting study of higher dose. | Chiriboga et al. [86] 2016 |
5 | ASO effect targeting deep intronic structures to restore full-length SMN expression in allele C (C/C) mice model | Targeting ISS-N2 | A small peripheral increase in SMN alleviates SMA symptoms in a gender-specific manner—restoration of peripheral SMN production has a significant impact on testicular function.Targeting deep intron sequences is effective and has great therapeutic potential, so there is a need for further research into this strategy. | Howell et al. [87] 2017 |
6 | Locked nucleic acid (LNA)-based antisense oligonucleotides (LNA/DNA mixmers) as therapeutic strategy using SMA patient fibroblasts | Targeting ISS-N1 | LNA/DNA mixmer-based antisense oligonucleotide may be a potential candidate for SMA therapy. | Touznik et al. [88] 2017 |
7 | Mechanisms influencing ASOs-induced intron retention. ASOs impact on transcript and protein expression in SMA patient fibroblasts | Targeting SMN2 exon 8 to slowing transcription | Induction of exon/intron 7 retention Model probably not useful for SMA patients. May prove beneficial in diseases in which protein repression is crucial for therapy, e. g., cancers | Flynn et al. [89] 2018 |
8 | Safety and efficacy of nusinersen administration in children with cohort of 126 children with SMA who had symptom onset after 6 months of age | Targeting ISS-N1 | Children with later-onset SMA showed a significant improvement in motor function after nusinersen administration compared to control group. | Mercuri et al. [90] 2018 |
9 | Safety and efficacy of nusinersen in the pre-symptomatic period or at the onset of symptoms in cohort of 25 children with genetically diagnosed SMA at a median follow-up of 2. 9 years | Targeting ISS-N1 | Early screening and implementation of nusinersen therapy in the presymptomatic period significantly increases the chances for successful therapy and further normal motor development of the child treated for SMA. | De Vivo et al. [91] 2019 |
10 | Effects of nusinersen on the behavior of Cajal bodies (CBs) in SMN∆7 mice | Targeting ISS-N1 | Improving motor function and preventing α-motoneuron loss Selective restoring of SMN expression in the spinal cord | Berciano et al. [47] 2020 |
Aim of Study | Mechanism of Action | Results | References | |
---|---|---|---|---|
1 | Identification and optimization of a pyridazine class of orally bioavailable, small molecules enhancing inclusion SMN exon 7 in mice. | Stabilization of U1 snRNP and SMN2 pre-mRNA complex Enhancing selectively the binding affinity of U1 snRNP to 5′ss. | Modification of splicing through small sequence-specific molecules can be used in various splicing-related diseases. | Palacino et al. [107] 2015 |
2 | Orally deliverable small molecules correcting alternative splicing of the SMN2 gene exon 7 in SMA Δ7 mice, SMA patient fibroblasts and rats | Enhancing of the U1−pre-mRNA interaction at the 5′ splice site of SMN2 intron 7. | Reduction of disease manifestations and a significant increase in the median survival time in models after tested molecules administration Supporting the development of an orally administered small molecule for the treatment of patients with SMA | Woll et al. [111] 2016 |
3 | SMN-C1 in the context of preclinical data for the clinic and further therapeutic development of this series of molecules for the treatment of SMA tested in SMN∆7 mice model. | Increasing the levels of spliceosomal and U7 snRNAs. Correcting RNA processing defects induced by SMN deficiency. | Lower dose SMN-C1 increases long-term survival of SMN∆7 mouse model with partially corrected phenotype. Higher dose of SMN-C1 results in increased body weight, longer survival, and in addition, improved SMN-dependent RNA processing, spinal cord histopathology, and neuromuscular junctions. | Zhao et al. [112] 2016 |
4 | Improvement of coumarin and isocoumarin series, optimization of the pyridopyrimidinone series in C/C-allele SMA mouse model, SMA patient fibroblasts, spinal motor neurons SMA type I and II, and patient-derived induced pluripotent stem cells. | Induction of alternative splicing of SMN2 to exon 7 inclusion. | Discovery of selective small molecules that modify alternative splicing. | Ratni et al. [113] 2016 |
5 | New advanced chemotype of a small molecule discovered with SMA Δ7 mice model. | Modification of SMN2 alternative splicing to increase SMN levels. | Discovery of the two orally administrated SMN2 splicing modifiers. | Pinard et al. [114] 2017 |
6 | Identification of a pyridazine SMN2 pre-mRNA splicing modulator and optimization to branaplam in SMNΔ7 mouse model and SMA patient fibroblasts. | Stabilization of the interaction between the spliceosome and SMN2 pre-mRNA. | Branaplam treatment increased full-length SMN RNA and protein levels and extended survival. | Cheung et al. [115] 2018 |
7 | SMN-C2 and SMN-C3 promoting binding FUBP1 and KHSRP to the SMN2 pre-mRNA complex in 293T cells. | SMN-C2—binding to the AGGAAG SMN2 pre-mRNA exon 7 SMN-C3—hypothetically targets a sequence of RNA on or close to exon 7 or a splicing regulatory protein or protein complex that is specific to exon 7. | Small molecules complementary to nucleic acids modulate pre-mRNA splicing and can have a therapeutic influence on SMA. Future studies should concern recognition sequence of FUBP1 and KHSRP and their contribution in splicing regulation. | Wang et al. [99] 2018 |
8 | Tolerance and safety testing of RG7800 in clinical trials in cohort of Male subjects aged 23–45 years, thirteen patients with SMA, aged 13–53 years. | Modification of splicing toward promoting full-length SMN expression and downregulating SMNΔ7. | RG7800 is safe and well tolerated, and that the level of SMN after oral administration increases by twofold over the baseline concentration which may be associated with future therapeutic benefits. | Kletzl et al. [116] 2019 |
9 | Safety, tolerability, pharmacokinetics, and pharmacodynamics of risdiplam in cohort of 25 adult males, aged 18–45 years. Itraconazole effect on the pharmacokinetics of risdiplam. | Highly specific for pre-mRNA SMN2 splicing modifier | The tested doses of risdiplam were well tolerated and safe, and produced the desired effect of increasing full-length SMN2 pre-mRNA levels CYP3A inhibitors in the form of itraconazole have little effect on the pharmacokinetics of risdiplam. | Sturm et al. [117] 2019 |
10 | Preclinical characterization and prospects of TEC-1 using SMAΔ7 mice and SMA patient fibroblasts. | Binding to purine-rich regions within exon 7 Interaction with the major groove of the RNA duplex generated by the 5ʹ splicing site of exon 7 and U1 snRNA17 | Low risk of acute or chronic side effects Promising for the long-term treatment of patients with SMA Potentially higher therapeutic window compared to the SMN-C series. | Ando et al. [2] 2020 |
11 | Drugs that boost the minigene reporter signal within the context of Drosophila motor neurons | Promoting the inclusion of SMN2 exon 7 in a dose-dependent manner | Increasing SMN and SRSF1 levels and decreasing level of hnRNP1 with moxifloxacin The effects of moxifloxacin need to be tested in murine models as a potential SMA therapy or scaffold for other variant molecules. | Konieczny and Artero [118] 2020 |
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Lejman, J.; Zieliński, G.; Gawda, P.; Lejman, M. Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy. Genes 2021, 12, 1346. https://doi.org/10.3390/genes12091346
Lejman J, Zieliński G, Gawda P, Lejman M. Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy. Genes. 2021; 12(9):1346. https://doi.org/10.3390/genes12091346
Chicago/Turabian StyleLejman, Jan, Grzegorz Zieliński, Piotr Gawda, and Monika Lejman. 2021. "Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy" Genes 12, no. 9: 1346. https://doi.org/10.3390/genes12091346
APA StyleLejman, J., Zieliński, G., Gawda, P., & Lejman, M. (2021). Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy. Genes, 12(9), 1346. https://doi.org/10.3390/genes12091346